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/Title (Genetic Testing for Lynch Syndrome in Individuals Newly Diagnosed with Colorectal Cancer to Reduce Morbidity and Mortality from Colorectal Cancer in Their Relatives � PLOS Currents Evidence on Genomic Tests)
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BT 15.000 718.042 Td /F2 21.0 Tf  [(Genetic Testing for Lynch Syndrome in Individuals Newly )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Diagnosed with Colorectal Cancer to Reduce Morbidity and )] TJ ET
BT 15.000 668.146 Td /F2 21.0 Tf  [(Mortality from Colorectal Cancer in Their Relatives)] TJ ET
Q
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BT 15.000 650.140 Td /F3 9.8 Tf  [(July 7, 2011)] TJ ET
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BT 26.250 638.299 Td /F1 9.8 Tf  [(Ralph Coates)] TJ ET
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BT 85.316 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
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BT 90.737 638.299 Td /F1 9.8 Tf  [(Marc Williams)] TJ ET
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BT 151.391 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
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BT 156.812 638.299 Td /F1 9.8 Tf  [(Stephanie Melillo)] TJ ET
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BT 231.049 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
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BT 236.470 638.299 Td /F1 9.8 Tf  [(Jim Gudgeon)] TJ ET
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BT 26.250 626.394 Td /F1 9.8 Tf  [(Coates R, Williams M, Melillo S, Gudgeon J. Genetic Testing for Lynch Syndrome in Individuals Newly Diagnosed with )] TJ ET
BT 26.250 614.490 Td /F1 9.8 Tf  [(Colorectal Cancer to Reduce Morbidity and Mortality from Colorectal Cancer in Their Relatives. PLOS Currents Evidence on )] TJ ET
BT 26.250 602.585 Td /F1 9.8 Tf  [(Genomic Tests. 2011 Jul 7 . Edition 1. doi: 10.1371/currents.RRN1246.)] TJ ET
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BT 26.250 573.482 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 553.528 Td /F1 9.8 Tf  [(Individuals with Lynch syndrome, sometimes referred to as hereditary non-polyposis colorectal cancer \(HNPCC\), have an )] TJ ET
BT 26.250 541.623 Td /F1 9.8 Tf  [(increased risk of developing colorectal cancer \(CRC\) as well as other cancers. The increased risk is due to inherited mutations )] TJ ET
BT 26.250 529.719 Td /F1 9.8 Tf  [(in mismatch repair \(MMR\) genes, which reduce the ability of cells to repair DNA damage. Screening for Lynch syndrome in )] TJ ET
BT 26.250 517.814 Td /F1 9.8 Tf  [(individuals newly diagnosed with colorectal cancer has been proposed as part of a strategy that combines tests and )] TJ ET
BT 26.250 505.909 Td /F1 9.8 Tf  [(interventions to reduce the risk of colorectal cancer in the relatives of the colorectal cancer patients with Lynch Syndrome.)] TJ ET
BT 26.250 469.307 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 449.352 Td /F1 9.8 Tf  [(Screening tests on tumor specimens and genetic testing for germ line mutations in mismatch repair \(MMR\) genes of individuals )] TJ ET
BT 26.250 437.448 Td /F1 9.8 Tf  [(newly diagnosed with colorectal cancer to identify patients with Lynch syndrome to reduce morbidity and mortality from Lynch )] TJ ET
BT 26.250 425.543 Td /F1 9.8 Tf  [(syndrome in their relatives )] TJ ET
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BT 142.743 425.543 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
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BT 180.690 425.543 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 388.940 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 368.986 Td /F4 9.8 Tf  [(Screening tests: )] TJ ET
BT 104.816 368.986 Td /F1 9.8 Tf  [( Before genetic testing for MMR mutations, preliminary screening tests on tumor tissue may be considered in )] TJ ET
BT 26.250 357.081 Td /F1 9.8 Tf  [(patients with colorectal cancer. This screening improves efficiency and reduces costs by identifying patients who would most )] TJ ET
BT 26.250 345.177 Td /F1 9.8 Tf  [(likely have MMR mutations )] TJ ET
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BT 145.444 345.177 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
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BT 183.391 345.177 Td /F1 9.8 Tf  [(. One or several of the following tests may be offered:)] TJ ET
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39.078 327.033 39.522 327.217 39.838 327.533 c
40.154 327.849 40.337 328.293 40.337 328.740 c f
BT 45.750 325.772 Td /F4 9.8 Tf  [(Microsatellite instability \(MSI\) testing)] TJ ET
BT 217.496 325.772 Td /F1 9.8 Tf  [(assesses the stability of small DNA sequences in tumors, a measure of the integrity )] TJ ET
BT 45.750 313.867 Td /F1 9.8 Tf  [(of DNA repair mechanisms. Patients with a high instability score from MSI testing can then be offered DNA sequencing for )] TJ ET
BT 45.750 301.962 Td /F1 9.8 Tf  [(the four most common MMR genes associated with Lynch syndrome \(MLH1, MSH2, MSH6,andPMS2\) )] TJ ET
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BT 528.005 301.962 Td /F1 9.8 Tf  [(.)] TJ ET
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BT 45.750 286.308 Td /F4 9.8 Tf  [(Immunohistochemical \(IHC\) staining )] TJ ET
BT 217.487 286.308 Td /F1 9.8 Tf  [(tests tumor tissue for the presence of the proteins produced by four MMR genes. )] TJ ET
BT 45.750 274.403 Td /F1 9.8 Tf  [(The absence of staining for one or more of the proteins indicates the high likelihood of the presence of a mutation in one of )] TJ ET
BT 45.750 262.498 Td /F1 9.8 Tf  [(the MMR genes which can be due either to a germ line mutation or a somatic abnormality limited to the tumor. The absence )] TJ ET
BT 45.750 250.593 Td /F1 9.8 Tf  [(of staining among the four specific proteins is used to identify specific genes for sequencing )] TJ ET
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BT 65.250 234.939 Td /F4 9.8 Tf  [(BRAF \(V600E\) and/or MLH1 promoter hypermethylation testing)] TJ ET
BT 356.707 234.939 Td /F1 9.8 Tf  [( may be performed on cases that have no IHC )] TJ ET
BT 65.250 223.034 Td /F1 9.8 Tf  [(staining for MLH1, as a substantial portion of tumors that lack staining for the MLH1 protein have a somatic mutation )] TJ ET
BT 65.250 211.129 Td /F1 9.8 Tf  [(inBRAF\(V600E\)orMLH1promoter hypermethylation, neither of which is commonly associated with Lynch syndrome. )] TJ ET
BT 65.250 199.224 Td /F1 9.8 Tf  [(Patients who do not have theBRAFmutation orMLH1promoter hypermethylation, or have neither, are then offered DNA )] TJ ET
BT 65.250 187.320 Td /F1 9.8 Tf  [(analysis of theMLH1gene )] TJ ET
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BT 215.917 187.320 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 160.415 Td /F4 9.8 Tf  [(Diagnostic test:)] TJ ET
BT 26.250 141.010 Td /F1 9.8 Tf  [(DNA sequencing, and possibly analysis for copy number variants, of the 4 major MMR genes \( )] TJ ET
BT 435.906 141.010 Td /F5 9.8 Tf  [(MLH1, MSH2, MSH6,)] TJ ET
BT 529.633 141.010 Td /F1 9.8 Tf  [( and )] TJ ET
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BT 26.250 129.105 Td /F1 9.8 Tf  [(\) associated with Lynch syndrome, is the practice standard test for diagnosing the syndrome after a positive screening test )] TJ ET
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BT 50.645 117.201 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 80.598 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 60.644 Td /F1 9.8 Tf  [(Of the approximately 143,000 individuals diagnosed with colorectal cancer each year, about 3% \(4,250\) have Lynch syndrome. )] TJ ET
BT 26.250 48.739 Td /F1 9.8 Tf  [(Approximately 20 to 65% of individuals with Lynch syndrome develop colorectal cancer during their lifetimes, whereas lifetime )] TJ ET
BT 26.250 36.834 Td /F1 9.8 Tf  [(risk in the general population is approximately 5%. In addition, about half of the first-degree biological relatives of those )] TJ ET
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BT 15.000 718.042 Td /F2 21.0 Tf  [(Genetic Testing for Lynch Syndrome in Individuals Newly )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Diagnosed with Colorectal Cancer to Reduce Morbidity and )] TJ ET
BT 15.000 668.146 Td /F2 21.0 Tf  [(Mortality from Colorectal Cancer in Their Relatives)] TJ ET
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BT 15.000 650.140 Td /F3 9.8 Tf  [(July 7, 2011)] TJ ET
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BT 26.250 638.299 Td /F1 9.8 Tf  [(Ralph Coates)] TJ ET
0.271 0.267 0.267 rg
BT 85.316 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 90.737 638.299 Td /F1 9.8 Tf  [(Marc Williams)] TJ ET
0.271 0.267 0.267 rg
BT 151.391 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 156.812 638.299 Td /F1 9.8 Tf  [(Stephanie Melillo)] TJ ET
0.271 0.267 0.267 rg
BT 231.049 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 236.470 638.299 Td /F1 9.8 Tf  [(Jim Gudgeon)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 626.394 Td /F1 9.8 Tf  [(Coates R, Williams M, Melillo S, Gudgeon J. Genetic Testing for Lynch Syndrome in Individuals Newly Diagnosed with )] TJ ET
BT 26.250 614.490 Td /F1 9.8 Tf  [(Colorectal Cancer to Reduce Morbidity and Mortality from Colorectal Cancer in Their Relatives. PLOS Currents Evidence on )] TJ ET
BT 26.250 602.585 Td /F1 9.8 Tf  [(Genomic Tests. 2011 Jul 7 . Edition 1. doi: 10.1371/currents.RRN1246.)] TJ ET
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BT 26.250 573.482 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 553.528 Td /F1 9.8 Tf  [(Individuals with Lynch syndrome, sometimes referred to as hereditary non-polyposis colorectal cancer \(HNPCC\), have an )] TJ ET
BT 26.250 541.623 Td /F1 9.8 Tf  [(increased risk of developing colorectal cancer \(CRC\) as well as other cancers. The increased risk is due to inherited mutations )] TJ ET
BT 26.250 529.719 Td /F1 9.8 Tf  [(in mismatch repair \(MMR\) genes, which reduce the ability of cells to repair DNA damage. Screening for Lynch syndrome in )] TJ ET
BT 26.250 517.814 Td /F1 9.8 Tf  [(individuals newly diagnosed with colorectal cancer has been proposed as part of a strategy that combines tests and )] TJ ET
BT 26.250 505.909 Td /F1 9.8 Tf  [(interventions to reduce the risk of colorectal cancer in the relatives of the colorectal cancer patients with Lynch Syndrome.)] TJ ET
BT 26.250 469.307 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 449.352 Td /F1 9.8 Tf  [(Screening tests on tumor specimens and genetic testing for germ line mutations in mismatch repair \(MMR\) genes of individuals )] TJ ET
BT 26.250 437.448 Td /F1 9.8 Tf  [(newly diagnosed with colorectal cancer to identify patients with Lynch syndrome to reduce morbidity and mortality from Lynch )] TJ ET
BT 26.250 425.543 Td /F1 9.8 Tf  [(syndrome in their relatives )] TJ ET
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BT 142.743 425.543 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 180.690 425.543 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 388.940 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 368.986 Td /F4 9.8 Tf  [(Screening tests: )] TJ ET
BT 104.816 368.986 Td /F1 9.8 Tf  [( Before genetic testing for MMR mutations, preliminary screening tests on tumor tissue may be considered in )] TJ ET
BT 26.250 357.081 Td /F1 9.8 Tf  [(patients with colorectal cancer. This screening improves efficiency and reduces costs by identifying patients who would most )] TJ ET
BT 26.250 345.177 Td /F1 9.8 Tf  [(likely have MMR mutations )] TJ ET
0.267 0.267 0.267 rg
BT 145.444 345.177 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 183.391 345.177 Td /F1 9.8 Tf  [(. One or several of the following tests may be offered:)] TJ ET
0.271 0.267 0.267 RG
40.337 328.740 m 
40.337 329.186 40.154 329.630 39.838 329.946 c
39.522 330.262 39.078 330.446 38.631 330.446 c
38.185 330.446 37.741 330.262 37.425 329.946 c
37.109 329.630 36.925 329.186 36.925 328.740 c
36.925 328.293 37.109 327.849 37.425 327.533 c
37.741 327.217 38.185 327.033 38.631 327.033 c
39.078 327.033 39.522 327.217 39.838 327.533 c
40.154 327.849 40.337 328.293 40.337 328.740 c f
BT 45.750 325.772 Td /F4 9.8 Tf  [(Microsatellite instability \(MSI\) testing)] TJ ET
BT 217.496 325.772 Td /F1 9.8 Tf  [(assesses the stability of small DNA sequences in tumors, a measure of the integrity )] TJ ET
BT 45.750 313.867 Td /F1 9.8 Tf  [(of DNA repair mechanisms. Patients with a high instability score from MSI testing can then be offered DNA sequencing for )] TJ ET
BT 45.750 301.962 Td /F1 9.8 Tf  [(the four most common MMR genes associated with Lynch syndrome \(MLH1, MSH2, MSH6,andPMS2\) )] TJ ET
0.267 0.267 0.267 rg
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0.271 0.267 0.267 rg
BT 528.005 301.962 Td /F1 9.8 Tf  [(.)] TJ ET
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38.185 290.982 37.741 290.798 37.425 290.482 c
37.109 290.166 36.925 289.722 36.925 289.275 c
36.925 288.829 37.109 288.385 37.425 288.069 c
37.741 287.753 38.185 287.569 38.631 287.569 c
39.078 287.569 39.522 287.753 39.838 288.069 c
40.154 288.385 40.337 288.829 40.337 289.275 c f
BT 45.750 286.308 Td /F4 9.8 Tf  [(Immunohistochemical \(IHC\) staining )] TJ ET
BT 217.487 286.308 Td /F1 9.8 Tf  [(tests tumor tissue for the presence of the proteins produced by four MMR genes. )] TJ ET
BT 45.750 274.403 Td /F1 9.8 Tf  [(The absence of staining for one or more of the proteins indicates the high likelihood of the presence of a mutation in one of )] TJ ET
BT 45.750 262.498 Td /F1 9.8 Tf  [(the MMR genes which can be due either to a germ line mutation or a somatic abnormality limited to the tumor. The absence )] TJ ET
BT 45.750 250.593 Td /F1 9.8 Tf  [(of staining among the four specific proteins is used to identify specific genes for sequencing )] TJ ET
0.267 0.267 0.267 rg
BT 442.985 250.593 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 480.932 250.593 Td /F1 9.8 Tf  [(. )] TJ ET
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59.837 237.906 m 
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59.022 239.429 58.578 239.613 58.131 239.613 c
57.685 239.613 57.241 239.429 56.925 239.113 c
56.609 238.797 56.425 238.353 56.425 237.906 c
56.425 237.460 56.609 237.016 56.925 236.700 c
57.241 236.384 57.685 236.200 58.131 236.200 c
58.578 236.200 59.022 236.384 59.338 236.700 c
59.654 237.016 59.837 237.460 59.837 237.906 c s
BT 65.250 234.939 Td /F4 9.8 Tf  [(BRAF \(V600E\) and/or MLH1 promoter hypermethylation testing)] TJ ET
BT 356.707 234.939 Td /F1 9.8 Tf  [( may be performed on cases that have no IHC )] TJ ET
BT 65.250 223.034 Td /F1 9.8 Tf  [(staining for MLH1, as a substantial portion of tumors that lack staining for the MLH1 protein have a somatic mutation )] TJ ET
BT 65.250 211.129 Td /F1 9.8 Tf  [(inBRAF\(V600E\)orMLH1promoter hypermethylation, neither of which is commonly associated with Lynch syndrome. )] TJ ET
BT 65.250 199.224 Td /F1 9.8 Tf  [(Patients who do not have theBRAFmutation orMLH1promoter hypermethylation, or have neither, are then offered DNA )] TJ ET
BT 65.250 187.320 Td /F1 9.8 Tf  [(analysis of theMLH1gene )] TJ ET
0.267 0.267 0.267 rg
BT 177.970 187.320 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 215.917 187.320 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 160.415 Td /F4 9.8 Tf  [(Diagnostic test:)] TJ ET
BT 26.250 141.010 Td /F1 9.8 Tf  [(DNA sequencing, and possibly analysis for copy number variants, of the 4 major MMR genes \( )] TJ ET
BT 435.906 141.010 Td /F5 9.8 Tf  [(MLH1, MSH2, MSH6,)] TJ ET
BT 529.633 141.010 Td /F1 9.8 Tf  [( and )] TJ ET
BT 551.317 141.010 Td /F5 9.8 Tf  [(PMS2)] TJ ET
BT 26.250 129.105 Td /F1 9.8 Tf  [(\) associated with Lynch syndrome, is the practice standard test for diagnosing the syndrome after a positive screening test )] TJ ET
0.267 0.267 0.267 rg
BT 555.694 129.105 Td /F1 9.8 Tf  [([1] )] TJ ET
BT 26.250 117.201 Td /F1 9.8 Tf  [([2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 50.645 117.201 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 80.598 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 60.644 Td /F1 9.8 Tf  [(Of the approximately 143,000 individuals diagnosed with colorectal cancer each year, about 3% \(4,250\) have Lynch syndrome. )] TJ ET
BT 26.250 48.739 Td /F1 9.8 Tf  [(Approximately 20 to 65% of individuals with Lynch syndrome develop colorectal cancer during their lifetimes, whereas lifetime )] TJ ET
BT 26.250 36.834 Td /F1 9.8 Tf  [(risk in the general population is approximately 5%. In addition, about half of the first-degree biological relatives of those )] TJ ET
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BT 15.000 718.042 Td /F2 21.0 Tf  [(Genetic Testing for Lynch Syndrome in Individuals Newly )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(Diagnosed with Colorectal Cancer to Reduce Morbidity and )] TJ ET
BT 15.000 668.146 Td /F2 21.0 Tf  [(Mortality from Colorectal Cancer in Their Relatives)] TJ ET
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0.271 0.267 0.267 rg
BT 15.000 650.140 Td /F3 9.8 Tf  [(July 7, 2011)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 638.299 Td /F1 9.8 Tf  [(Ralph Coates)] TJ ET
0.271 0.267 0.267 rg
BT 85.316 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 90.737 638.299 Td /F1 9.8 Tf  [(Marc Williams)] TJ ET
0.271 0.267 0.267 rg
BT 151.391 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 156.812 638.299 Td /F1 9.8 Tf  [(Stephanie Melillo)] TJ ET
0.271 0.267 0.267 rg
BT 231.049 638.299 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 236.470 638.299 Td /F1 9.8 Tf  [(Jim Gudgeon)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 626.394 Td /F1 9.8 Tf  [(Coates R, Williams M, Melillo S, Gudgeon J. Genetic Testing for Lynch Syndrome in Individuals Newly Diagnosed with )] TJ ET
BT 26.250 614.490 Td /F1 9.8 Tf  [(Colorectal Cancer to Reduce Morbidity and Mortality from Colorectal Cancer in Their Relatives. PLOS Currents Evidence on )] TJ ET
BT 26.250 602.585 Td /F1 9.8 Tf  [(Genomic Tests. 2011 Jul 7 . Edition 1. doi: 10.1371/currents.RRN1246.)] TJ ET
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BT 26.250 573.482 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 553.528 Td /F1 9.8 Tf  [(Individuals with Lynch syndrome, sometimes referred to as hereditary non-polyposis colorectal cancer \(HNPCC\), have an )] TJ ET
BT 26.250 541.623 Td /F1 9.8 Tf  [(increased risk of developing colorectal cancer \(CRC\) as well as other cancers. The increased risk is due to inherited mutations )] TJ ET
BT 26.250 529.719 Td /F1 9.8 Tf  [(in mismatch repair \(MMR\) genes, which reduce the ability of cells to repair DNA damage. Screening for Lynch syndrome in )] TJ ET
BT 26.250 517.814 Td /F1 9.8 Tf  [(individuals newly diagnosed with colorectal cancer has been proposed as part of a strategy that combines tests and )] TJ ET
BT 26.250 505.909 Td /F1 9.8 Tf  [(interventions to reduce the risk of colorectal cancer in the relatives of the colorectal cancer patients with Lynch Syndrome.)] TJ ET
BT 26.250 469.307 Td /F4 12.0 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 449.352 Td /F1 9.8 Tf  [(Screening tests on tumor specimens and genetic testing for germ line mutations in mismatch repair \(MMR\) genes of individuals )] TJ ET
BT 26.250 437.448 Td /F1 9.8 Tf  [(newly diagnosed with colorectal cancer to identify patients with Lynch syndrome to reduce morbidity and mortality from Lynch )] TJ ET
BT 26.250 425.543 Td /F1 9.8 Tf  [(syndrome in their relatives )] TJ ET
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BT 142.743 425.543 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
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BT 180.690 425.543 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 388.940 Td /F4 12.0 Tf  [(Test Description)] TJ ET
BT 26.250 368.986 Td /F4 9.8 Tf  [(Screening tests: )] TJ ET
BT 104.816 368.986 Td /F1 9.8 Tf  [( Before genetic testing for MMR mutations, preliminary screening tests on tumor tissue may be considered in )] TJ ET
BT 26.250 357.081 Td /F1 9.8 Tf  [(patients with colorectal cancer. This screening improves efficiency and reduces costs by identifying patients who would most )] TJ ET
BT 26.250 345.177 Td /F1 9.8 Tf  [(likely have MMR mutations )] TJ ET
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BT 145.444 345.177 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
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BT 183.391 345.177 Td /F1 9.8 Tf  [(. One or several of the following tests may be offered:)] TJ ET
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37.741 327.217 38.185 327.033 38.631 327.033 c
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BT 45.750 325.772 Td /F4 9.8 Tf  [(Microsatellite instability \(MSI\) testing)] TJ ET
BT 217.496 325.772 Td /F1 9.8 Tf  [(assesses the stability of small DNA sequences in tumors, a measure of the integrity )] TJ ET
BT 45.750 313.867 Td /F1 9.8 Tf  [(of DNA repair mechanisms. Patients with a high instability score from MSI testing can then be offered DNA sequencing for )] TJ ET
BT 45.750 301.962 Td /F1 9.8 Tf  [(the four most common MMR genes associated with Lynch syndrome \(MLH1, MSH2, MSH6,andPMS2\) )] TJ ET
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BT 490.058 301.962 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
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BT 528.005 301.962 Td /F1 9.8 Tf  [(.)] TJ ET
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BT 45.750 286.308 Td /F4 9.8 Tf  [(Immunohistochemical \(IHC\) staining )] TJ ET
BT 217.487 286.308 Td /F1 9.8 Tf  [(tests tumor tissue for the presence of the proteins produced by four MMR genes. )] TJ ET
BT 45.750 274.403 Td /F1 9.8 Tf  [(The absence of staining for one or more of the proteins indicates the high likelihood of the presence of a mutation in one of )] TJ ET
BT 45.750 262.498 Td /F1 9.8 Tf  [(the MMR genes which can be due either to a germ line mutation or a somatic abnormality limited to the tumor. The absence )] TJ ET
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BT 442.985 250.593 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
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59.837 237.906 m 
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BT 65.250 234.939 Td /F4 9.8 Tf  [(BRAF \(V600E\) and/or MLH1 promoter hypermethylation testing)] TJ ET
BT 356.707 234.939 Td /F1 9.8 Tf  [( may be performed on cases that have no IHC )] TJ ET
BT 65.250 223.034 Td /F1 9.8 Tf  [(staining for MLH1, as a substantial portion of tumors that lack staining for the MLH1 protein have a somatic mutation )] TJ ET
BT 65.250 211.129 Td /F1 9.8 Tf  [(inBRAF\(V600E\)orMLH1promoter hypermethylation, neither of which is commonly associated with Lynch syndrome. )] TJ ET
BT 65.250 199.224 Td /F1 9.8 Tf  [(Patients who do not have theBRAFmutation orMLH1promoter hypermethylation, or have neither, are then offered DNA )] TJ ET
BT 65.250 187.320 Td /F1 9.8 Tf  [(analysis of theMLH1gene )] TJ ET
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BT 215.917 187.320 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 160.415 Td /F4 9.8 Tf  [(Diagnostic test:)] TJ ET
BT 26.250 141.010 Td /F1 9.8 Tf  [(DNA sequencing, and possibly analysis for copy number variants, of the 4 major MMR genes \( )] TJ ET
BT 435.906 141.010 Td /F5 9.8 Tf  [(MLH1, MSH2, MSH6,)] TJ ET
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BT 26.250 129.105 Td /F1 9.8 Tf  [(\) associated with Lynch syndrome, is the practice standard test for diagnosing the syndrome after a positive screening test )] TJ ET
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BT 26.250 80.598 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 60.644 Td /F1 9.8 Tf  [(Of the approximately 143,000 individuals diagnosed with colorectal cancer each year, about 3% \(4,250\) have Lynch syndrome. )] TJ ET
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40.337 78.233 m 
40.337 78.679 40.154 79.123 39.838 79.439 c
39.522 79.755 39.078 79.939 38.631 79.939 c
38.185 79.939 37.741 79.755 37.425 79.439 c
37.109 79.123 36.925 78.679 36.925 78.233 c
36.925 77.786 37.109 77.342 37.425 77.026 c
37.741 76.710 38.185 76.526 38.631 76.526 c
39.078 76.526 39.522 76.710 39.838 77.026 c
40.154 77.342 40.337 77.786 40.337 78.233 c f
BT 45.750 75.265 Td /F4 9.8 Tf  [(MSI)] TJ ET
BT 63.085 75.265 Td /F1 9.8 Tf  [(: Studies enrolling a total of 150 patients with Lynch syndrome and using a variety of MSI methods found that high MSI )] TJ ET
BT 45.750 63.360 Td /F1 9.8 Tf  [(score test results were adequately sensitive and specific in identifying individuals who had tested positive for some MMR )] TJ ET
BT 45.750 51.456 Td /F1 9.8 Tf  [(genes )] TJ ET
0.267 0.267 0.267 rg
BT 75.019 51.456 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 112.966 51.456 Td /F1 9.8 Tf  [(.)] TJ ET
Q
q
15.000 45.325 577.500 731.675 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(colorectal cancer patients with Lynch syndrome, about 8,000 individuals, also have Lynch syndrome mutation and are at )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(increased risk of developing a Lynch syndrome-associated cancer. Screening and treatment for colorectal cancer has been )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(found to substantially reduce the risk of developing colorectal cancer in individuals with Lynch syndrome as well as in the )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(general population. Identifying Lynch syndrome in newly diagnosed colorectal patients, offering testing to relatives of patients )] TJ ET
BT 26.250 719.857 Td /F1 9.8 Tf  [(with Lynch, finding those relatives who have Lynch syndrome before they develop cancer, and offering screening to those )] TJ ET
BT 26.250 707.952 Td /F1 9.8 Tf  [(relatives could reduce their risk of colorectal cancer. Potentially more than a thousand cases of colorectal cancer could be )] TJ ET
BT 26.250 696.048 Td /F1 9.8 Tf  [(prevented each year if all individuals with Lynch were identified, screened, and treated appropriately )] TJ ET
0.267 0.267 0.267 rg
BT 459.784 696.048 Td /F1 9.8 Tf  [([1] [2] [3] [4] [5] [6] [7] [8])] TJ ET
0.271 0.267 0.267 rg
BT 565.493 696.048 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 676.643 Td /F4 9.8 Tf  [(Systematic Evidence Reviews)] TJ ET
BT 26.250 657.238 Td /F1 9.8 Tf  [(Agency for Healthcare Research and Quality, Evidence Report/Technology Assessment \(Bonis\) )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 645.333 Td /F1 9.8 Tf  [(https://www.ahrq.gov/clinic/tp/hnpcctp.htm)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 625.929 Td /F1 9.8 Tf  [(Evaluation of Genomic Applications in Practice and Prevention Supplemental Evidence Review \(Palomaki\) )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 614.024 Td /F1 9.8 Tf  [(https://www.egappreviews.org/docs/EGAPPWG-LynchRev.pdf)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 594.619 Td /F4 9.8 Tf  [(Recommendations by an Independent Group*)] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(The Evaluation of Genomic Applications in Practice and Prevention Working Group recommended offering genetic testing for )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(Lynch syndrome in individuals newly diagnosed with colorectal cancer to reduce morbidity and mortality in relatives. \(EGAPP\) )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 551.405 Td /F1 9.8 Tf  [(https://www.egappreviews.org/docs/EGAPPWG-LynchRec.pdf)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 532.000 Td /F4 9.8 Tf  [(Guidelines by Professional Groups)] TJ ET
BT 26.250 512.595 Td /F1 9.8 Tf  [(The American College of Gastroenterology recommends that colorectal cancer patients who have a family history of colorectal )] TJ ET
BT 26.250 500.691 Td /F1 9.8 Tf  [(cancer that indicates increased risk of HNPCC according to either Bethesda or Amsterdam family history criteria have tumors )] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(screened by MSI or IHC )] TJ ET
0.267 0.267 0.267 rg
BT 132.993 488.786 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 143.835 488.786 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 469.381 Td /F1 9.8 Tf  [(The National Comprehensive Cancer Network recommends tumor screening and/or genetic testing for individuals with family )] TJ ET
BT 26.250 457.476 Td /F1 9.8 Tf  [(histories meeting the Bethesda or Amsterdam criteria, for individuals diagnosed with endometrial cancer before age 50, and )] TJ ET
BT 26.250 445.572 Td /F1 9.8 Tf  [(individuals with a family member with Lynch syndrome )] TJ ET
0.267 0.267 0.267 rg
BT 263.565 445.572 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 279.828 445.572 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 426.167 Td /F1 9.8 Tf  [(A task force with representatives from several medical professions and the American Cancer Society recommends colonoscopy )] TJ ET
BT 26.250 414.262 Td /F1 9.8 Tf  [(every 1 to 2 years beginning at age 20 to 25 for individuals who have a clinical or genetic diagnosis of HNPCC or are at )] TJ ET
BT 26.250 402.357 Td /F1 9.8 Tf  [(increased risk of HNPCC based on the modified Bethesda criteria )] TJ ET
0.267 0.267 0.267 rg
BT 311.818 402.357 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
BT 328.081 402.357 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 365.755 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 345.801 Td /F6 9.8 Tf  [(Analytic validity)] TJ ET
BT 100.487 345.801 Td /F1 9.8 Tf  [(: The accuracy and reliability of the tests in detecting the genetic changes of interest.)] TJ ET
BT 26.250 326.396 Td /F1 9.8 Tf  [(Based on evidence reviews, the EGAPP Working Group reported that overall the analytic validity of the tests was high although )] TJ ET
BT 26.250 314.491 Td /F1 9.8 Tf  [(there were gaps in research on analytic validity and proficiency testing, as described below )] TJ ET
0.267 0.267 0.267 rg
BT 420.209 314.491 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 458.156 314.491 Td /F1 9.8 Tf  [(:)] TJ ET
0.271 0.267 0.267 RG
40.337 298.054 m 
40.337 298.501 40.154 298.945 39.838 299.261 c
39.522 299.576 39.078 299.760 38.631 299.760 c
38.185 299.760 37.741 299.576 37.425 299.261 c
37.109 298.945 36.925 298.501 36.925 298.054 c
36.925 297.607 37.109 297.163 37.425 296.847 c
37.741 296.532 38.185 296.348 38.631 296.348 c
39.078 296.348 39.522 296.532 39.838 296.847 c
40.154 297.163 40.337 297.607 40.337 298.054 c f
BT 45.750 295.086 Td /F4 9.8 Tf  [(MMR)] TJ ET
BT 69.033 295.086 Td /F1 9.8 Tf  [(: DNA sequencing of 4 MMR genes \()] TJ ET
BT 227.802 295.086 Td /F5 9.8 Tf  [(MLH1, MSH2, MSH6, )] TJ ET
BT 324.239 295.086 Td /F1 9.8 Tf  [(and)] TJ ET
BT 340.502 295.086 Td /F5 9.8 Tf  [(PMS2)] TJ ET
BT 367.052 295.086 Td /F1 9.8 Tf  [(\) is the practice standard, but actual )] TJ ET
BT 45.750 283.182 Td /F1 9.8 Tf  [(performance is difficult to estimate, and it is not known if laboratory proficiency testing will be an adequate validity measure. )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 271.277 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 83.697 271.277 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 258.590 m 
40.337 259.036 40.154 259.480 39.838 259.796 c
39.522 260.112 39.078 260.296 38.631 260.296 c
38.185 260.296 37.741 260.112 37.425 259.796 c
37.109 259.480 36.925 259.036 36.925 258.590 c
36.925 258.143 37.109 257.699 37.425 257.383 c
37.741 257.067 38.185 256.883 38.631 256.883 c
39.078 256.883 39.522 257.067 39.838 257.383 c
40.154 257.699 40.337 258.143 40.337 258.590 c f
BT 45.750 255.622 Td /F4 9.8 Tf  [(MSI)] TJ ET
BT 63.085 255.622 Td /F1 9.8 Tf  [(: Testing is offered by many laboratories that participate in proficiency testing programs, and performance in such )] TJ ET
BT 45.750 243.717 Td /F1 9.8 Tf  [(testing programs is high so adherence to best practices may provide valid testing )] TJ ET
0.267 0.267 0.267 rg
BT 397.442 243.717 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 435.389 243.717 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 231.030 m 
40.337 231.477 40.154 231.921 39.838 232.237 c
39.522 232.553 39.078 232.736 38.631 232.736 c
38.185 232.736 37.741 232.553 37.425 232.237 c
37.109 231.921 36.925 231.477 36.925 231.030 c
36.925 230.584 37.109 230.140 37.425 229.824 c
37.741 229.508 38.185 229.324 38.631 229.324 c
39.078 229.324 39.522 229.508 39.838 229.824 c
40.154 230.140 40.337 230.584 40.337 231.030 c f
BT 45.750 228.063 Td /F4 9.8 Tf  [(IHC)] TJ ET
BT 62.540 228.063 Td /F1 9.8 Tf  [(: IHC proficiency testing is offered for other proteins, but not specifically for MMR gene proteins \(1-3, 19\))] TJ ET
0.267 0.267 0.267 rg
BT 511.215 228.063 Td /F1 9.8 Tf  [([1] [2] [3] [12])] TJ ET
0.271 0.267 0.267 rg
BT 568.135 228.063 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 215.375 m 
40.337 215.822 40.154 216.266 39.838 216.582 c
39.522 216.898 39.078 217.082 38.631 217.082 c
38.185 217.082 37.741 216.898 37.425 216.582 c
37.109 216.266 36.925 215.822 36.925 215.375 c
36.925 214.929 37.109 214.485 37.425 214.169 c
37.741 213.853 38.185 213.669 38.631 213.669 c
39.078 213.669 39.522 213.853 39.838 214.169 c
40.154 214.485 40.337 214.929 40.337 215.375 c f
BT 45.750 212.408 Td /F6 9.8 Tf  [(BRAF)] TJ ET
BT 72.826 212.408 Td /F1 9.8 Tf  [(: Given that this test is to identify a single mutation and proficiency testing for some other single mutations has been )] TJ ET
BT 45.750 200.503 Td /F1 9.8 Tf  [(high, analytic validity is likely to be high )] TJ ET
0.267 0.267 0.267 rg
BT 217.525 200.503 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 255.472 200.503 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 177.348 Td /F6 9.8 Tf  [(Clinical validity)] TJ ET
BT 97.240 177.348 Td /F1 9.8 Tf  [(: The accuracy and reliability of the test in identifying patients with the disorder.)] TJ ET
BT 26.250 157.944 Td /F1 9.8 Tf  [(Based on the evidence reviews, the EGAPP working group reported that there was adequate evidence of clinical validity for the )] TJ ET
BT 26.250 146.039 Td /F1 9.8 Tf  [(preliminary tests, although evidence varied and research gaps were identified on which tests and which combinations perform )] TJ ET
BT 26.250 134.134 Td /F1 9.8 Tf  [(best and on the use of family history with tests, as described below )] TJ ET
0.267 0.267 0.267 rg
BT 317.258 134.134 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 355.205 134.134 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 117.697 m 
40.337 118.144 40.154 118.588 39.838 118.904 c
39.522 119.219 39.078 119.403 38.631 119.403 c
38.185 119.403 37.741 119.219 37.425 118.904 c
37.109 118.588 36.925 118.144 36.925 117.697 c
36.925 117.250 37.109 116.806 37.425 116.490 c
37.741 116.175 38.185 115.991 38.631 115.991 c
39.078 115.991 39.522 116.175 39.838 116.490 c
40.154 116.806 40.337 117.250 40.337 117.697 c f
BT 45.750 114.729 Td /F4 9.8 Tf  [(MMR)] TJ ET
BT 69.033 114.729 Td /F1 9.8 Tf  [(: DNA sequencing of 4 MMR genes \()] TJ ET
BT 227.802 114.729 Td /F5 9.8 Tf  [(MLH1, MSH2, MSH6, )] TJ ET
BT 324.239 114.729 Td /F1 9.8 Tf  [(and)] TJ ET
BT 340.502 114.729 Td /F5 9.8 Tf  [(PMS2)] TJ ET
BT 367.052 114.729 Td /F1 9.8 Tf  [(\) is the current standard for diagnosing patients )] TJ ET
BT 45.750 102.825 Td /F1 9.8 Tf  [(with Lynch syndrome, although research may identify additional MMR genes. Lifetime risk of colorectal cancer among )] TJ ET
BT 45.750 90.920 Td /F1 9.8 Tf  [(individuals with Lynch syndrome is approximately 20 to 65% )] TJ ET
0.267 0.267 0.267 rg
BT 308.015 90.920 Td /F1 9.8 Tf  [([1] [2] [3] [7] [8])] TJ ET
0.271 0.267 0.267 rg
BT 373.067 90.920 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 78.233 m 
40.337 78.679 40.154 79.123 39.838 79.439 c
39.522 79.755 39.078 79.939 38.631 79.939 c
38.185 79.939 37.741 79.755 37.425 79.439 c
37.109 79.123 36.925 78.679 36.925 78.233 c
36.925 77.786 37.109 77.342 37.425 77.026 c
37.741 76.710 38.185 76.526 38.631 76.526 c
39.078 76.526 39.522 76.710 39.838 77.026 c
40.154 77.342 40.337 77.786 40.337 78.233 c f
BT 45.750 75.265 Td /F4 9.8 Tf  [(MSI)] TJ ET
BT 63.085 75.265 Td /F1 9.8 Tf  [(: Studies enrolling a total of 150 patients with Lynch syndrome and using a variety of MSI methods found that high MSI )] TJ ET
BT 45.750 63.360 Td /F1 9.8 Tf  [(score test results were adequately sensitive and specific in identifying individuals who had tested positive for some MMR )] TJ ET
BT 45.750 51.456 Td /F1 9.8 Tf  [(genes )] TJ ET
0.267 0.267 0.267 rg
BT 75.019 51.456 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 112.966 51.456 Td /F1 9.8 Tf  [(.)] TJ ET
Q
q
15.000 45.325 577.500 731.675 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(colorectal cancer patients with Lynch syndrome, about 8,000 individuals, also have Lynch syndrome mutation and are at )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(increased risk of developing a Lynch syndrome-associated cancer. Screening and treatment for colorectal cancer has been )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(found to substantially reduce the risk of developing colorectal cancer in individuals with Lynch syndrome as well as in the )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(general population. Identifying Lynch syndrome in newly diagnosed colorectal patients, offering testing to relatives of patients )] TJ ET
BT 26.250 719.857 Td /F1 9.8 Tf  [(with Lynch, finding those relatives who have Lynch syndrome before they develop cancer, and offering screening to those )] TJ ET
BT 26.250 707.952 Td /F1 9.8 Tf  [(relatives could reduce their risk of colorectal cancer. Potentially more than a thousand cases of colorectal cancer could be )] TJ ET
BT 26.250 696.048 Td /F1 9.8 Tf  [(prevented each year if all individuals with Lynch were identified, screened, and treated appropriately )] TJ ET
0.267 0.267 0.267 rg
BT 459.784 696.048 Td /F1 9.8 Tf  [([1] [2] [3] [4] [5] [6] [7] [8])] TJ ET
0.271 0.267 0.267 rg
BT 565.493 696.048 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 676.643 Td /F4 9.8 Tf  [(Systematic Evidence Reviews)] TJ ET
BT 26.250 657.238 Td /F1 9.8 Tf  [(Agency for Healthcare Research and Quality, Evidence Report/Technology Assessment \(Bonis\) )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 645.333 Td /F1 9.8 Tf  [(https://www.ahrq.gov/clinic/tp/hnpcctp.htm)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 625.929 Td /F1 9.8 Tf  [(Evaluation of Genomic Applications in Practice and Prevention Supplemental Evidence Review \(Palomaki\) )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 614.024 Td /F1 9.8 Tf  [(https://www.egappreviews.org/docs/EGAPPWG-LynchRev.pdf)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 594.619 Td /F4 9.8 Tf  [(Recommendations by an Independent Group*)] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(The Evaluation of Genomic Applications in Practice and Prevention Working Group recommended offering genetic testing for )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(Lynch syndrome in individuals newly diagnosed with colorectal cancer to reduce morbidity and mortality in relatives. \(EGAPP\) )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 551.405 Td /F1 9.8 Tf  [(https://www.egappreviews.org/docs/EGAPPWG-LynchRec.pdf)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 532.000 Td /F4 9.8 Tf  [(Guidelines by Professional Groups)] TJ ET
BT 26.250 512.595 Td /F1 9.8 Tf  [(The American College of Gastroenterology recommends that colorectal cancer patients who have a family history of colorectal )] TJ ET
BT 26.250 500.691 Td /F1 9.8 Tf  [(cancer that indicates increased risk of HNPCC according to either Bethesda or Amsterdam family history criteria have tumors )] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(screened by MSI or IHC )] TJ ET
0.267 0.267 0.267 rg
BT 132.993 488.786 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 143.835 488.786 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 469.381 Td /F1 9.8 Tf  [(The National Comprehensive Cancer Network recommends tumor screening and/or genetic testing for individuals with family )] TJ ET
BT 26.250 457.476 Td /F1 9.8 Tf  [(histories meeting the Bethesda or Amsterdam criteria, for individuals diagnosed with endometrial cancer before age 50, and )] TJ ET
BT 26.250 445.572 Td /F1 9.8 Tf  [(individuals with a family member with Lynch syndrome )] TJ ET
0.267 0.267 0.267 rg
BT 263.565 445.572 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 279.828 445.572 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 426.167 Td /F1 9.8 Tf  [(A task force with representatives from several medical professions and the American Cancer Society recommends colonoscopy )] TJ ET
BT 26.250 414.262 Td /F1 9.8 Tf  [(every 1 to 2 years beginning at age 20 to 25 for individuals who have a clinical or genetic diagnosis of HNPCC or are at )] TJ ET
BT 26.250 402.357 Td /F1 9.8 Tf  [(increased risk of HNPCC based on the modified Bethesda criteria )] TJ ET
0.267 0.267 0.267 rg
BT 311.818 402.357 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
BT 328.081 402.357 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 365.755 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 345.801 Td /F6 9.8 Tf  [(Analytic validity)] TJ ET
BT 100.487 345.801 Td /F1 9.8 Tf  [(: The accuracy and reliability of the tests in detecting the genetic changes of interest.)] TJ ET
BT 26.250 326.396 Td /F1 9.8 Tf  [(Based on evidence reviews, the EGAPP Working Group reported that overall the analytic validity of the tests was high although )] TJ ET
BT 26.250 314.491 Td /F1 9.8 Tf  [(there were gaps in research on analytic validity and proficiency testing, as described below )] TJ ET
0.267 0.267 0.267 rg
BT 420.209 314.491 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 458.156 314.491 Td /F1 9.8 Tf  [(:)] TJ ET
0.271 0.267 0.267 RG
40.337 298.054 m 
40.337 298.501 40.154 298.945 39.838 299.261 c
39.522 299.576 39.078 299.760 38.631 299.760 c
38.185 299.760 37.741 299.576 37.425 299.261 c
37.109 298.945 36.925 298.501 36.925 298.054 c
36.925 297.607 37.109 297.163 37.425 296.847 c
37.741 296.532 38.185 296.348 38.631 296.348 c
39.078 296.348 39.522 296.532 39.838 296.847 c
40.154 297.163 40.337 297.607 40.337 298.054 c f
BT 45.750 295.086 Td /F4 9.8 Tf  [(MMR)] TJ ET
BT 69.033 295.086 Td /F1 9.8 Tf  [(: DNA sequencing of 4 MMR genes \()] TJ ET
BT 227.802 295.086 Td /F5 9.8 Tf  [(MLH1, MSH2, MSH6, )] TJ ET
BT 324.239 295.086 Td /F1 9.8 Tf  [(and)] TJ ET
BT 340.502 295.086 Td /F5 9.8 Tf  [(PMS2)] TJ ET
BT 367.052 295.086 Td /F1 9.8 Tf  [(\) is the practice standard, but actual )] TJ ET
BT 45.750 283.182 Td /F1 9.8 Tf  [(performance is difficult to estimate, and it is not known if laboratory proficiency testing will be an adequate validity measure. )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 271.277 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 83.697 271.277 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 258.590 m 
40.337 259.036 40.154 259.480 39.838 259.796 c
39.522 260.112 39.078 260.296 38.631 260.296 c
38.185 260.296 37.741 260.112 37.425 259.796 c
37.109 259.480 36.925 259.036 36.925 258.590 c
36.925 258.143 37.109 257.699 37.425 257.383 c
37.741 257.067 38.185 256.883 38.631 256.883 c
39.078 256.883 39.522 257.067 39.838 257.383 c
40.154 257.699 40.337 258.143 40.337 258.590 c f
BT 45.750 255.622 Td /F4 9.8 Tf  [(MSI)] TJ ET
BT 63.085 255.622 Td /F1 9.8 Tf  [(: Testing is offered by many laboratories that participate in proficiency testing programs, and performance in such )] TJ ET
BT 45.750 243.717 Td /F1 9.8 Tf  [(testing programs is high so adherence to best practices may provide valid testing )] TJ ET
0.267 0.267 0.267 rg
BT 397.442 243.717 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 435.389 243.717 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 231.030 m 
40.337 231.477 40.154 231.921 39.838 232.237 c
39.522 232.553 39.078 232.736 38.631 232.736 c
38.185 232.736 37.741 232.553 37.425 232.237 c
37.109 231.921 36.925 231.477 36.925 231.030 c
36.925 230.584 37.109 230.140 37.425 229.824 c
37.741 229.508 38.185 229.324 38.631 229.324 c
39.078 229.324 39.522 229.508 39.838 229.824 c
40.154 230.140 40.337 230.584 40.337 231.030 c f
BT 45.750 228.063 Td /F4 9.8 Tf  [(IHC)] TJ ET
BT 62.540 228.063 Td /F1 9.8 Tf  [(: IHC proficiency testing is offered for other proteins, but not specifically for MMR gene proteins \(1-3, 19\))] TJ ET
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BT 511.215 228.063 Td /F1 9.8 Tf  [([1] [2] [3] [12])] TJ ET
0.271 0.267 0.267 rg
BT 568.135 228.063 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 215.375 m 
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38.185 217.082 37.741 216.898 37.425 216.582 c
37.109 216.266 36.925 215.822 36.925 215.375 c
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37.741 213.853 38.185 213.669 38.631 213.669 c
39.078 213.669 39.522 213.853 39.838 214.169 c
40.154 214.485 40.337 214.929 40.337 215.375 c f
BT 45.750 212.408 Td /F6 9.8 Tf  [(BRAF)] TJ ET
BT 72.826 212.408 Td /F1 9.8 Tf  [(: Given that this test is to identify a single mutation and proficiency testing for some other single mutations has been )] TJ ET
BT 45.750 200.503 Td /F1 9.8 Tf  [(high, analytic validity is likely to be high )] TJ ET
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BT 217.525 200.503 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 255.472 200.503 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 177.348 Td /F6 9.8 Tf  [(Clinical validity)] TJ ET
BT 97.240 177.348 Td /F1 9.8 Tf  [(: The accuracy and reliability of the test in identifying patients with the disorder.)] TJ ET
BT 26.250 157.944 Td /F1 9.8 Tf  [(Based on the evidence reviews, the EGAPP working group reported that there was adequate evidence of clinical validity for the )] TJ ET
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BT 26.250 134.134 Td /F1 9.8 Tf  [(best and on the use of family history with tests, as described below )] TJ ET
0.267 0.267 0.267 rg
BT 317.258 134.134 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 355.205 134.134 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 117.697 m 
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40.154 116.806 40.337 117.250 40.337 117.697 c f
BT 45.750 114.729 Td /F4 9.8 Tf  [(MMR)] TJ ET
BT 69.033 114.729 Td /F1 9.8 Tf  [(: DNA sequencing of 4 MMR genes \()] TJ ET
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BT 324.239 114.729 Td /F1 9.8 Tf  [(and)] TJ ET
BT 340.502 114.729 Td /F5 9.8 Tf  [(PMS2)] TJ ET
BT 367.052 114.729 Td /F1 9.8 Tf  [(\) is the current standard for diagnosing patients )] TJ ET
BT 45.750 102.825 Td /F1 9.8 Tf  [(with Lynch syndrome, although research may identify additional MMR genes. Lifetime risk of colorectal cancer among )] TJ ET
BT 45.750 90.920 Td /F1 9.8 Tf  [(individuals with Lynch syndrome is approximately 20 to 65% )] TJ ET
0.267 0.267 0.267 rg
BT 308.015 90.920 Td /F1 9.8 Tf  [([1] [2] [3] [7] [8])] TJ ET
0.271 0.267 0.267 rg
BT 373.067 90.920 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 78.233 m 
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39.078 76.526 39.522 76.710 39.838 77.026 c
40.154 77.342 40.337 77.786 40.337 78.233 c f
BT 45.750 75.265 Td /F4 9.8 Tf  [(MSI)] TJ ET
BT 63.085 75.265 Td /F1 9.8 Tf  [(: Studies enrolling a total of 150 patients with Lynch syndrome and using a variety of MSI methods found that high MSI )] TJ ET
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BT 45.750 51.456 Td /F1 9.8 Tf  [(genes )] TJ ET
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BT 112.966 51.456 Td /F1 9.8 Tf  [(.)] TJ ET
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BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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BT 45.750 767.476 Td /F4 9.8 Tf  [(IHC)] TJ ET
BT 62.540 767.476 Td /F1 9.8 Tf  [(: Studies with a total of 149 patients found that IHC testing was adequately sensitive and specific in identifying )] TJ ET
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0.271 0.267 0.267 rg
BT 332.419 755.571 Td /F1 9.8 Tf  [(.)] TJ ET
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BT 45.750 739.917 Td /F6 9.8 Tf  [(BRAF)] TJ ET
BT 72.826 739.917 Td /F1 9.8 Tf  [(: Multiple studies have found)] TJ ET
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BT 222.391 739.917 Td /F1 9.8 Tf  [(mutation testing to be highly sensitive in identifying CRC tumor tissue abnormal for )] TJ ET
BT 45.750 728.012 Td /F1 9.8 Tf  [(the MLH1 protein due to somatic changes. Thus, it is a highly effective test for ruling out the presence of Lynch Syndrome )] TJ ET
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BT 83.697 716.107 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(Research has shown that concordance between IHC and MSI test results varies )] TJ ET
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BT 374.149 692.952 Td /F1 9.8 Tf  [([12] [13])] TJ ET
0.271 0.267 0.267 rg
BT 409.386 692.952 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(The EGAPP Working Group found insufficient evidence to recommend any one of the screening-diagnostic testing combinations )] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(or sequences over the others )] TJ ET
0.267 0.267 0.267 rg
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BT 193.180 661.643 Td /F1 9.8 Tf  [(, and there appears to be no consensus among practitioners on a best practice.)] TJ ET
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BT 26.250 610.929 Td /F1 9.8 Tf  [(Based on the evidence reviews, the EGAPP working group reported that there was adequate evidence from research that more )] TJ ET
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BT 26.250 563.310 Td /F1 9.8 Tf  [(cancer. Harms appeared to be minimal in comparison with benefits. However, additional research was needed on the overall )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(strategy and on each step from offering genetic testing to patients through studying the long term health benefits to relatives. )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(Additional cost-benefit analyses are also needed. Screening or prophylactic surgery for prevention of other Lynch syndrome )] TJ ET
BT 26.250 527.595 Td /F1 9.8 Tf  [(associated cancers \(particularly endometrial\) has not been fully assessed for utility )] TJ ET
0.267 0.267 0.267 rg
BT 384.426 527.595 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 422.373 527.595 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(The EGAPP Working Group found insufficient evidence of benefit to CRC patient from modification of clinical management )] TJ ET
BT 26.250 496.286 Td /F1 9.8 Tf  [(options based on testing for Lynch )] TJ ET
0.267 0.267 0.267 rg
BT 177.463 496.286 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 215.410 496.286 Td /F1 9.8 Tf  [(. The American College of Gastroenterology found moderate quality evidence for )] TJ ET
BT 26.250 484.381 Td /F1 9.8 Tf  [(their recommendation that colorectal cancer patients with Lynch syndrome undergo colonoscopy every 2 years beginning at age )] TJ ET
BT 26.250 472.476 Td /F1 9.8 Tf  [(20-25 and then annually after age 40 )] TJ ET
0.267 0.267 0.267 rg
BT 188.315 472.476 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 199.157 472.476 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(A cost-effectiveness analysis has reported that a testing strategy using IHC as the preliminary test for individuals newly )] TJ ET
BT 26.250 441.167 Td /F1 9.8 Tf  [(diagnosed with colorectal cancer has an incremental cost-effectiveness ratio of)] TJ ET
BT 26.250 421.762 Td /F1 9.8 Tf  [(<$25,000 per life-year saved compared to no testing for a Lynch syndrome)] TJ ET
0.267 0.267 0.267 rg
BT 348.429 421.762 Td /F1 9.8 Tf  [([14])] TJ ET
0.271 0.267 0.267 rg
BT 364.692 421.762 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(Some researchers, practitioners, and members of the public have raised questions about how best to implement testing beyond )] TJ ET
BT 26.250 397.953 Td /F1 9.8 Tf  [(research settings, how feasible it is, and how potential harms from implementation might be addressed )] TJ ET
0.267 0.267 0.267 rg
BT 471.142 397.953 Td /F1 9.8 Tf  [([15] [16] [17])] TJ ET
0.271 0.267 0.267 rg
BT 525.352 397.953 Td /F1 9.8 Tf  [(. These )] TJ ET
BT 26.250 386.048 Td /F1 9.8 Tf  [(questions raise issues about the clinical utility and cost effectiveness of testing in common practice.)] TJ ET
BT 26.250 366.643 Td /F1 9.8 Tf  [(Research is continuing on the potential utility of screening CRC patients for Lynch syndrome to assist in treatment decisions )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 354.738 Td /F1 9.8 Tf  [([18] [19])] TJ ET
0.271 0.267 0.267 rg
BT 61.486 354.738 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 335.334 Td /F4 9.8 Tf  [(Contextual issues:)] TJ ET
BT 112.937 335.334 Td /F1 9.8 Tf  [( Including clinical alternatives to genetic testing, practice, ethical, legal, social issues.)] TJ ET
BT 26.250 315.929 Td /F1 9.8 Tf  [(The EGAPP Working Group, based on the evidence reviews, found that methods using family history, either the Amsterdam or )] TJ ET
BT 26.250 304.024 Td /F1 9.8 Tf  [(Bethesda criteria, to identify patients with Lynch syndrome produced inconsistent results and identified a lower percentage of )] TJ ET
BT 26.250 292.119 Td /F1 9.8 Tf  [(patients with Lynch syndrome than did tumor-based screening protocols. They also recommended informed consent for )] TJ ET
BT 26.250 280.215 Td /F1 9.8 Tf  [(preliminary testing of patients, noted that studies suggest adverse psychosocial outcomes should be minimal, and stated that )] TJ ET
BT 26.250 268.310 Td /F1 9.8 Tf  [(resource requirements appeared to be justified by willingness of relatives to participate and health benefits for relatives )] TJ ET
0.267 0.267 0.267 rg
BT 539.977 268.310 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 577.924 268.310 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 248.905 Td /F1 9.8 Tf  [(A report suggests that more research is needed on psychosocial issues because of evidence that some subgroups are more )] TJ ET
BT 26.250 237.000 Td /F1 9.8 Tf  [(vulnerable to testing-related stress )] TJ ET
0.267 0.267 0.267 rg
BT 177.980 237.000 Td /F1 9.8 Tf  [([20])] TJ ET
0.271 0.267 0.267 rg
BT 194.243 237.000 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 217.596 Td /F1 9.8 Tf  [(Lynch syndrome is associated with increased risk of a number of other cancers, including cancers of the endometrium, )] TJ ET
BT 26.250 205.691 Td /F1 9.8 Tf  [(stomach, small intestine, bladder, brain, kidney, and biliary tract, and individuals diagnosed with Lynch syndrome may be )] TJ ET
BT 26.250 193.786 Td /F1 9.8 Tf  [(monitored by their clinicians for those cancers as well \(2-3\).)] TJ ET
BT 26.250 174.381 Td /F1 9.8 Tf  [(The Amsterdam criteria may be used to screen individuals for presnce of Lynch syndrome based on their family history of Lynch )] TJ ET
BT 26.250 162.477 Td /F1 9.8 Tf  [(syndrome-asociated cancers \(3\). The revised Amsterdam criteria include the following: at least 3 relatives with Lynch-)] TJ ET
BT 26.250 150.572 Td /F1 9.8 Tf  [(associated cancer, one should be a 1st degree relative of the other two, at least 2 generations with Lynch-associated cancers, )] TJ ET
BT 26.250 138.667 Td /F1 9.8 Tf  [(at least 1 diagnosed before age 50, excluding familial adenomatous polyposis, and with tumors verified by pathologic )] TJ ET
BT 26.250 126.762 Td /F1 9.8 Tf  [(examination \(3\). The Bethesda criteria may be used to identify patients with colorectal cancer who could benefit from genetic )] TJ ET
BT 26.250 114.858 Td /F1 9.8 Tf  [(testing for MMR gene mutations \(3\). The revised Bethesda criteria include the following: colorectal cancer diagnosed in a )] TJ ET
BT 26.250 102.953 Td /F1 9.8 Tf  [(patient younger than age 50, presence of synchronous, metachronous, colorectal or other Lynch-associated cancers regardless )] TJ ET
BT 26.250 91.048 Td /F1 9.8 Tf  [(of age, colorectal cancer with the MSI-H-like histology diagnosed in a patient age less than 60, colorectal cancer diagnosed in a )] TJ ET
BT 26.250 79.143 Td /F1 9.8 Tf  [(pateint with one or more 1st degree relatives with Lynch syndrome-related tumor � with one of the cancers being diagnosed )] TJ ET
BT 26.250 67.239 Td /F1 9.8 Tf  [(under age 50, or colorectal cancer in a patient with two or more 1st or 2nd degree relatiaves with Lynch syndrome-associated )] TJ ET
BT 26.250 55.334 Td /F1 9.8 Tf  [(cancers regardless of age.)] TJ ET
Q
q
15.000 45.453 577.500 731.547 re W n
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
40.337 770.444 m 
40.337 770.890 40.154 771.334 39.838 771.650 c
39.522 771.966 39.078 772.150 38.631 772.150 c
38.185 772.150 37.741 771.966 37.425 771.650 c
37.109 771.334 36.925 770.890 36.925 770.444 c
36.925 769.997 37.109 769.553 37.425 769.237 c
37.741 768.921 38.185 768.738 38.631 768.738 c
39.078 768.738 39.522 768.921 39.838 769.237 c
40.154 769.553 40.337 769.997 40.337 770.444 c f
BT 45.750 767.476 Td /F4 9.8 Tf  [(IHC)] TJ ET
BT 62.540 767.476 Td /F1 9.8 Tf  [(: Studies with a total of 149 patients found that IHC testing was adequately sensitive and specific in identifying )] TJ ET
BT 45.750 755.571 Td /F1 9.8 Tf  [(individuals who had tested positive for some MMR genes )] TJ ET
0.267 0.267 0.267 rg
BT 294.472 755.571 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 332.419 755.571 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 742.884 m 
40.337 743.331 40.154 743.775 39.838 744.091 c
39.522 744.407 39.078 744.590 38.631 744.590 c
38.185 744.590 37.741 744.407 37.425 744.091 c
37.109 743.775 36.925 743.331 36.925 742.884 c
36.925 742.438 37.109 741.994 37.425 741.678 c
37.741 741.362 38.185 741.178 38.631 741.178 c
39.078 741.178 39.522 741.362 39.838 741.678 c
40.154 741.994 40.337 742.438 40.337 742.884 c f
BT 45.750 739.917 Td /F6 9.8 Tf  [(BRAF)] TJ ET
BT 72.826 739.917 Td /F1 9.8 Tf  [(: Multiple studies have found)] TJ ET
BT 196.387 739.917 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 222.391 739.917 Td /F1 9.8 Tf  [(mutation testing to be highly sensitive in identifying CRC tumor tissue abnormal for )] TJ ET
BT 45.750 728.012 Td /F1 9.8 Tf  [(the MLH1 protein due to somatic changes. Thus, it is a highly effective test for ruling out the presence of Lynch Syndrome )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 716.107 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 83.697 716.107 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(Research has shown that concordance between IHC and MSI test results varies )] TJ ET
0.267 0.267 0.267 rg
BT 374.149 692.952 Td /F1 9.8 Tf  [([12] [13])] TJ ET
0.271 0.267 0.267 rg
BT 409.386 692.952 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(The EGAPP Working Group found insufficient evidence to recommend any one of the screening-diagnostic testing combinations )] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(or sequences over the others )] TJ ET
0.267 0.267 0.267 rg
BT 155.233 661.643 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 193.180 661.643 Td /F1 9.8 Tf  [(, and there appears to be no consensus among practitioners on a best practice.)] TJ ET
BT 26.250 642.238 Td /F6 9.8 Tf  [(Clinical utility)] TJ ET
BT 89.644 642.238 Td /F1 9.8 Tf  [(: The possibility that implementing a screening/testing and intervention program for Lynch Syndrome will lead to )] TJ ET
BT 26.250 630.333 Td /F1 9.8 Tf  [(improved health.)] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(Based on the evidence reviews, the EGAPP working group reported that there was adequate evidence from research that more )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(than about 90% of relatives of patients with Lynch would consent to genetic testing and that more than half of those who were )] TJ ET
BT 26.250 587.119 Td /F1 9.8 Tf  [(identified as having Lynch syndrome began screening with colonoscopy, beginning at age 20-25. A single study of relatives at )] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(high risk provides evidence that screening colonoscopy results in an approximately 60% reduction in the incidence of colorectal )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(cancer. Harms appeared to be minimal in comparison with benefits. However, additional research was needed on the overall )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(strategy and on each step from offering genetic testing to patients through studying the long term health benefits to relatives. )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(Additional cost-benefit analyses are also needed. Screening or prophylactic surgery for prevention of other Lynch syndrome )] TJ ET
BT 26.250 527.595 Td /F1 9.8 Tf  [(associated cancers \(particularly endometrial\) has not been fully assessed for utility )] TJ ET
0.267 0.267 0.267 rg
BT 384.426 527.595 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 422.373 527.595 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(The EGAPP Working Group found insufficient evidence of benefit to CRC patient from modification of clinical management )] TJ ET
BT 26.250 496.286 Td /F1 9.8 Tf  [(options based on testing for Lynch )] TJ ET
0.267 0.267 0.267 rg
BT 177.463 496.286 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 215.410 496.286 Td /F1 9.8 Tf  [(. The American College of Gastroenterology found moderate quality evidence for )] TJ ET
BT 26.250 484.381 Td /F1 9.8 Tf  [(their recommendation that colorectal cancer patients with Lynch syndrome undergo colonoscopy every 2 years beginning at age )] TJ ET
BT 26.250 472.476 Td /F1 9.8 Tf  [(20-25 and then annually after age 40 )] TJ ET
0.267 0.267 0.267 rg
BT 188.315 472.476 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 199.157 472.476 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(A cost-effectiveness analysis has reported that a testing strategy using IHC as the preliminary test for individuals newly )] TJ ET
BT 26.250 441.167 Td /F1 9.8 Tf  [(diagnosed with colorectal cancer has an incremental cost-effectiveness ratio of)] TJ ET
BT 26.250 421.762 Td /F1 9.8 Tf  [(<$25,000 per life-year saved compared to no testing for a Lynch syndrome)] TJ ET
0.267 0.267 0.267 rg
BT 348.429 421.762 Td /F1 9.8 Tf  [([14])] TJ ET
0.271 0.267 0.267 rg
BT 364.692 421.762 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 409.857 Td /F1 9.8 Tf  [(Some researchers, practitioners, and members of the public have raised questions about how best to implement testing beyond )] TJ ET
BT 26.250 397.953 Td /F1 9.8 Tf  [(research settings, how feasible it is, and how potential harms from implementation might be addressed )] TJ ET
0.267 0.267 0.267 rg
BT 471.142 397.953 Td /F1 9.8 Tf  [([15] [16] [17])] TJ ET
0.271 0.267 0.267 rg
BT 525.352 397.953 Td /F1 9.8 Tf  [(. These )] TJ ET
BT 26.250 386.048 Td /F1 9.8 Tf  [(questions raise issues about the clinical utility and cost effectiveness of testing in common practice.)] TJ ET
BT 26.250 366.643 Td /F1 9.8 Tf  [(Research is continuing on the potential utility of screening CRC patients for Lynch syndrome to assist in treatment decisions )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 354.738 Td /F1 9.8 Tf  [([18] [19])] TJ ET
0.271 0.267 0.267 rg
BT 61.486 354.738 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 335.334 Td /F4 9.8 Tf  [(Contextual issues:)] TJ ET
BT 112.937 335.334 Td /F1 9.8 Tf  [( Including clinical alternatives to genetic testing, practice, ethical, legal, social issues.)] TJ ET
BT 26.250 315.929 Td /F1 9.8 Tf  [(The EGAPP Working Group, based on the evidence reviews, found that methods using family history, either the Amsterdam or )] TJ ET
BT 26.250 304.024 Td /F1 9.8 Tf  [(Bethesda criteria, to identify patients with Lynch syndrome produced inconsistent results and identified a lower percentage of )] TJ ET
BT 26.250 292.119 Td /F1 9.8 Tf  [(patients with Lynch syndrome than did tumor-based screening protocols. They also recommended informed consent for )] TJ ET
BT 26.250 280.215 Td /F1 9.8 Tf  [(preliminary testing of patients, noted that studies suggest adverse psychosocial outcomes should be minimal, and stated that )] TJ ET
BT 26.250 268.310 Td /F1 9.8 Tf  [(resource requirements appeared to be justified by willingness of relatives to participate and health benefits for relatives )] TJ ET
0.267 0.267 0.267 rg
BT 539.977 268.310 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 577.924 268.310 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 248.905 Td /F1 9.8 Tf  [(A report suggests that more research is needed on psychosocial issues because of evidence that some subgroups are more )] TJ ET
BT 26.250 237.000 Td /F1 9.8 Tf  [(vulnerable to testing-related stress )] TJ ET
0.267 0.267 0.267 rg
BT 177.980 237.000 Td /F1 9.8 Tf  [([20])] TJ ET
0.271 0.267 0.267 rg
BT 194.243 237.000 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 217.596 Td /F1 9.8 Tf  [(Lynch syndrome is associated with increased risk of a number of other cancers, including cancers of the endometrium, )] TJ ET
BT 26.250 205.691 Td /F1 9.8 Tf  [(stomach, small intestine, bladder, brain, kidney, and biliary tract, and individuals diagnosed with Lynch syndrome may be )] TJ ET
BT 26.250 193.786 Td /F1 9.8 Tf  [(monitored by their clinicians for those cancers as well \(2-3\).)] TJ ET
BT 26.250 174.381 Td /F1 9.8 Tf  [(The Amsterdam criteria may be used to screen individuals for presnce of Lynch syndrome based on their family history of Lynch )] TJ ET
BT 26.250 162.477 Td /F1 9.8 Tf  [(syndrome-asociated cancers \(3\). The revised Amsterdam criteria include the following: at least 3 relatives with Lynch-)] TJ ET
BT 26.250 150.572 Td /F1 9.8 Tf  [(associated cancer, one should be a 1st degree relative of the other two, at least 2 generations with Lynch-associated cancers, )] TJ ET
BT 26.250 138.667 Td /F1 9.8 Tf  [(at least 1 diagnosed before age 50, excluding familial adenomatous polyposis, and with tumors verified by pathologic )] TJ ET
BT 26.250 126.762 Td /F1 9.8 Tf  [(examination \(3\). The Bethesda criteria may be used to identify patients with colorectal cancer who could benefit from genetic )] TJ ET
BT 26.250 114.858 Td /F1 9.8 Tf  [(testing for MMR gene mutations \(3\). The revised Bethesda criteria include the following: colorectal cancer diagnosed in a )] TJ ET
BT 26.250 102.953 Td /F1 9.8 Tf  [(patient younger than age 50, presence of synchronous, metachronous, colorectal or other Lynch-associated cancers regardless )] TJ ET
BT 26.250 91.048 Td /F1 9.8 Tf  [(of age, colorectal cancer with the MSI-H-like histology diagnosed in a patient age less than 60, colorectal cancer diagnosed in a )] TJ ET
BT 26.250 79.143 Td /F1 9.8 Tf  [(pateint with one or more 1st degree relatives with Lynch syndrome-related tumor � with one of the cancers being diagnosed )] TJ ET
BT 26.250 67.239 Td /F1 9.8 Tf  [(under age 50, or colorectal cancer in a patient with two or more 1st or 2nd degree relatiaves with Lynch syndrome-associated )] TJ ET
BT 26.250 55.334 Td /F1 9.8 Tf  [(cancers regardless of age.)] TJ ET
Q
q
15.000 45.453 577.500 731.547 re W n
0.271 0.267 0.267 rg
0.271 0.267 0.267 RG
40.337 770.444 m 
40.337 770.890 40.154 771.334 39.838 771.650 c
39.522 771.966 39.078 772.150 38.631 772.150 c
38.185 772.150 37.741 771.966 37.425 771.650 c
37.109 771.334 36.925 770.890 36.925 770.444 c
36.925 769.997 37.109 769.553 37.425 769.237 c
37.741 768.921 38.185 768.738 38.631 768.738 c
39.078 768.738 39.522 768.921 39.838 769.237 c
40.154 769.553 40.337 769.997 40.337 770.444 c f
BT 45.750 767.476 Td /F4 9.8 Tf  [(IHC)] TJ ET
BT 62.540 767.476 Td /F1 9.8 Tf  [(: Studies with a total of 149 patients found that IHC testing was adequately sensitive and specific in identifying )] TJ ET
BT 45.750 755.571 Td /F1 9.8 Tf  [(individuals who had tested positive for some MMR genes )] TJ ET
0.267 0.267 0.267 rg
BT 294.472 755.571 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 332.419 755.571 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 742.884 m 
40.337 743.331 40.154 743.775 39.838 744.091 c
39.522 744.407 39.078 744.590 38.631 744.590 c
38.185 744.590 37.741 744.407 37.425 744.091 c
37.109 743.775 36.925 743.331 36.925 742.884 c
36.925 742.438 37.109 741.994 37.425 741.678 c
37.741 741.362 38.185 741.178 38.631 741.178 c
39.078 741.178 39.522 741.362 39.838 741.678 c
40.154 741.994 40.337 742.438 40.337 742.884 c f
BT 45.750 739.917 Td /F6 9.8 Tf  [(BRAF)] TJ ET
BT 72.826 739.917 Td /F1 9.8 Tf  [(: Multiple studies have found)] TJ ET
BT 196.387 739.917 Td /F5 9.8 Tf  [(BRAF)] TJ ET
BT 222.391 739.917 Td /F1 9.8 Tf  [(mutation testing to be highly sensitive in identifying CRC tumor tissue abnormal for )] TJ ET
BT 45.750 728.012 Td /F1 9.8 Tf  [(the MLH1 protein due to somatic changes. Thus, it is a highly effective test for ruling out the presence of Lynch Syndrome )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 716.107 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 83.697 716.107 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 692.952 Td /F1 9.8 Tf  [(Research has shown that concordance between IHC and MSI test results varies )] TJ ET
0.267 0.267 0.267 rg
BT 374.149 692.952 Td /F1 9.8 Tf  [([12] [13])] TJ ET
0.271 0.267 0.267 rg
BT 409.386 692.952 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 673.548 Td /F1 9.8 Tf  [(The EGAPP Working Group found insufficient evidence to recommend any one of the screening-diagnostic testing combinations )] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(or sequences over the others )] TJ ET
0.267 0.267 0.267 rg
BT 155.233 661.643 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 193.180 661.643 Td /F1 9.8 Tf  [(, and there appears to be no consensus among practitioners on a best practice.)] TJ ET
BT 26.250 642.238 Td /F6 9.8 Tf  [(Clinical utility)] TJ ET
BT 89.644 642.238 Td /F1 9.8 Tf  [(: The possibility that implementing a screening/testing and intervention program for Lynch Syndrome will lead to )] TJ ET
BT 26.250 630.333 Td /F1 9.8 Tf  [(improved health.)] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(Based on the evidence reviews, the EGAPP working group reported that there was adequate evidence from research that more )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(than about 90% of relatives of patients with Lynch would consent to genetic testing and that more than half of those who were )] TJ ET
BT 26.250 587.119 Td /F1 9.8 Tf  [(identified as having Lynch syndrome began screening with colonoscopy, beginning at age 20-25. A single study of relatives at )] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(high risk provides evidence that screening colonoscopy results in an approximately 60% reduction in the incidence of colorectal )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(cancer. Harms appeared to be minimal in comparison with benefits. However, additional research was needed on the overall )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(strategy and on each step from offering genetic testing to patients through studying the long term health benefits to relatives. )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(Additional cost-benefit analyses are also needed. Screening or prophylactic surgery for prevention of other Lynch syndrome )] TJ ET
BT 26.250 527.595 Td /F1 9.8 Tf  [(associated cancers \(particularly endometrial\) has not been fully assessed for utility )] TJ ET
0.267 0.267 0.267 rg
BT 384.426 527.595 Td /F1 9.8 Tf  [([1] [2] [3])] TJ ET
0.271 0.267 0.267 rg
BT 422.373 527.595 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 508.191 Td /F1 9.8 Tf  [(The EGAPP Working Group found insufficient evidence of benefit to CRC patient from modification of clinical management )] TJ ET
BT 26.250 496.286 Td /F1 9.8 Tf  [(options based on testing for Lynch )] TJ ET
0.267 0.267 0.267 rg
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BT 26.250 217.596 Td /F1 9.8 Tf  [(Lynch syndrome is associated with increased risk of a number of other cancers, including cancers of the endometrium, )] TJ ET
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BT 26.250 767.476 Td /F1 9.8 Tf  [(Given the variety of screening approaches, including scoring of histopathological characteristics, family history criteria, and )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(inconsistencies in the recommendations from various groups, practicing clinicians face multiple options for Lynch syndrome )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(screening. At present, there is limited published research on how to effectively implement testing in routine clinical practice and )] TJ ET
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BT 290.202 731.762 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 695.159 Td /F4 12.0 Tf  [(Additional Links)] TJ ET
BT 26.250 675.205 Td /F1 9.8 Tf  [(Epidemiologic research on genes associated with Lynch, HNPCC: )] TJ ET
BT 26.250 663.300 Td /F1 9.8 Tf  [(https://hugenavigator.net/HuGENavigator/phenoPedia.do?firstQuery=Colorectal Neoplasms, Hereditary )] TJ ET
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BT 26.250 631.991 Td /F1 9.8 Tf  [(https://hugenavigator.net/HuGENavigator/phenoPedia.do?firstQuery=Lynch Syndrome II&cuiID=C1333991 )] TJ ET
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BT 26.250 583.484 Td /F4 12.0 Tf  [(Acknowledgements:)] TJ ET
BT 26.250 563.529 Td /F1 9.8 Tf  [(We would like to thank Katherine Kolor, PhD, MS, Office of Public Health Genomics, Centers for Disease Control and )] TJ ET
BT 26.250 551.625 Td /F1 9.8 Tf  [(Prevention, Atlanta, GA and Cecelia A. Bellcross, Ph.D. MS. Emory University, Atlanta, GA for reviewing and commenting on )] TJ ET
BT 26.250 539.720 Td /F1 9.8 Tf  [(this brief review prior to submission for publication.)] TJ ET
BT 26.250 503.117 Td /F4 12.0 Tf  [(Funding Information:)] TJ ET
BT 26.250 483.163 Td /F1 9.8 Tf  [(Ralph Coates and Stephanie Melillo were supported by their employer, the Centers for Disease Control and Prevention, Atlanta, )] TJ ET
BT 26.250 471.258 Td /F1 9.8 Tf  [(GA, USA. Marc Williams and Jim Gudgeon were supported by their employer, Intermountain Healthcare, Salt Lake City, UT, )] TJ ET
BT 26.250 459.354 Td /F1 9.8 Tf  [(USA.)] TJ ET
BT 26.250 422.751 Td /F4 12.0 Tf  [(Competing Interests:)] TJ ET
BT 26.250 402.797 Td /F1 9.8 Tf  [(The authors have declared that no competing interests exist.)] TJ ET
BT 26.250 383.392 Td /F1 9.8 Tf  [(*Independent groups include the Advisory Committee on Heritable Disorders in Newborns and Children, the Evaluation of )] TJ ET
BT 26.250 371.487 Td /F1 9.8 Tf  [(Genomic Applications in Practice and Prevention \(EGAPP\) Working Group, the United Kingdom�s National Institute for Health )] TJ ET
BT 26.250 359.583 Td /F1 9.8 Tf  [(and Clinical Excellence, and the US Preventive Services Task Force \(USPSTF\).)] TJ ET
BT 26.250 322.980 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 295.526 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 295.526 Td /F1 9.8 Tf  [(Evaluation of Genomic Applications in Practice and Prevention \(EGAPP\) Working Group. Recommendations from the )] TJ ET
BT 26.250 283.621 Td /F1 9.8 Tf  [(EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing )] TJ ET
BT 26.250 271.716 Td /F1 9.8 Tf  [(morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009 Jan;11\(1\):35-41. PubMed PMID: 19125126; )] TJ ET
BT 26.250 259.812 Td /F1 9.8 Tf  [(PubMed Central PMCID: PMC2743612.)] TJ ET
BT 26.250 240.407 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 240.407 Td /F1 9.8 Tf  [(Palomaki GE, McClain MR, Melillo S, Hampel HL, Thibodeau SN. EGAPP supplementary evidence review: DNA testing )] TJ ET
BT 26.250 228.502 Td /F1 9.8 Tf  [(strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 2009 Jan;11\(1\):42-65. Review. PubMed )] TJ ET
BT 26.250 216.597 Td /F1 9.8 Tf  [(PMID: 19125127; PubMed Central PMCID: PMC2743613.)] TJ ET
BT 26.250 197.193 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 197.193 Td /F1 9.8 Tf  [(Bonis PA, Trikalinos TA, Chung M, Chew P, Ip S, DeVine DA, Lau J. Hereditary nonpolyposis colorectal cancer: diagnostic )] TJ ET
BT 26.250 185.288 Td /F1 9.8 Tf  [(strategies and their implications. Evid Rep Technol Assess \(Full Rep\). 2007 May;\(150\):1-180. Review. PubMed PMID: )] TJ ET
BT 26.250 173.383 Td /F1 9.8 Tf  [(17764220.)] TJ ET
BT 26.250 153.978 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 153.978 Td /F1 9.8 Tf  [(U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999�2007 Incidence and Mortality Web-based )] TJ ET
BT 26.250 142.074 Td /F1 9.8 Tf  [(Report. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National )] TJ ET
BT 26.250 130.169 Td /F1 9.8 Tf  [(Cancer Institute; 2010. )] TJ ET
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BT 38.132 103.133 Td /F1 9.8 Tf  [(Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, Mariotto )] TJ ET
BT 26.250 91.228 Td /F1 9.8 Tf  [(A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK \(eds\). SEER Cancer Statistics Review, )] TJ ET
BT 26.250 79.323 Td /F1 9.8 Tf  [(1975-2007, National Cancer Institute. Bethesda, MD,)] TJ ET
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BT 26.250 70.837 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
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BT 38.132 52.287 Td /F1 9.8 Tf  [(U.S. Preventive Services Task Force. Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation )] TJ ET
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BT 290.202 731.762 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 695.159 Td /F4 12.0 Tf  [(Additional Links)] TJ ET
BT 26.250 675.205 Td /F1 9.8 Tf  [(Epidemiologic research on genes associated with Lynch, HNPCC: )] TJ ET
BT 26.250 663.300 Td /F1 9.8 Tf  [(https://hugenavigator.net/HuGENavigator/phenoPedia.do?firstQuery=Colorectal Neoplasms, Hereditary )] TJ ET
BT 26.250 651.396 Td /F1 9.8 Tf  [(Nonpolyposis&cuiID=C0009405 &typeSubmit=GO&check=y&which=2&pubOrderType=pubD/)] TJ ET
BT 26.250 631.991 Td /F1 9.8 Tf  [(https://hugenavigator.net/HuGENavigator/phenoPedia.do?firstQuery=Lynch Syndrome II&cuiID=C1333991 )] TJ ET
BT 26.250 620.086 Td /F1 9.8 Tf  [(&typeSubmit=GO&check=y&which=2&pubOrderType=pubD/)] TJ ET
BT 26.250 583.484 Td /F4 12.0 Tf  [(Acknowledgements:)] TJ ET
BT 26.250 563.529 Td /F1 9.8 Tf  [(We would like to thank Katherine Kolor, PhD, MS, Office of Public Health Genomics, Centers for Disease Control and )] TJ ET
BT 26.250 551.625 Td /F1 9.8 Tf  [(Prevention, Atlanta, GA and Cecelia A. Bellcross, Ph.D. MS. Emory University, Atlanta, GA for reviewing and commenting on )] TJ ET
BT 26.250 539.720 Td /F1 9.8 Tf  [(this brief review prior to submission for publication.)] TJ ET
BT 26.250 503.117 Td /F4 12.0 Tf  [(Funding Information:)] TJ ET
BT 26.250 483.163 Td /F1 9.8 Tf  [(Ralph Coates and Stephanie Melillo were supported by their employer, the Centers for Disease Control and Prevention, Atlanta, )] TJ ET
BT 26.250 471.258 Td /F1 9.8 Tf  [(GA, USA. Marc Williams and Jim Gudgeon were supported by their employer, Intermountain Healthcare, Salt Lake City, UT, )] TJ ET
BT 26.250 459.354 Td /F1 9.8 Tf  [(USA.)] TJ ET
BT 26.250 422.751 Td /F4 12.0 Tf  [(Competing Interests:)] TJ ET
BT 26.250 402.797 Td /F1 9.8 Tf  [(The authors have declared that no competing interests exist.)] TJ ET
BT 26.250 383.392 Td /F1 9.8 Tf  [(*Independent groups include the Advisory Committee on Heritable Disorders in Newborns and Children, the Evaluation of )] TJ ET
BT 26.250 371.487 Td /F1 9.8 Tf  [(Genomic Applications in Practice and Prevention \(EGAPP\) Working Group, the United Kingdom�s National Institute for Health )] TJ ET
BT 26.250 359.583 Td /F1 9.8 Tf  [(and Clinical Excellence, and the US Preventive Services Task Force \(USPSTF\).)] TJ ET
BT 26.250 322.980 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 295.526 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 295.526 Td /F1 9.8 Tf  [(Evaluation of Genomic Applications in Practice and Prevention \(EGAPP\) Working Group. Recommendations from the )] TJ ET
BT 26.250 283.621 Td /F1 9.8 Tf  [(EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing )] TJ ET
BT 26.250 271.716 Td /F1 9.8 Tf  [(morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009 Jan;11\(1\):35-41. PubMed PMID: 19125126; )] TJ ET
BT 26.250 259.812 Td /F1 9.8 Tf  [(PubMed Central PMCID: PMC2743612.)] TJ ET
BT 26.250 240.407 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 240.407 Td /F1 9.8 Tf  [(Palomaki GE, McClain MR, Melillo S, Hampel HL, Thibodeau SN. EGAPP supplementary evidence review: DNA testing )] TJ ET
BT 26.250 228.502 Td /F1 9.8 Tf  [(strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 2009 Jan;11\(1\):42-65. Review. PubMed )] TJ ET
BT 26.250 216.597 Td /F1 9.8 Tf  [(PMID: 19125127; PubMed Central PMCID: PMC2743613.)] TJ ET
BT 26.250 197.193 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 197.193 Td /F1 9.8 Tf  [(Bonis PA, Trikalinos TA, Chung M, Chew P, Ip S, DeVine DA, Lau J. Hereditary nonpolyposis colorectal cancer: diagnostic )] TJ ET
BT 26.250 185.288 Td /F1 9.8 Tf  [(strategies and their implications. Evid Rep Technol Assess \(Full Rep\). 2007 May;\(150\):1-180. Review. PubMed PMID: )] TJ ET
BT 26.250 173.383 Td /F1 9.8 Tf  [(17764220.)] TJ ET
BT 26.250 153.978 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 153.978 Td /F1 9.8 Tf  [(U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999�2007 Incidence and Mortality Web-based )] TJ ET
BT 26.250 142.074 Td /F1 9.8 Tf  [(Report. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National )] TJ ET
BT 26.250 130.169 Td /F1 9.8 Tf  [(Cancer Institute; 2010. )] TJ ET
0.267 0.267 0.267 rg
BT 26.250 121.683 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 103.133 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 103.133 Td /F1 9.8 Tf  [(Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, Mariotto )] TJ ET
BT 26.250 91.228 Td /F1 9.8 Tf  [(A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK \(eds\). SEER Cancer Statistics Review, )] TJ ET
BT 26.250 79.323 Td /F1 9.8 Tf  [(1975-2007, National Cancer Institute. Bethesda, MD,)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 70.837 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 52.287 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 52.287 Td /F1 9.8 Tf  [(U.S. Preventive Services Task Force. Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation )] TJ ET
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BT 26.250 767.476 Td /F1 9.8 Tf  [(Given the variety of screening approaches, including scoring of histopathological characteristics, family history criteria, and )] TJ ET
BT 26.250 755.571 Td /F1 9.8 Tf  [(inconsistencies in the recommendations from various groups, practicing clinicians face multiple options for Lynch syndrome )] TJ ET
BT 26.250 743.667 Td /F1 9.8 Tf  [(screening. At present, there is limited published research on how to effectively implement testing in routine clinical practice and )] TJ ET
BT 26.250 731.762 Td /F1 9.8 Tf  [(on the benefits and costs of implementation )] TJ ET
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BT 217.018 731.762 Td /F1 9.8 Tf  [([15] [16] [17] [21])] TJ ET
0.271 0.267 0.267 rg
BT 290.202 731.762 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 695.159 Td /F4 12.0 Tf  [(Additional Links)] TJ ET
BT 26.250 675.205 Td /F1 9.8 Tf  [(Epidemiologic research on genes associated with Lynch, HNPCC: )] TJ ET
BT 26.250 663.300 Td /F1 9.8 Tf  [(https://hugenavigator.net/HuGENavigator/phenoPedia.do?firstQuery=Colorectal Neoplasms, Hereditary )] TJ ET
BT 26.250 651.396 Td /F1 9.8 Tf  [(Nonpolyposis&cuiID=C0009405 &typeSubmit=GO&check=y&which=2&pubOrderType=pubD/)] TJ ET
BT 26.250 631.991 Td /F1 9.8 Tf  [(https://hugenavigator.net/HuGENavigator/phenoPedia.do?firstQuery=Lynch Syndrome II&cuiID=C1333991 )] TJ ET
BT 26.250 620.086 Td /F1 9.8 Tf  [(&typeSubmit=GO&check=y&which=2&pubOrderType=pubD/)] TJ ET
BT 26.250 583.484 Td /F4 12.0 Tf  [(Acknowledgements:)] TJ ET
BT 26.250 563.529 Td /F1 9.8 Tf  [(We would like to thank Katherine Kolor, PhD, MS, Office of Public Health Genomics, Centers for Disease Control and )] TJ ET
BT 26.250 551.625 Td /F1 9.8 Tf  [(Prevention, Atlanta, GA and Cecelia A. Bellcross, Ph.D. MS. Emory University, Atlanta, GA for reviewing and commenting on )] TJ ET
BT 26.250 539.720 Td /F1 9.8 Tf  [(this brief review prior to submission for publication.)] TJ ET
BT 26.250 503.117 Td /F4 12.0 Tf  [(Funding Information:)] TJ ET
BT 26.250 483.163 Td /F1 9.8 Tf  [(Ralph Coates and Stephanie Melillo were supported by their employer, the Centers for Disease Control and Prevention, Atlanta, )] TJ ET
BT 26.250 471.258 Td /F1 9.8 Tf  [(GA, USA. Marc Williams and Jim Gudgeon were supported by their employer, Intermountain Healthcare, Salt Lake City, UT, )] TJ ET
BT 26.250 459.354 Td /F1 9.8 Tf  [(USA.)] TJ ET
BT 26.250 422.751 Td /F4 12.0 Tf  [(Competing Interests:)] TJ ET
BT 26.250 402.797 Td /F1 9.8 Tf  [(The authors have declared that no competing interests exist.)] TJ ET
BT 26.250 383.392 Td /F1 9.8 Tf  [(*Independent groups include the Advisory Committee on Heritable Disorders in Newborns and Children, the Evaluation of )] TJ ET
BT 26.250 371.487 Td /F1 9.8 Tf  [(Genomic Applications in Practice and Prevention \(EGAPP\) Working Group, the United Kingdom�s National Institute for Health )] TJ ET
BT 26.250 359.583 Td /F1 9.8 Tf  [(and Clinical Excellence, and the US Preventive Services Task Force \(USPSTF\).)] TJ ET
BT 26.250 322.980 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 295.526 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 295.526 Td /F1 9.8 Tf  [(Evaluation of Genomic Applications in Practice and Prevention \(EGAPP\) Working Group. Recommendations from the )] TJ ET
BT 26.250 283.621 Td /F1 9.8 Tf  [(EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing )] TJ ET
BT 26.250 271.716 Td /F1 9.8 Tf  [(morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009 Jan;11\(1\):35-41. PubMed PMID: 19125126; )] TJ ET
BT 26.250 259.812 Td /F1 9.8 Tf  [(PubMed Central PMCID: PMC2743612.)] TJ ET
BT 26.250 240.407 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 240.407 Td /F1 9.8 Tf  [(Palomaki GE, McClain MR, Melillo S, Hampel HL, Thibodeau SN. EGAPP supplementary evidence review: DNA testing )] TJ ET
BT 26.250 228.502 Td /F1 9.8 Tf  [(strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 2009 Jan;11\(1\):42-65. Review. PubMed )] TJ ET
BT 26.250 216.597 Td /F1 9.8 Tf  [(PMID: 19125127; PubMed Central PMCID: PMC2743613.)] TJ ET
BT 26.250 197.193 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 197.193 Td /F1 9.8 Tf  [(Bonis PA, Trikalinos TA, Chung M, Chew P, Ip S, DeVine DA, Lau J. Hereditary nonpolyposis colorectal cancer: diagnostic )] TJ ET
BT 26.250 185.288 Td /F1 9.8 Tf  [(strategies and their implications. Evid Rep Technol Assess \(Full Rep\). 2007 May;\(150\):1-180. Review. PubMed PMID: )] TJ ET
BT 26.250 173.383 Td /F1 9.8 Tf  [(17764220.)] TJ ET
BT 26.250 153.978 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 153.978 Td /F1 9.8 Tf  [(U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999�2007 Incidence and Mortality Web-based )] TJ ET
BT 26.250 142.074 Td /F1 9.8 Tf  [(Report. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National )] TJ ET
BT 26.250 130.169 Td /F1 9.8 Tf  [(Cancer Institute; 2010. )] TJ ET
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BT 38.132 103.133 Td /F1 9.8 Tf  [(Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, Mariotto )] TJ ET
BT 26.250 91.228 Td /F1 9.8 Tf  [(A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK \(eds\). SEER Cancer Statistics Review, )] TJ ET
BT 26.250 79.323 Td /F1 9.8 Tf  [(1975-2007, National Cancer Institute. Bethesda, MD,)] TJ ET
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BT 26.250 70.837 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
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BT 26.250 52.287 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 52.287 Td /F1 9.8 Tf  [(U.S. Preventive Services Task Force. Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation )] TJ ET
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BT 26.250 767.476 Td /F1 9.8 Tf  [(statement. Ann Intern Med. 2008 Nov 4;149\(9\):627-37. Epub 2008 Oct 6. PubMed PMID: 18838716.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 748.071 Td /F1 9.8 Tf  [(Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, Gomez Garcia EB, Vriends AH; Dutch Lynch Syndrome Study )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(Group, Cartwright NR, Barnetson RA, Farrington SM, Tenesa A, Hampel H, Buchanan D, Arnold S, Young J, Walsh MD, Jass J, )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(Macrae F, Antill Y, Winship IM, Giles GG, Goldblatt J, Parry S, Suthers G, Leggett B, Butz M, Aronson M, Poynter JN, Baron )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(JA, Le Marchand L, Haile R, Gallinger S, Hopper JL, Potter J, de la Chapelle A, Vasen HF, Dunlop MG, Thibodeau SN, Jenkins )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(MA. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010 Feb 3;102\(3\):193-201. Epub 2009 )] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(Dec 22. PubMed PMID: 20028993; PubMed Central PMCID: PMC2815724.)] TJ ET
BT 26.250 669.143 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 669.143 Td /F1 9.8 Tf  [(Stoffel E, Mukherjee B, Raymond VM, Tayob N, Kastrinos F, Sparr J, Wang F, Bandipalliam P, Syngal S, Gruber SB. )] TJ ET
BT 26.250 657.238 Td /F1 9.8 Tf  [(Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology. 2009 )] TJ ET
BT 26.250 645.333 Td /F1 9.8 Tf  [(Nov;137\(5\):1621-7. Epub 2009 Jul 18. PubMed PMID: 19622357; PubMed Central PMCID: PMC2767441.)] TJ ET
BT 26.250 625.929 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 625.929 Td /F1 9.8 Tf  [(Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM; American College of Gastroenterology. )] TJ ET
BT 26.250 614.024 Td /F1 9.8 Tf  [(American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol. 2009 )] TJ ET
BT 26.250 602.119 Td /F1 9.8 Tf  [(Mar;104\(3\):739-50. Epub 2009 Feb 24. Erratum in: Am J Gastroenterol. 2009 Jun;104\(6\):1613. PubMed PMID: 19240699.)] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 582.714 Td /F1 9.8 Tf  [(National Cancer Center Network Guidelines Version 2.2011.)] TJ ET
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BT 26.250 574.228 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 555.678 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 555.678 Td /F1 9.8 Tf  [(Levin B, Lieberman DA, McFarland B, Smith RA, Brooks D, Andrews KS, Dash C, Giardiello FM, Glick S, Levin TR, )] TJ ET
BT 26.250 543.774 Td /F1 9.8 Tf  [(Pickhardt P, Rex DK, Thorson A, Winawer SJ; American Cancer Society Colorectal Cancer Advisory Group; US Multi-Society )] TJ ET
BT 26.250 531.869 Td /F1 9.8 Tf  [(Task Force; American College of Radiology Colon Cancer Committee. Screening and surveillance for the early detection of )] TJ ET
BT 26.250 519.964 Td /F1 9.8 Tf  [(colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society )] TJ ET
BT 26.250 508.059 Td /F1 9.8 Tf  [(Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. 2008 May-Jun;58\(3\):130-60. Epub )] TJ ET
BT 26.250 496.155 Td /F1 9.8 Tf  [(2008 Mar 5. PubMed PMID: 18322143.)] TJ ET
BT 26.250 476.750 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 476.750 Td /F1 9.8 Tf  [(Overbeek LI, Ligtenberg MJ, Willems RW, Hermens RP, Blokx WA, Dubois SV, van der Linden H, Meijer JW, Mlynek-)] TJ ET
BT 26.250 464.845 Td /F1 9.8 Tf  [(Kersjes ML, Hoogerbrugge N, Hebeda KM, van Krieken JH. Interpretation of immunohistochemistry for mismatch repair proteins )] TJ ET
BT 26.250 452.940 Td /F1 9.8 Tf  [(is only reliable in a specialized setting. Am J Surg Pathol. 2008 Aug;32\(8\):1246-51. PubMed PMID: 18677806.)] TJ ET
BT 26.250 433.536 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 433.536 Td /F1 9.8 Tf  [(Engel C, Forberg J, Holinski-Feder E, Pagenstecher C, Plaschke J, Kloor M, Poremba C, Pox CP, R�schoff J, Keller G, )] TJ ET
BT 26.250 421.631 Td /F1 9.8 Tf  [(Dietmaier W, R�mmele P, Friedrichs N, Mangold E, Buettner R, Schackert HK, Kienle P, Stemmler S, Moeslein G, Loeffler M; )] TJ ET
BT 26.250 409.726 Td /F1 9.8 Tf  [(German HNPCC Consortium. Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and )] TJ ET
BT 26.250 397.821 Td /F1 9.8 Tf  [(microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2006 Jan 1;118\(1\):115-22. )] TJ ET
BT 26.250 385.917 Td /F1 9.8 Tf  [(PubMed PMID: 16003745.)] TJ ET
BT 26.250 366.512 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 366.512 Td /F1 9.8 Tf  [(Mvundura M, Grosse SD, Hampel H, Palomaki GE. The cost-effectiveness of genetic testing strategies for Lynch syndrome )] TJ ET
BT 26.250 354.607 Td /F1 9.8 Tf  [(among newly diagnosed patients with colorectal cancer. Genet Med. 2010 Feb;12\(2\):93-104. PubMed PMID: 20084010.)] TJ ET
BT 26.250 335.202 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 335.202 Td /F1 9.8 Tf  [(Institute of Medicine \(US\) Roundtable on Translating Genomic-Based Research for Health. The Value of Genetic and )] TJ ET
BT 26.250 323.298 Td /F1 9.8 Tf  [(Genomic Technologies: Workshop Summary. Washington \(DC\): National Academies Press \(US\); 2010. PubMed PMID: )] TJ ET
BT 26.250 311.393 Td /F1 9.8 Tf  [(21391344.)] TJ ET
BT 26.250 291.988 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 291.988 Td /F1 9.8 Tf  [(Hall MJ. Counterpoint: implementing population genetic screening for Lynch Syndrome among newly diagnosed colorectal )] TJ ET
BT 26.250 280.083 Td /F1 9.8 Tf  [(cancer patients--will the ends justify the means? J Natl Compr Canc Netw. 2010 May;8\(5\):606-11. PubMed PMID: 20495087.)] TJ ET
BT 26.250 260.679 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 260.679 Td /F1 9.8 Tf  [(Peres J. To screen or not to screen for Lynch syndrome. J Natl Cancer Inst. 2010 Sep 22;102\(18\):1382-4. Epub 2010 Sep )] TJ ET
BT 26.250 248.774 Td /F1 9.8 Tf  [(8. PubMed PMID: 20826733.)] TJ ET
BT 26.250 229.369 Td /F1 9.8 Tf  [(18.)] TJ ET
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BT 26.250 217.464 Td /F1 9.8 Tf  [(Lynch syndrome. Dis Colon Rectum. 2010 Jan;53\(1\):77-82. PubMed PMID: 20010355.)] TJ ET
BT 26.250 198.060 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 198.060 Td /F1 9.8 Tf  [(Des Guetz G, Schischmanoff O, Nicolas P, Perret GY, Morere JF, Uzzan B. Does microsatellite instability predict the )] TJ ET
BT 26.250 186.155 Td /F1 9.8 Tf  [(efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009 )] TJ ET
BT 26.250 174.250 Td /F1 9.8 Tf  [(Jul;45\(10\):1890-6. Epub 2009 May 6. Review. PubMed PMID: 19427194.)] TJ ET
BT 26.250 154.845 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 154.845 Td /F1 9.8 Tf  [(Landsbergen KM, Prins JB, Brunner HG, Kraaimaat FW, Hoogerbrugge N. Genetic testing for Lynch syndrome in the first )] TJ ET
BT 26.250 142.941 Td /F1 9.8 Tf  [(year of colorectal cancer: a review of the psychological impact. Fam Cancer. 2009;8\(4\):325-37. Epub 2009 Mar 28. Review. )] TJ ET
BT 26.250 131.036 Td /F1 9.8 Tf  [(PubMed PMID: 19330464; PubMed Central PMCID: PMC2771129.)] TJ ET
BT 26.250 111.631 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 111.631 Td /F1 9.8 Tf  [(Gudgeon JM, Williams JL, Burt RW, Samowitz WS, Snow GL, Williams MS. Lynch Syndrome Screening Implementation: )] TJ ET
BT 26.250 99.726 Td /F1 9.8 Tf  [(Business Analysis by a Healthcare System. Am J Managed Care, Aug 2011 Accepted for Publication)] TJ ET
Q
q
15.000 82.346 577.500 694.654 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(statement. Ann Intern Med. 2008 Nov 4;149\(9\):627-37. Epub 2008 Oct 6. PubMed PMID: 18838716.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 748.071 Td /F1 9.8 Tf  [(Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, Gomez Garcia EB, Vriends AH; Dutch Lynch Syndrome Study )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(Group, Cartwright NR, Barnetson RA, Farrington SM, Tenesa A, Hampel H, Buchanan D, Arnold S, Young J, Walsh MD, Jass J, )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(Macrae F, Antill Y, Winship IM, Giles GG, Goldblatt J, Parry S, Suthers G, Leggett B, Butz M, Aronson M, Poynter JN, Baron )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(JA, Le Marchand L, Haile R, Gallinger S, Hopper JL, Potter J, de la Chapelle A, Vasen HF, Dunlop MG, Thibodeau SN, Jenkins )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(MA. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010 Feb 3;102\(3\):193-201. Epub 2009 )] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(Dec 22. PubMed PMID: 20028993; PubMed Central PMCID: PMC2815724.)] TJ ET
BT 26.250 669.143 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 669.143 Td /F1 9.8 Tf  [(Stoffel E, Mukherjee B, Raymond VM, Tayob N, Kastrinos F, Sparr J, Wang F, Bandipalliam P, Syngal S, Gruber SB. )] TJ ET
BT 26.250 657.238 Td /F1 9.8 Tf  [(Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology. 2009 )] TJ ET
BT 26.250 645.333 Td /F1 9.8 Tf  [(Nov;137\(5\):1621-7. Epub 2009 Jul 18. PubMed PMID: 19622357; PubMed Central PMCID: PMC2767441.)] TJ ET
BT 26.250 625.929 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 625.929 Td /F1 9.8 Tf  [(Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM; American College of Gastroenterology. )] TJ ET
BT 26.250 614.024 Td /F1 9.8 Tf  [(American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol. 2009 )] TJ ET
BT 26.250 602.119 Td /F1 9.8 Tf  [(Mar;104\(3\):739-50. Epub 2009 Feb 24. Erratum in: Am J Gastroenterol. 2009 Jun;104\(6\):1613. PubMed PMID: 19240699.)] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 582.714 Td /F1 9.8 Tf  [(National Cancer Center Network Guidelines Version 2.2011.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 574.228 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 555.678 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 555.678 Td /F1 9.8 Tf  [(Levin B, Lieberman DA, McFarland B, Smith RA, Brooks D, Andrews KS, Dash C, Giardiello FM, Glick S, Levin TR, )] TJ ET
BT 26.250 543.774 Td /F1 9.8 Tf  [(Pickhardt P, Rex DK, Thorson A, Winawer SJ; American Cancer Society Colorectal Cancer Advisory Group; US Multi-Society )] TJ ET
BT 26.250 531.869 Td /F1 9.8 Tf  [(Task Force; American College of Radiology Colon Cancer Committee. Screening and surveillance for the early detection of )] TJ ET
BT 26.250 519.964 Td /F1 9.8 Tf  [(colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society )] TJ ET
BT 26.250 508.059 Td /F1 9.8 Tf  [(Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. 2008 May-Jun;58\(3\):130-60. Epub )] TJ ET
BT 26.250 496.155 Td /F1 9.8 Tf  [(2008 Mar 5. PubMed PMID: 18322143.)] TJ ET
BT 26.250 476.750 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 476.750 Td /F1 9.8 Tf  [(Overbeek LI, Ligtenberg MJ, Willems RW, Hermens RP, Blokx WA, Dubois SV, van der Linden H, Meijer JW, Mlynek-)] TJ ET
BT 26.250 464.845 Td /F1 9.8 Tf  [(Kersjes ML, Hoogerbrugge N, Hebeda KM, van Krieken JH. Interpretation of immunohistochemistry for mismatch repair proteins )] TJ ET
BT 26.250 452.940 Td /F1 9.8 Tf  [(is only reliable in a specialized setting. Am J Surg Pathol. 2008 Aug;32\(8\):1246-51. PubMed PMID: 18677806.)] TJ ET
BT 26.250 433.536 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 433.536 Td /F1 9.8 Tf  [(Engel C, Forberg J, Holinski-Feder E, Pagenstecher C, Plaschke J, Kloor M, Poremba C, Pox CP, R�schoff J, Keller G, )] TJ ET
BT 26.250 421.631 Td /F1 9.8 Tf  [(Dietmaier W, R�mmele P, Friedrichs N, Mangold E, Buettner R, Schackert HK, Kienle P, Stemmler S, Moeslein G, Loeffler M; )] TJ ET
BT 26.250 409.726 Td /F1 9.8 Tf  [(German HNPCC Consortium. Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and )] TJ ET
BT 26.250 397.821 Td /F1 9.8 Tf  [(microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2006 Jan 1;118\(1\):115-22. )] TJ ET
BT 26.250 385.917 Td /F1 9.8 Tf  [(PubMed PMID: 16003745.)] TJ ET
BT 26.250 366.512 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 366.512 Td /F1 9.8 Tf  [(Mvundura M, Grosse SD, Hampel H, Palomaki GE. The cost-effectiveness of genetic testing strategies for Lynch syndrome )] TJ ET
BT 26.250 354.607 Td /F1 9.8 Tf  [(among newly diagnosed patients with colorectal cancer. Genet Med. 2010 Feb;12\(2\):93-104. PubMed PMID: 20084010.)] TJ ET
BT 26.250 335.202 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 335.202 Td /F1 9.8 Tf  [(Institute of Medicine \(US\) Roundtable on Translating Genomic-Based Research for Health. The Value of Genetic and )] TJ ET
BT 26.250 323.298 Td /F1 9.8 Tf  [(Genomic Technologies: Workshop Summary. Washington \(DC\): National Academies Press \(US\); 2010. PubMed PMID: )] TJ ET
BT 26.250 311.393 Td /F1 9.8 Tf  [(21391344.)] TJ ET
BT 26.250 291.988 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 291.988 Td /F1 9.8 Tf  [(Hall MJ. Counterpoint: implementing population genetic screening for Lynch Syndrome among newly diagnosed colorectal )] TJ ET
BT 26.250 280.083 Td /F1 9.8 Tf  [(cancer patients--will the ends justify the means? J Natl Compr Canc Netw. 2010 May;8\(5\):606-11. PubMed PMID: 20495087.)] TJ ET
BT 26.250 260.679 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 260.679 Td /F1 9.8 Tf  [(Peres J. To screen or not to screen for Lynch syndrome. J Natl Cancer Inst. 2010 Sep 22;102\(18\):1382-4. Epub 2010 Sep )] TJ ET
BT 26.250 248.774 Td /F1 9.8 Tf  [(8. PubMed PMID: 20826733.)] TJ ET
BT 26.250 229.369 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 229.369 Td /F1 9.8 Tf  [(Natarajan N, Watson P, Silva-Lopez E, Lynch HT. Comparison of extended colectomy and limited resection in patients with )] TJ ET
BT 26.250 217.464 Td /F1 9.8 Tf  [(Lynch syndrome. Dis Colon Rectum. 2010 Jan;53\(1\):77-82. PubMed PMID: 20010355.)] TJ ET
BT 26.250 198.060 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 198.060 Td /F1 9.8 Tf  [(Des Guetz G, Schischmanoff O, Nicolas P, Perret GY, Morere JF, Uzzan B. Does microsatellite instability predict the )] TJ ET
BT 26.250 186.155 Td /F1 9.8 Tf  [(efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009 )] TJ ET
BT 26.250 174.250 Td /F1 9.8 Tf  [(Jul;45\(10\):1890-6. Epub 2009 May 6. Review. PubMed PMID: 19427194.)] TJ ET
BT 26.250 154.845 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 154.845 Td /F1 9.8 Tf  [(Landsbergen KM, Prins JB, Brunner HG, Kraaimaat FW, Hoogerbrugge N. Genetic testing for Lynch syndrome in the first )] TJ ET
BT 26.250 142.941 Td /F1 9.8 Tf  [(year of colorectal cancer: a review of the psychological impact. Fam Cancer. 2009;8\(4\):325-37. Epub 2009 Mar 28. Review. )] TJ ET
BT 26.250 131.036 Td /F1 9.8 Tf  [(PubMed PMID: 19330464; PubMed Central PMCID: PMC2771129.)] TJ ET
BT 26.250 111.631 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 111.631 Td /F1 9.8 Tf  [(Gudgeon JM, Williams JL, Burt RW, Samowitz WS, Snow GL, Williams MS. Lynch Syndrome Screening Implementation: )] TJ ET
BT 26.250 99.726 Td /F1 9.8 Tf  [(Business Analysis by a Healthcare System. Am J Managed Care, Aug 2011 Accepted for Publication)] TJ ET
Q
q
15.000 82.346 577.500 694.654 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(statement. Ann Intern Med. 2008 Nov 4;149\(9\):627-37. Epub 2008 Oct 6. PubMed PMID: 18838716.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 748.071 Td /F1 9.8 Tf  [(Baglietto L, Lindor NM, Dowty JG, White DM, Wagner A, Gomez Garcia EB, Vriends AH; Dutch Lynch Syndrome Study )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(Group, Cartwright NR, Barnetson RA, Farrington SM, Tenesa A, Hampel H, Buchanan D, Arnold S, Young J, Walsh MD, Jass J, )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(Macrae F, Antill Y, Winship IM, Giles GG, Goldblatt J, Parry S, Suthers G, Leggett B, Butz M, Aronson M, Poynter JN, Baron )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(JA, Le Marchand L, Haile R, Gallinger S, Hopper JL, Potter J, de la Chapelle A, Vasen HF, Dunlop MG, Thibodeau SN, Jenkins )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(MA. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010 Feb 3;102\(3\):193-201. Epub 2009 )] TJ ET
BT 26.250 688.548 Td /F1 9.8 Tf  [(Dec 22. PubMed PMID: 20028993; PubMed Central PMCID: PMC2815724.)] TJ ET
BT 26.250 669.143 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 669.143 Td /F1 9.8 Tf  [(Stoffel E, Mukherjee B, Raymond VM, Tayob N, Kastrinos F, Sparr J, Wang F, Bandipalliam P, Syngal S, Gruber SB. )] TJ ET
BT 26.250 657.238 Td /F1 9.8 Tf  [(Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology. 2009 )] TJ ET
BT 26.250 645.333 Td /F1 9.8 Tf  [(Nov;137\(5\):1621-7. Epub 2009 Jul 18. PubMed PMID: 19622357; PubMed Central PMCID: PMC2767441.)] TJ ET
BT 26.250 625.929 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 625.929 Td /F1 9.8 Tf  [(Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM; American College of Gastroenterology. )] TJ ET
BT 26.250 614.024 Td /F1 9.8 Tf  [(American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol. 2009 )] TJ ET
BT 26.250 602.119 Td /F1 9.8 Tf  [(Mar;104\(3\):739-50. Epub 2009 Feb 24. Erratum in: Am J Gastroenterol. 2009 Jun;104\(6\):1613. PubMed PMID: 19240699.)] TJ ET
BT 26.250 582.714 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 582.714 Td /F1 9.8 Tf  [(National Cancer Center Network Guidelines Version 2.2011.)] TJ ET
0.267 0.267 0.267 rg
BT 26.250 574.228 Td /F1 7.5 Tf  [(REFERENCE LINK)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 555.678 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 555.678 Td /F1 9.8 Tf  [(Levin B, Lieberman DA, McFarland B, Smith RA, Brooks D, Andrews KS, Dash C, Giardiello FM, Glick S, Levin TR, )] TJ ET
BT 26.250 543.774 Td /F1 9.8 Tf  [(Pickhardt P, Rex DK, Thorson A, Winawer SJ; American Cancer Society Colorectal Cancer Advisory Group; US Multi-Society )] TJ ET
BT 26.250 531.869 Td /F1 9.8 Tf  [(Task Force; American College of Radiology Colon Cancer Committee. Screening and surveillance for the early detection of )] TJ ET
BT 26.250 519.964 Td /F1 9.8 Tf  [(colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society )] TJ ET
BT 26.250 508.059 Td /F1 9.8 Tf  [(Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin. 2008 May-Jun;58\(3\):130-60. Epub )] TJ ET
BT 26.250 496.155 Td /F1 9.8 Tf  [(2008 Mar 5. PubMed PMID: 18322143.)] TJ ET
BT 26.250 476.750 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 476.750 Td /F1 9.8 Tf  [(Overbeek LI, Ligtenberg MJ, Willems RW, Hermens RP, Blokx WA, Dubois SV, van der Linden H, Meijer JW, Mlynek-)] TJ ET
BT 26.250 464.845 Td /F1 9.8 Tf  [(Kersjes ML, Hoogerbrugge N, Hebeda KM, van Krieken JH. Interpretation of immunohistochemistry for mismatch repair proteins )] TJ ET
BT 26.250 452.940 Td /F1 9.8 Tf  [(is only reliable in a specialized setting. Am J Surg Pathol. 2008 Aug;32\(8\):1246-51. PubMed PMID: 18677806.)] TJ ET
BT 26.250 433.536 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 433.536 Td /F1 9.8 Tf  [(Engel C, Forberg J, Holinski-Feder E, Pagenstecher C, Plaschke J, Kloor M, Poremba C, Pox CP, R�schoff J, Keller G, )] TJ ET
BT 26.250 421.631 Td /F1 9.8 Tf  [(Dietmaier W, R�mmele P, Friedrichs N, Mangold E, Buettner R, Schackert HK, Kienle P, Stemmler S, Moeslein G, Loeffler M; )] TJ ET
BT 26.250 409.726 Td /F1 9.8 Tf  [(German HNPCC Consortium. Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and )] TJ ET
BT 26.250 397.821 Td /F1 9.8 Tf  [(microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2006 Jan 1;118\(1\):115-22. )] TJ ET
BT 26.250 385.917 Td /F1 9.8 Tf  [(PubMed PMID: 16003745.)] TJ ET
BT 26.250 366.512 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 366.512 Td /F1 9.8 Tf  [(Mvundura M, Grosse SD, Hampel H, Palomaki GE. The cost-effectiveness of genetic testing strategies for Lynch syndrome )] TJ ET
BT 26.250 354.607 Td /F1 9.8 Tf  [(among newly diagnosed patients with colorectal cancer. Genet Med. 2010 Feb;12\(2\):93-104. PubMed PMID: 20084010.)] TJ ET
BT 26.250 335.202 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 335.202 Td /F1 9.8 Tf  [(Institute of Medicine \(US\) Roundtable on Translating Genomic-Based Research for Health. The Value of Genetic and )] TJ ET
BT 26.250 323.298 Td /F1 9.8 Tf  [(Genomic Technologies: Workshop Summary. Washington \(DC\): National Academies Press \(US\); 2010. PubMed PMID: )] TJ ET
BT 26.250 311.393 Td /F1 9.8 Tf  [(21391344.)] TJ ET
BT 26.250 291.988 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 291.988 Td /F1 9.8 Tf  [(Hall MJ. Counterpoint: implementing population genetic screening for Lynch Syndrome among newly diagnosed colorectal )] TJ ET
BT 26.250 280.083 Td /F1 9.8 Tf  [(cancer patients--will the ends justify the means? J Natl Compr Canc Netw. 2010 May;8\(5\):606-11. PubMed PMID: 20495087.)] TJ ET
BT 26.250 260.679 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 260.679 Td /F1 9.8 Tf  [(Peres J. To screen or not to screen for Lynch syndrome. J Natl Cancer Inst. 2010 Sep 22;102\(18\):1382-4. Epub 2010 Sep )] TJ ET
BT 26.250 248.774 Td /F1 9.8 Tf  [(8. PubMed PMID: 20826733.)] TJ ET
BT 26.250 229.369 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 229.369 Td /F1 9.8 Tf  [(Natarajan N, Watson P, Silva-Lopez E, Lynch HT. Comparison of extended colectomy and limited resection in patients with )] TJ ET
BT 26.250 217.464 Td /F1 9.8 Tf  [(Lynch syndrome. Dis Colon Rectum. 2010 Jan;53\(1\):77-82. PubMed PMID: 20010355.)] TJ ET
BT 26.250 198.060 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 198.060 Td /F1 9.8 Tf  [(Des Guetz G, Schischmanoff O, Nicolas P, Perret GY, Morere JF, Uzzan B. Does microsatellite instability predict the )] TJ ET
BT 26.250 186.155 Td /F1 9.8 Tf  [(efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009 )] TJ ET
BT 26.250 174.250 Td /F1 9.8 Tf  [(Jul;45\(10\):1890-6. Epub 2009 May 6. Review. PubMed PMID: 19427194.)] TJ ET
BT 26.250 154.845 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 154.845 Td /F1 9.8 Tf  [(Landsbergen KM, Prins JB, Brunner HG, Kraaimaat FW, Hoogerbrugge N. Genetic testing for Lynch syndrome in the first )] TJ ET
BT 26.250 142.941 Td /F1 9.8 Tf  [(year of colorectal cancer: a review of the psychological impact. Fam Cancer. 2009;8\(4\):325-37. Epub 2009 Mar 28. Review. )] TJ ET
BT 26.250 131.036 Td /F1 9.8 Tf  [(PubMed PMID: 19330464; PubMed Central PMCID: PMC2771129.)] TJ ET
BT 26.250 111.631 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 111.631 Td /F1 9.8 Tf  [(Gudgeon JM, Williams JL, Burt RW, Samowitz WS, Snow GL, Williams MS. Lynch Syndrome Screening Implementation: )] TJ ET
BT 26.250 99.726 Td /F1 9.8 Tf  [(Business Analysis by a Healthcare System. Am J Managed Care, Aug 2011 Accepted for Publication)] TJ ET
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q
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BT 291.710 19.825 Td /F1 11.0 Tf  [(5)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET
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