Coronary artery disease (CAD) is a leading cause of death worldwide and in the United States it is responsible for more than 500,000 deaths each year. Genome-wide association studies (GWAS) have revealed connections between a number of common single nucleotide polymorphisms (SNPs) and CAD and other cardiovascular diseases. The p.Trp719Arg SNP in the kinesin-like family 6 (KIF6) gene has recently been reported as a potential risk factor for CAD as well as a predictor of response to statin therapy.
Colon and rectal cancer (CRC) are the third most common cancer in the United States and cause approximately 50,000 deaths per year. The anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab (Erbitux®) and panitumumab (Vectibix®) have been recently introduced to treat CRC. However, the response rate with these agents is low and they are associated with serious adverse effects. Accordingly biomarkers that can predict those patients that will respond to treatment may have clinical utility. The p.Val600Glu sequence variant (often called V600E) in the BRAF gene has been investigated as a biomarker to predict patients that will not respond to treatment with the anti-EGFR monoclonal antibodies.
It is estimated that approximately 22,000 Americans will be diagnosed with tumor of the brain or nervous system in 2010. Among primary brain tumors, approximately 60% are gliomas, the most common and most malignant of which is glioblastoma multiforme (GBM).The DecisionDx-GBM test is a multigene expression assay that is designed to predict which patients are likely to experience long-term (> 2 years) progression-free survival.
Tamoxifen, a selective estrogen receptor modulator, is the standard of care for premenopausal women with estrogen or progesterone receptor-positive breast cancer and a valid option for treating post-menopausal women. However, a substantial number of tamoxifen-treated patients relapse following surgical resection, while others remain disease-free for many years. It appears that the primary effectors of tamoxifen activity are its active metabolites, rather than tamoxifen itself. Cytochrome P450 (CYP) enzymes, CYP2D6 in particular, play a major role in the metabolism of tamoxifen to active metabolites. More than 75 germline CYP2D6 variants have been identified.
A test predicting lack of response to tamoxifen could supplement information used by clinicians and patients in treatment decision-making. For example, physicians and patients may opt to switch to an alternative therapy upfront.
The anti-platelet agent clopidogrel bisulfate (sold under the trade name Plavix in the United States) is a widely prescribed medication for the prevention of blood clots in patients with acute coronary syndrome, in those who have suffered other cardiovascular disease-related events such as ischemic stroke, and in patients who are undergoing percutaneous coronary intervention. Response to clopidogrel varies substantially due to genetic and acquired factors. Patients who experience recurrent cardiovascular ischemic or thrombotic events while taking clopidogrel are typically described as non-responsive or resistant.
The drug’s oxidation is mainly dependent on the cytochrome P450 enzyme 2C19 (CYP2C19). Patients with certain genetic variants in CYP2C19 have been found to have lower levels of the active metabolite, less platelet inhibition, and greater risk of major adverse cardiovascular events such as heart attack, stroke, and death. Testing for CYP2C19 polymorphisms may identify patients who will not respond adequately to the standard clopidogrel regimen and who should, consequently, be given an alternate treatment strategy. This article outlines the evidence concerning pharmacogenetic testing for clopidogrel response, including data on clinical validity and clinical utility, and summarizes the currently available tests marketed for this purpose.
Warfarin is an oral anticoagulant that is widely prescribed to prevent thromboembolic events in persons at increased risk. The optimal dose is difficult to establish because it can vary 10-fold among individuals due to clinical and demographic factors. Testing for variants of the vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes has been proposed for use in guiding the initial dose of warfarin, thus achieving optimal dosing more quickly and with lower risk of bleeding.
KRAS mutational analysis is a genetic test used in clinical practice for determining the status of the KRAS gene (wild type or mutant) in tumors from patients with metastatic colorectal cancer (CRC). Persons whose tumors are wild type may respond to therapies cetuximab (Erbitux) or panitumumab (Vectibix).
Overall five-year survival for patients with stage-II colon cancer averages 75% after surgery alone. However, some of these patients have poorer outcomes, similar to patients with stage-III disease. The proposed use of the Oncotype DX assay is to improve risk stratification for recurrence in stage-II colon cancer.
Differences in the expression of specific genes within breast tumors have been associated with risk of recurrence after treatment. Most women with Stage I or II node-negative breast cancer (especially when estrogen-receptor positive and treated with tamoxifen) remain disease-free at 10 years. Information on risk of recurrence could help identify women most likely to benefit from chemotherapy. Several clinically available gene expression profiles (GEP) provide “recurrence risk scores” that are intended to supplement information used by clinicians and patients in treatment decision-making.
Evidence on Genomic Tests is an open access publication option for communicating high-quality, scientific information that is needed to evaluate health applications of genomic research. By using Google’s knol platform, we aim to reduce conventional barriers to sharing, updating, and accessing the results of knowledge synthesis and to increase the benefits to authors and users alike.