Genome-wide association studies of cancer predisposition.

Genome-wide association studies (GWAS) have now been performed in nearly all common malignancies and have identified more than 100 common genetic risk variants that confer a modest increased risk of cancer. For most discovered germline risk variants, the per allele effect size is small (<1.5) and the biologic mechanism of the detected association remains unexplained. Exceptions are the risk variants identified in JAK2 in myeloproliferative neoplasm and in the KITLG gene in testicular cancer, which are each associated with nearly a 3-fold increased risk of disease. GWAS have provided an efficient approach to identifying common, low-penetrance risk variants, and have implicated several novel cancer susceptibility loci. However, the identified low-penetrance risk variants explain only a small fraction of the heritability of cancer and the clinical usefulness of using these variants for cancer-risk prediction is to date limited. Studies involving more heterogeneous populations, determination of the causal variants, and functional studies are now necessary to further elucidate the potential biologic and clinical significance of the observed associations.

Genome-wide association studies of cancer: principles and potential utility.

Genome-wide association studies (GWAS) have emerged as a new approach for investigating the genetic basis of complex diseases. In oncology, genome-wide studies of nearly all common malignancies have been performed and more than 100 genetic variants associated with increased risks have been identified. GWAS approaches are powerful research tools that are revealing novel pathways important in carcinogenesis and promise to further enhance our understanding of the basis of inherited cancer susceptibility. However, "personal genomic tests" based on cancer GWAS results that are currently being offered by for-profit commercial companies for cancer risk prediction have unproven clinical utility and may risk false conveyance of reassurance or alarm.

Ethicolegal aspects of cancer genetics.

In the wake of efficacious preventive interventions based on hereditary cancer risk assessment, a number of ethical and legal challenges have emerged. These include issues such as appropriate testing of children and embryos, the "duty to warn" relatives about familial risk, reproductive genetic testing, the risk of genetic discrimination, and equitable access to testing. These and other issues will be discussed within the framework of a bioethical model, with reference to recent case law.

Genome-wide association studies of cancer.

Knowledge of the inherited risk for cancer is an important component of preventive oncology. In addition to well-established syndromes of cancer predisposition, much remains to be discovered about the genetic variation underlying susceptibility to common malignancies. Increased knowledge about the human genome and advances in genotyping technology have made possible genome-wide association studies (GWAS) of human diseases. These studies have identified many important regions of genetic variation associated with an increased risk for human traits and diseases including cancer. Understanding the principles, major findings, and limitations of GWAS is becoming increasingly important for oncologists as dissemination of genomic risk tests directly to consumers is already occurring through commercial companies. GWAS have contributed to our understanding of the genetic basis of cancer and will shed light on biologic pathways and possible new strategies for targeted prevention. To date, however, the clinical utility of GWAS-derived risk markers remains limited.

Ethical and legal aspects of cancer genetic testing.

As a result of the increasing effectiveness of cancer screening and preventive interventions, ethical issues, as well as legal liabilities, are increasingly associated with cancer genetic testing. These issues include the possible "duty to warn" relatives of inherited cancer risk, the appropriateness of testing of children and embryos, equity of access to genetics services, and potential harms of testing including the risk of genetic discrimination. An approach to these and other ethical challenges will be presented, drawing not only on recent case law but also on a broader bioethical framework.