Multigene Panels in Prostate Cancer Risk Assessment

Prostate cancer is the fifth most common malignancy in the world, with a large variation in incidence rates. In 2010, it was estimated that almost a quarter of a million new cases were diagnosed in North America, and more than 36,000 men died from the disease. Apart from age, ethnic group, and family history, the risk factors associated with prostate cancer are unclear, making primary prevention difficult. Striking differences in incidence have been observed for different ethnic groups and populations. A high incidence has been observed in populations of African descent in several countries. First-degree relatives of men with prostate cancer have a two- to threefold increased risk for developing the disease, and its estimated heritability is high. Some patterns of familial aggregation have been observed that are consistent with an autosomal dominant mode of inheritance of a susceptibility gene, but this accounts for no more than 15 percent of cases. Prostate cancer is currently considered to be a complex, multifactorial disease with the vast majority of familial clustering attributed to the interaction of multiple shared moderate to low penetrance susceptibility genes and shared environmental factors within these families. Many epidemiological studies have suggested a wide range of other risk factors for prostate cancer, but these have not been confirmed in controlled trials. The natural history of prostate cancer is highly variable. In a large proportion of men, the disease is indolent, and it is difficult to predict which tumors will be aggressive. African-American men have a poorer prognosis than other groups, independent of comorbidity or access to health services. The value of aggressive management for localized prostate cancer is also debated, and only a small proportion of men with early stage prostate cancer die from the disease within 10 to 15 years of diagnosis. Prostate-specific antigen (PSA) was approved by the U.S. Food and Drug Administration in 1986 for monitoring progression in patients with prostate cancer, and later approved for the detection of the disease in symptomatic men (but not for screening asymptomatic men). A meta-analysis of seven randomized controlled trials of screening using PSA testing alone, or in combination with digital rectal examination, suggested no evidence of benefit in reducing mortality, and some evidence of harms from overdiagnosis. Amidst substantial debate, the argument has been made for developing more accurate screening tests, including possible genetic markers. Single nucleotide polymorphisms (SNPs) are minute inherited variations in the DNA sequence. SNPs occur about once in every 800 base pairs and are the most common type of genetic variation in humans. Since 2001, there have been about 1,000 published studies reporting associations between prostate cancer, SNPs, and other genetic variants. To date, genome-wide association (GWA) studies have identified replicated associations between prostate cancer and almost 40 specific SNPs. The aim of this review is to assess the evidence on the possible value of SNP panels in the detection of and prediction of risk for prostate cancer, and their value in predicting disease prognosis in affected men. This report addresses the evidence on the validity and utility of using SNP panels in the detection, diagnosis, and clinical management of prostate cancer. The specific Key Questions are: 1. What is the analytic validity of currently available SNP-based panels designed for prostate cancer risk assessment? 2. What is the clinical validity of currently available SNP-based panels designed for prostate cancer risk assessment? 3. What is the clinical utility of currently available SNP-based panels for prostate cancer risk assessment, in terms of the process of care, health outcomes, harms, and economic considerations?