Identification of Germline Genetic Variants that Increase Prostate Cancer Risk and Influence Development of Aggressive Disease

Abstract

Prostate cancer (PrCa) is a heterogeneous disease, which presents in individual patients across a diverse phenotypic spectrum ranging from indolent to fatal forms. No robust biomarkers are currently available to enable routine screening for PrCa or to distinguish clinically significant forms, therefore late stage identification of advanced disease and overdiagnosis plus overtreatment of insignificant disease both remain areas of concern in healthcare provision. PrCa has a substantial heritable component, and technological advances since the completion of the Human Genome Project have facilitated improved identification of inherited genetic factors influencing susceptibility to development of the disease within families and populations. These genetic markers hold promise to enable improved understanding of the biological mechanisms underpinning PrCa development, facilitate genetically informed PrCa screening programmes and guide appropriate treatment provision. However, insight remains largely lacking regarding many aspects of their manifestation; especially in relation to genes associated with aggressive phenotypes, risk factors in non-European populations and appropriate approaches to enable accurate stratification of higher and lower risk individuals. This review discusses the methodology used in the elucidation of genetic loci, genes and individual causal variants responsible for modulating PrCa susceptibility; the current state of understanding of the allelic spectrum contributing to PrCa risk; and prospective future translational applications of these discoveries in the developing eras of genomics and personalised medicine.

Keywords: aggressive prostate cancer; genome-wide association studies; massively parallel sequencing studies; prostate cancer; prostate cancer genetics; prostate cancer susceptibility.

Figure 1

Karyogram depicting the approximate locations of candidate PrCa risk loci reported through linkage, GWAS and sequencing study approaches. To the right of the chromosome ideogram, triangle symbols indicate the position of 269 reported independent GWAS index variants [127] and circle symbols the locations of DNA repair genes reported as a potential candidate for risk in two or more PrCa sequencing studies (listed within Table 1). To the left of the chromosome ideogram, line symbols show the approximate intervals of linkage peaks according to representative markers for the region or cytogenetic band co-ordinates. Grey coloured symbols indicate no or limited evidence for association with risk of aggressive PrCa, the black colour denotes moderate or conflicting evidence for risk of aggressive disease and black symbols with a red border signify stronger evidence for a contribution towards poorer prognosis phenotypes. The karyogram is overlaid with a heat map depicting gene density across the human genome in 1 Mb windows and was generated using RIdeogram [128] and custom plotting functions.

Figure 2

Venn diagrams comparing the proportion of the 269 independent GWAS index variants reported to date that were (a) present at ≥1% risk allele frequency, and (b) present at ≥5% risk allele frequency in European (EUR), African (AFR) and East Asian (EAS) ancestral super-populations.