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.

Updates in Prostate Cancer Research and Screening in Men at Genetically Higher Risk

“…FH is one of the strongest risk factors, with risk increasing with the number of relatives affected and the younger their age at diagnosis [9]. Men with one first-degree relative have an estimated risk of 2.5 times the general population risk.…”

“…Research is required to further clarify the level of risk conferred by pathogenic variants in each of these genes and the association of these variants with aggressive disease and age at onset to inform their inclusion in gene panel tests [9,57].…”

“…Common genetic variants, or single nucleotide polymorphisms (SNPs), occur in > 5% of the population. Largescale genome-wide association studies (GWAS) have led to the discovery of over 200 SNPs associated with PrCa risk (reviewed in [9]). Each SNP has a low penetrance and confers a small increase in PrCa risk if occurring alone, but are thought to act multiplicatively.…”

“…PrCa risk is influenced by a combination of common and rare germline variants, with rare variants important within specific families and sub-groups and common variants a substantial contributor at the population level [9]. Identifying an underlying genetic predisposition to PrCa is important for a number of reasons.…”

Extensive germline-somatic interplay drives prostate cancer through HNF1B co-option of TMPRSS2-ERG

“…Therefore, unravelling PCa risk-associated genetic factors and investigating their underlying mechanisms and biological impacts are expected to greatly inform our understanding of PCa pathogenesis, progression, and clinical management. Comprehensive GWAS analyses have been performed in men with PCa across diverse ancestry groups, and these studies have jointly identified 270 susceptibility loci harboring over 400 SNPs that reach genomewide significance (P ≤ 5x10 -8 ) in association with PCa risk and aggressiveness [10][11][12][13] . Of these PCa risk loci, the 17q12/HNF1B locus variants rs4430796, rs11263763 and rs11651052 have been reproducibly found to be associated with PCa susceptibility [14][15][16][17][18][19][20][21] .…”