Prostate cancer genomics, biology, and risk assessment through genome-wide association studies

Abstract

Prostate cancer (PC) is the most common malignancy observed in men. It is evident that genetic factors play some important roles in PC etiology. Recently, genome-wide association studies in diverse ethnic groups have identified more than 40 germline variants of various genes or chromosomal loci that are significantly associated with PC susceptibility, including multiple 8q24 loci, prostate-specific genes, metabolic and hormone-related genes, and many regions where no coding gene is annotated. However, there are only a few variants or genes for which biological significance or functions have been elucidated so far. The greatest challenge related to genome-wide association studies loci in prostate genomics is to understand the functional consequences of these PC-associated loci and their involvement in PC biology and carcinogenesis. There have been attempts to determine PC risk estimations by combining multiple PC-associated variants for clinical tests, and these can identify a very minor population with high risk of PC. However, they cannot distinguish risk of aggressive PC from that of non-aggressive PC. Further identification of PC-susceptibility loci in larger genome-wide association studies cohorts and biological insights gained from such functional analyses have the potential to translate into clinical benefits, including the development of reliable biomarkers, risk estimation, and effective strategies for screening and prevention of PC.

Figure 1

Manhatton plot of GWAS for prostate cancer. The y‐axis indicates −log₁₀ (P‐value for the association with PC), and the x‐axis shows the location of each chromosome. The characteristic pattern of GWAS for PC indicates many peaks of −log₁₀ (P‐value) across the genome, including extremely high multiple peaks in chromosome 8q24. GPRC6A,G protein‐coupled receptor, family C, group 6, member A; GWAS, genome‐wide association study; HNF1B, hepatocyte nuclear factor 1‐β;MSMB, microseminoprotein‐beta;NKX3.1,NK3 homeobox; PC, prostate cancer.

Figure 2

Multiple PC‐susceptibility loci in chromosome 8q24. At least three regions or five blocks are independently associated with PC and other types of cancer. Region 1 is suggested to affect c‐MYC expression as an enhancer element. Region 2 is likely to be involved with androgen receptor pathway possible through non‐coding RNA PRNCR1. This −log₁₀ P plot is based on GWAS of the Japanese PC.27, 46 GWAS, genome‐wide association study; PC, prostate cancer; PRNCR1, prostate cancer non‐coding RNA1.

Figure 3

An example of distribution of the OR for PC risk estimated by combining 18 SNPs in the dataset of a Japanese population.27 The x‐axis indicates log₁₀ (OR of PC risk) and y‐axis indicates cumulative frequency. The top 2–3% of men is estimated to have more than three times of OR of PC risk (indicated by the red area). GWAS, genome‐wide association study; PC, prostate cancer; SNP, single nucleotide polymorphism.