Abstract
Since prostate cancer is highly heritable, common variants associated with prostate cancer have been studied in various populations, including those in Korea. However, rare and low-frequency variants have a significant influence on the heritability of the disease. The contributions of rare variants to prostate cancer susceptibility have not yet been systematically evaluated in a Korean population. In this work, we present a large-scale exome-wide rare variant analysis of 7,258 individuals (985 cases with prostate cancer and 6,273 controls). In total, 19 rare variant loci spanning 7 genes contributed to an association with prostate cancer susceptibility. In addition to replicating previously known susceptibility genes (e.g., CDYL2, MST1R, GPER1, and PARD3B), 3 novel genes were identified (FDR q < 0.05), including the non-coding RNAs ENTPD3-AS1, LOC102724438, and protein-coding gene SPATA3. Additionally, 6 pathways were identified based on identified variants and genes, including estrogen signaling pathway, signaling by MST1, IL-15 production, MSP-RON signaling pathway, and IL-12 signaling and production in macrophages, which are known to be associated with prostate cancer. In summary, we report novel genes and rare variants that potentially play a role in prostate cancer susceptibility in the Korean population. These observations demonstrated a path towards one of the fundamental goals of precision medicine, which is to identify biomarkers for a subset of the population with a greater risk of disease than others.
Highlights
Since prostate cancer is highly heritable, common variants associated with prostate cancer have been studied in various populations, including those in Korea
6,438 patients were obtained from the Korean Association Resource (KARE) study, which is a part of the Korean Genome and Epidemiology Study (KoGES)[17]
Though common variants have been studied previously in the Korean population, this is the first exome-wide study of rare variants associated with prostate cancer in the Korean population
Summary
Since prostate cancer is highly heritable, common variants associated with prostate cancer have been studied in various populations, including those in Korea. We report novel genes and rare variants that potentially play a role in prostate cancer susceptibility in the Korean population These observations demonstrated a path towards one of the fundamental goals of precision medicine, which is to identify biomarkers for a subset of the population with a greater risk of disease than others. More than 100 loci have been identified in GWAS studies using European cohorts[7,8], while studies that have performed GWAS using participants of Chinese and Japanese ethnicities have identified only 12 significant loci associated with prostate cancer[8] Another GWAS study using common variants identified 5 significant loci associated with prostate cancer in a Korean population[9]. The common variants discovered to date explain only a small portion of heritability of prostate cancer, leaving the majority of genetic risk unexplained[10]
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