Department of Urology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Sci Rep. 2019 Nov 20;9(1):17173. doi: 10.1038/s41598-019-53445-2.
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.
由于前列腺癌具有高度遗传性，因此已经在包括韩国在内的各种人群中研究了与前列腺癌相关的常见变异体。然而，罕见和低频变异体对疾病的遗传性有重大影响。在韩国人群中，罕见变异体对前列腺癌易感性的贡献尚未得到系统评估。在这项工作中，我们对 7258 个人（985 例前列腺癌病例和 6273 例对照）进行了大规模外显子稀有变异分析。总共 19 个稀有变异体位点跨越 7 个基因，与前列腺癌易感性相关。除了复制先前已知的易感基因（例如 CDYL2、MST1R、GPER1 和 PARD3B）外，还鉴定了 3 个新基因（FDR q < 0.05），包括非编码 RNA ENTPD3-AS1、LOC102724438 和蛋白编码基因 SPATA3。此外，根据鉴定的变异体和基因，确定了 6 条途径，包括雌激素信号通路、MST1 信号、IL-15 产生、MSP-RON 信号通路以及巨噬细胞中的 IL-12 信号和产生，这些途径已知与前列腺癌有关。总之，我们报告了在韩国人群中可能与前列腺癌易感性相关的新基因和稀有变异体。这些观察结果为实现精准医学的一个基本目标奠定了基础，即确定具有比其他人更大疾病风险的人群的生物标志物。
