Oncogenetics, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK.
Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.
Br J Cancer. 2018 Jul;119(1):96-104. doi: 10.1038/s41416-018-0141-7. Epub 2018 Jun 19.
Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes.
We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants.
Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects.
Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application.
前列腺癌（PrCa）表现出从惰性到致命的异质性临床特征。我们试图确定一种罕见遗传变异的特征，以区分这两种极端表型。
我们对 139 例侵袭性（转移性，诊断年龄<60 岁）和 141 例非侵袭性（低临床分级，诊断年龄≥60 岁）前列腺癌病例的生殖系全外显子进行了测序。我们使用 SKAT 和贝叶斯风险指数技术在基因和基因集水平上进行了罕见变异关联分析。对具有最高差异破坏性罕见变异负担的基因进行了 GO 术语富集分析。
侵袭性表型患者中特定 DNA 修复基因中的蛋白截断变异（PTVs）明显过度表达，BRCA2、ATM 和 NBN 是最常突变的基因。在涉及血管生成的几个基因中，也发现了转移性和非侵袭性病例之间罕见变异的差异负担，这既赋予了有害效应，也赋予了保护效应。
几种 DNA 修复基因中的遗传 PTVs 可区分侵袭性和非侵袭性前列腺癌病例。此外，在血管生成相关基因中的遗传变异可能是转移风险的潜在预测因子。如果在更大的数据集上得到验证，这些发现具有未来临床应用的潜力。
