Koboldt Daniel C, Kanchi Krishna L, Gui Bin, Larson David E, Fulton Robert S, Isaacs William B, Kraja Aldi, Borecki Ingrid B, Jia Li, Wilson Richard K, Mardis Elaine R, Kibel Adam S
The McDonnell Genome Institute at Washington University, St. Louis, Missouri.
Division of Urology, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Cancer Epidemiol Biomarkers Prev. 2016 Nov;25(11):1456-1463. doi: 10.1158/1055-9965.EPI-16-0373. Epub 2016 Aug 2.
Common variants have been associated with prostate cancer risk. Unfortunately, few are reproducibly linked to aggressive disease, the phenotype of greatest clinical relevance. One possible explanation is that rare genetic variants underlie a significant proportion of the risk for aggressive disease.
To identify such variants, we performed a two-stage approach using whole-exome sequencing followed by targeted sequencing of 800 genes in 652 aggressive prostate cancer patients and 752 disease-free controls in both African and European Americans. In each population, we tested rare variants for association using two gene-based aggregation tests. We established a study-wide significance threshold of 3.125 × 10 to correct for multiple testing.
TET2 in African Americans was associated with aggressive disease, with 24.4% of cases harboring a rare deleterious variant compared with 9.6% of controls (FET P = 1.84 × 10, OR = 3.0; SKAT-O P = 2.74 × 10). We report 8 additional genes with suggestive evidence of association, including the DNA repair genes PARP2 and MSH6 Finally, we observed an excess of rare truncation variants in 5 genes, including the DNA repair genes MSH6, BRCA1, and BRCA2 This adds to the growing body of evidence that DNA repair pathway defects may influence susceptibility to aggressive prostate cancer.
Our findings suggest that rare variants influence risk of clinically relevant prostate cancer and, if validated, could serve to identify men for screening, prophylaxis, and treatment.
This study provides evidence that rare variants in TET2 may help identify African American men at increased risk for clinically relevant prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(11); 1456-63. ©2016 AACR.
常见变异与前列腺癌风险相关。遗憾的是，很少有变异能被反复证实与侵袭性疾病相关，而侵袭性疾病是临床上最具相关性的表型。一种可能的解释是，罕见基因变异在很大程度上构成了侵袭性疾病风险的基础。
为了识别此类变异，我们采用了两阶段方法，先进行全外显子组测序，然后对652例侵袭性前列腺癌患者和752例无病对照（包括非裔美国人和欧裔美国人）的800个基因进行靶向测序。在每个群体中，我们使用两种基于基因的聚集性检验来检测罕见变异的关联性。我们设定了一个全研究范围的显著性阈值为3.125×10，以校正多重检验。
在非裔美国人中，TET2与侵袭性疾病相关，24.4%的病例携带罕见有害变异，而对照组为9.6%（Fisher精确检验P = 1.84×10，比值比=3.0；SKAT-O检验P = 2.74×10）。我们报告了另外8个有提示性关联证据的基因，包括DNA修复基因PARP2和MSH6。最后，我们在5个基因中观察到罕见截短变异过多，包括DNA修复基因MSH6、BRCA1和BRCA2。这进一步证明了DNA修复途径缺陷可能影响对侵袭性前列腺癌的易感性。
我们的研究结果表明，罕见变异会影响临床相关前列腺癌的风险，如果得到验证，可用于识别需要进行筛查、预防和治疗的男性。
本研究提供了证据表明TET2中的罕见变异可能有助于识别患临床相关前列腺癌风险增加的非裔美国男性。《癌症流行病学、生物标志物与预防》；25(11)；1456 - 63。©2016美国癌症研究协会。
