PDF(Pubmed)
Abstract：
Altered DNA damage response (DDR) has emerged as an important mechanism for the development of aggressive prostate cancer among men of European ancestry but not other ancestry groups. Because common mechanisms for aggressive disease are expected, we explored a large panel of DDR genes and pathways to demonstrate that DDR alterations contribute to development of aggressive prostate cancer in both African American and European American men.
We performed a case-case study of 764 African American and European American men with lethal or indolent prostate cancer treated at 4 US hospitals. We calculated carrier frequencies of germline pathogenic or likely pathogenic sequence variants within 306 DDR genes, summarized by DDR pathway, and compared lethal cases against indolent cases using 2-sided Fisher\'s exact tests. Secondary analysis examined if carrier frequencies differed by ancestry.
Lethal cases were more likely to carry a pathogenic sequence variant in a DDR gene compared with indolent cases (18.5% vs 9.6%, P = 4.30 × 10-4), even after excluding BRCA2 (14.6% vs 9.6%, P = .04). The carrier frequency was similar among lethal cases of African (16.7% including and 15.8% excluding BRCA2) and lethal cases of European (19.3% including and 14.2% excluding BRCA2) ancestry. Three DDR pathways were statistically significantly associated with lethal disease: homologous recombination (P = .003), Fanconi anemia (P = .002), and checkpoint factor (P = .02).
Our findings suggest that altered DDR is an important mechanism for aggressive prostate cancer not only in men of European but also of African ancestry. Therefore, interrogation of entire DDR pathways is needed to fully characterize and better define genetic risk of lethal disease.
We performed a case-case study of 764 African American and European American men with lethal or indolent prostate cancer treated at 4 US hospitals. We calculated carrier frequencies of germline pathogenic or likely pathogenic sequence variants within 306 DDR genes, summarized by DDR pathway, and compared lethal cases against indolent cases using 2-sided Fisher\'s exact tests. Secondary analysis examined if carrier frequencies differed by ancestry.
Lethal cases were more likely to carry a pathogenic sequence variant in a DDR gene compared with indolent cases (18.5% vs 9.6%, P = 4.30 × 10-4), even after excluding BRCA2 (14.6% vs 9.6%, P = .04). The carrier frequency was similar among lethal cases of African (16.7% including and 15.8% excluding BRCA2) and lethal cases of European (19.3% including and 14.2% excluding BRCA2) ancestry. Three DDR pathways were statistically significantly associated with lethal disease: homologous recombination (P = .003), Fanconi anemia (P = .002), and checkpoint factor (P = .02).
Our findings suggest that altered DDR is an important mechanism for aggressive prostate cancer not only in men of European but also of African ancestry. Therefore, interrogation of entire DDR pathways is needed to fully characterize and better define genetic risk of lethal disease.
摘要：
改变的DNA损伤反应（DDR）已成为欧洲血统而非其他血统人群中侵袭性前列腺癌发展的重要机制。因为侵袭性疾病的共同机制是预期的，我们探索了大量的DDR基因和通路,以证明DDR改变有助于非裔美国人和欧美男性侵袭性前列腺癌的发展.
我们对在美国4家医院接受治疗的764名患有致死性或惰性前列腺癌的非洲裔美国人和欧洲裔美国人进行了病例-病例研究。我们计算了306个DDR基因内种系致病或可能致病序列变异的携带者频率，通过DDR途径总结，并使用双侧Fisher精确检验将致命病例与惰性病例进行了比较。二次分析检查了载波频率是否因祖先而异。
与惰性病例相比，致死病例更可能携带DDR基因中的致病序列变异（18.5％vs9.6％，P=4.30×10-4),即使在排除BRCA2(14.6%对9.6%，P=.04）。在非洲的致命病例（包括16.7％，不包括BRCA2的15.8％）和欧洲的致命病例（包括19.3％，不包括BRCA2的14.2％）祖先中，载波频率相似。3个DDR途径与致死性疾病有统计学意义：同源重组（P=0.003），范可尼贫血（P=0.002），和检查点因子(P=.02)。
我们的研究结果表明，DDR改变是侵袭性前列腺癌的重要机制，不仅在欧洲男性中，而且在非洲血统的男性中。因此,需要对整个DDR途径进行询问，以充分表征和更好地确定致命疾病的遗传风险。
我们对在美国4家医院接受治疗的764名患有致死性或惰性前列腺癌的非洲裔美国人和欧洲裔美国人进行了病例-病例研究。我们计算了306个DDR基因内种系致病或可能致病序列变异的携带者频率，通过DDR途径总结，并使用双侧Fisher精确检验将致命病例与惰性病例进行了比较。二次分析检查了载波频率是否因祖先而异。
与惰性病例相比，致死病例更可能携带DDR基因中的致病序列变异（18.5％vs9.6％，P=4.30×10-4),即使在排除BRCA2(14.6%对9.6%，P=.04）。在非洲的致命病例（包括16.7％，不包括BRCA2的15.8％）和欧洲的致命病例（包括19.3％，不包括BRCA2的14.2％）祖先中，载波频率相似。3个DDR途径与致死性疾病有统计学意义：同源重组（P=0.003），范可尼贫血（P=0.002），和检查点因子(P=.02)。
我们的研究结果表明，DDR改变是侵袭性前列腺癌的重要机制，不仅在欧洲男性中，而且在非洲血统的男性中。因此,需要对整个DDR途径进行询问，以充分表征和更好地确定致命疾病的遗传风险。
