DNA Repair Pathways and Their Association With Lethal Prostate Cancer in African American and European American Men.
DNA Repair Pathways and Their Association With Lethal Prostate Cancer in African American and European American Men.
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DOI：
10.1093/jncics/pkab097
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发表时间：
2022-03
影响因子：
4.4
通讯作者：
Kibel AS
中科院分区：
文献类型：
--
作者：
Plym A;Dióssy M;Szallasi Z;Sartor O;Silberstein J;Powell IJ;Rebbeck TR;Penney KL;Mucci LA;Pomerantz MM;Kibel AS
DNA损伤反应改变（DDR）已成为欧洲血统男性（而不是其他血统群体）发生侵袭性前列腺癌的重要机制。由于侵袭性疾病的共同机制是预期的，我们探索了一个大面板的DDR基因和途径，以证明DDR的改变有助于非洲裔美国人和欧洲裔美国人男性侵袭性前列腺癌的发展。我们对764名在4家美国医院接受治疗的非洲裔美国人和欧洲裔美国人致命性或惰性前列腺癌患者进行了病例研究。我们计算了306个DDR基因内的生殖系致病性或可能致病性序列变异的携带者频率，通过DDR途径总结，并使用双侧Fisher精确检验比较了致死病例与惰性病例。次要分析检查了载波频率是否因血统而异。与惰性病例相比，致命病例更可能携带DDR基因中的致病序列变异（18.5% vs 9.6%，P = 4.30 × 10−4），即使排除BRCA2（14.6% vs 9.6%，P = 0.04）。非洲血统致死病例（16.7%包括BRCA2，15.8%不包括BRCA2）和欧洲血统致死病例（19.3%包括BRCA2，14.2%不包括BRCA2）的携带者频率相似。三种DDR途径与致死性疾病具有统计学显著相关性：同源重组（P = .003）、范可尼贫血（P = .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，而且在非洲血统的男性。因此，需要询问整个DDR途径，以充分表征和更好地定义致命疾病的遗传风险。
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.
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DOI：
10.1002/pros.24123
发表时间：
2021-05
期刊：
The Prostate
影响因子：
--
作者：
Ledet EM;Burgess EF;Sokolova AO;Jaeger EB;Hatton W;Moses M;Miller P;Cotogno P;Layton J;Barata P;Lewis BE;Nakazawa M;Zhu J;Dellinger B;Elrefai S;Nafissi NN;Egan JB;Shore N;McKay RR;Bryce AH;Cheng HH;Antonarakis ES;Sartor O
通讯作者：
Sartor O
影响因子：
12.4
作者：
Roig, M. B.;Roset, R.;Gil-Gomez, G.
通讯作者：
Gil-Gomez, G.
影响因子：
9.8
作者：
Li, Quan;Wang, Kai
通讯作者：
Wang, Kai
影响因子：
4.6
作者：
Matejcic，Marco;Patel，Yesha;Haiman，Christopher A.
通讯作者：
Haiman，Christopher A.
影响因子：
3.5
作者：
Rantapero, Tommi;Wahlfors, Tiina;Wiklund, Fredrik
通讯作者：
Wiklund, Fredrik