Association of Inherited Mutations in DNA Repair Genes with Localized Prostate Cancer.
Association of Inherited Mutations in DNA Repair Genes with Localized Prostate Cancer.
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DOI：
10.1016/j.eururo.2021.09.029
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发表时间：
2022-06
期刊：
影响因子：
23.4
通讯作者：
Maxwell, Kara N.
中科院分区：
文献类型：
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作者：
Lee, Daniel J.;Hausler, Ryan;Le, Anh N.;Kelly, Gregory;Powers, Jacquelyn;Ding, James;Feld, Emily;Desai, Heena;Morrison, Casey;Doucette, Abigail;Gabriel, Peter;Regeneron Genetics Ctr, Marcus;Judy, Renae L.;Weaver, Joellen;Kember, Rachel;Damrauer, Scott M.;Rader, Daniel J.;Domchek, Susan M.;Narayan, Vivek;Schwartz, Lauren E.;Maxwell, Kara N.
DNA修复基因种系突变的鉴定对于前列腺癌（PrCa）患者的个性化治疗具有重要意义。在不同的学术生物库中确定与局部PrCa相关的DNA修复基因，并确定基因检测负担。对2391例局部PrCa患者进行了横断面研究。在1588名局部PrCa患者和3273名无癌男性中确定了17个DNA修复基因的遗传祖先和突变率（不包括体细胞干扰）。在生物库PrCa病例和无癌生物库和gnomAD男性之间进行了遗传决定的欧洲（EUR）和非洲（AFR）血统个体的负担测试。具有局部PrCa的AFR个体的DNA修复基因突变率低于EUR个体（1.4% vs 4.0%，p = 0.02）。局部PrCa患者的突变率与生物库和gnomAD对照组相似（EUR：4.0% vs 2.8%，p = 0.15，vs 3.1%，p = 0.04; AFR：1.4% vs 1.8%，p = 0.8，vs 2.1%，p = 0.5）。基于基因的罕见变异关联检测显示，与EUR血统的gnomAD对照相比，只有BRCA 2突变显著富集（1.0% vs 0.28%，p = 0.03）。在参与者中，21%和11%符合高风险和极高风险标准;其中，3.7%和6.2%有任何生殖系基因突变，1.0%和2.5%分别有BRCA 2突变。本研究的局限性包括对相对较小的单机构队列的分析。DNA修复基因生殖细胞突变率低，在学术生物库队列的本地化PrCa患者，特别是在个体的AFR遗传祖先。仅在高危、极高危局限性和淋巴结阳性PrCa患者中，已发表证据表明与PrCa相关的基因突变率超过2.5%。这些发现强调了局部PrCa患者风险分层的重要性，以确定合适的患者进行生殖系基因检测。在大多数发展为局限性前列腺癌的患者中，生殖系基因检测不太可能揭示遗传性DNA修复突变，无论种族如何。高风险特征增加了生殖系DNA修复突变的可能性。
Identification of germline mutations in DNA repair genes has significant implications for the personalized treatment of individuals with prostate cancer (PrCa). To determine DNA repair genes associated with localized PrCa in a diverse academic biobank and to determine genetic testing burden. A cross-sectional study of 2391 localized PrCa patients was carried out. Genetic ancestry and mutation rates (excluding somatic interference) in 17 DNA repair genes were determined in 1588 localized PrCa patients and 3273 cancer-free males. Burden testing within individuals of genetically determined European (EUR) and African (AFR) ancestry was performed between biobank PrCa cases and cancer-free biobank and gnomAD males. AFR individuals with localized PrCa had lower DNA repair gene mutation rates than EUR individuals (1.4% vs 4.0%, p = 0.02). Mutation rates in localized PrCa patients were similar to those in biobank and gnomAD controls (EUR: 4.0% vs 2.8%, p = 0.15, vs 3.1%, p = 0.04; AFR: 1.4% vs 1.8%, p = 0.8, vs 2.1%, p = 0.5). Gene-based rare variant association testing revealed that only BRCA2 mutations were significantly enriched compared with gnomAD controls of EUR ancestry (1.0% vs 0.28%, p = 0.03). Of the participants, 21% and 11% met high-risk and very-high-risk criteria; of them, 3.7% and 6.2% had any germline genetic mutation and 1.0% and 2.5% had a BRCA2 mutation, respectively. Limitations of this study include an analysis of a relatively small, single-institution cohort. DNA repair gene germline mutation rates are low in an academic biobank cohort of localized PrCa patients, particularly among individuals of AFR genetic ancestry. Mutation rates in genes with published evidence of association with PrCa exceed 2.5% only in high-risk, very-high-risk localized, and node-positive PrCa patients. These findings highlight the importance of risk stratification in localized PrCa patients to identify appropriate patients for germline genetic testing. In the majority of patients who develop localized prostate cancer, germline genetic testing is unlikely to reveal an inherited DNA repair mutation, regardless of race. High-risk features increase the possibility of a germline DNA repair mutation.
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影响因子：
2.8
作者：
Beebe-Dimmer, Jennifer L.;Zuhlke, Kimberly A.;Cooney, Kathleen A.
通讯作者：
Cooney, Kathleen A.
影响因子：
64.8
作者：
Cummings, Beryl B.;Karczewski, Konrad J.;MacArthur, Daniel G.
通讯作者：
MacArthur, Daniel G.
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
4.8
作者：
Petrovics, Gyorgy;Price, Douglas K.;Dean, Michael
通讯作者：
Dean, Michael
具有转移性cast割前列腺癌的男性的鲁卡巴里（Rucaparib）具有BRCA1或BRCA2基因改变。
DOI：
10.1200/jco.20.01035
发表时间：
2020-11-10
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Abida W;Patnaik A;Campbell D;Shapiro J;Bryce AH;McDermott R;Sautois B;Vogelzang NJ;Bambury RM;Voog E;Zhang J;Piulats JM;Ryan CJ;Merseburger AS;Daugaard G;Heidenreich A;Fizazi K;Higano CS;Krieger LE;Sternberg CN;Watkins SP;Despain D;Simmons AD;Loehr A;Dowson M;Golsorkhi T;Chowdhury S;TRITON2 investigators
通讯作者：
TRITON2 investigators