Inherited Mutations in Women With Ovarian Carcinoma.
Inherited Mutations in Women With Ovarian Carcinoma.
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DOI：
10.1001/jamaoncol.2015.5495
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发表时间：
2016-04
期刊：
影响因子：
28.4
通讯作者：
Birrer MJ
中科院分区：
文献类型：
--
作者：
Norquist BM;Harrell MI;Brady MF;Walsh T;Lee MK;Gulsuner S;Bernards SS;Casadei S;Yi Q;Burger RA;Chan JK;Davidson SA;Mannel RS;DiSilvestro PA;Lankes HA;Ramirez NC;King MC;Swisher EM;Birrer MJ
BRCA1和BRCA2的种系突变在卵巢癌、输卵管癌和腹膜癌（OC）患者中相对常见，导致这些癌症的终生风险大大增加，但其他基因遗传突变的频率和相关性尚未得到很好的表征。目的：确定癌相关基因种系突变的频率和重要性。研究对象来自两项新诊断的晚期卵巢癌（GOG 218和GOG 262）的III期临床试验，以及一个大学妇科肿瘤组织库。使用靶向捕获和多重测序法BROCA对OC女性的种系DNA进行测序。参与NRG肿瘤学研究的转诊中心，以及大学妇科肿瘤学实践（UW）。研究人群为1915名在OC诊断时具有可用种系DNA的OC女性，未选择年龄或家族史（GOG 218， N=788; GOG 262， N=557； UW， N=570）。将OC的突变频率与NHLBI GO外显子组测序项目（ESP）和外显子组聚集联盟（ExAC）进行比较。通过突变状态评估临床特征和生存率。在1915名受试者中，280人（15%）有BRCA1（182）或BRCA2（98）突变，8人（0.4%）有DNA错配修复（MMR）基因突变。BRIP1（26个）、RAD51C（11个）、RAD51D（11个）、PALB2（12个）和BARD1（4个）的突变在OC患者中比在ESP或ExAC中更常见，总共有3.3%的患者存在突变。人种、组织学亚型和疾病部位不能预测突变频率。突变状态影响生存，特别是BRCA2突变携带者，无进展生存的HR为0.60 (95% CI 0.45 - 0.79, p<0.001)， GOG患者总生存的HR为0.39 （95% CI 0.25 - 0.60, p<0.001）。总共有347/1915 (18%)OC患者携带与OC风险相关的致病种系突变基因。PALB2和BARD1是怀疑的OC基因，加上已建立的OC基因（BRCA1、BRCA2、BRIP1、RAD51C、RAD51D、MSH2、MLH1、PMS2和MSH6），怀疑导致遗传性OC的基因总数达到11个。
Germline mutations in BRCA1 and BRCA2 are relatively common in women with ovarian, fallopian tube, and peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency and relevance of inherited mutations in other genes is less well characterized. To determine the frequency and importance of germline mutations in cancer-associated genes in OC. Subjects were ascertained from two phase III clinical trials in newly diagnosed advanced stage OC (GOG 218 and GOG 262), and a university-based gynecologic oncology tissue bank. Germline DNA was sequenced from women with OC using the targeted capture and multiplex sequencing assay BROCA. Referral centers participating in NRG Oncology studies, and a University-based gynecologic oncology practice (UW). The study population was 1915 women with OC with available germline DNA, unselected for age or family history, enrolled at the time of OC diagnosis (GOG 218, N=788; GOG 262, N=557; UW, N=570). Mutation frequencies in OC were compared to the NHLBI GO Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC). Clinical characteristics and survival were assessed by mutation status. Of 1915 subjects, 280 (15%) had mutations in BRCA1 (182), or BRCA2 (98) and 8 (0.4%) had mutations in DNA mismatch repair (MMR) genes. Mutations in BRIP1 (26), RAD51C (11), RAD51D (11), PALB2 (12) and BARD1 (4), were significantly more common in OC patients than in the ESP or ExAC, and in total were present in 3.3% of patients. Race, histologic subtype, and disease site were not predictive of mutation frequency. Mutation status affected survival, in particular for BRCA2 mutation carriers with HR 0.60 (95% CI 0.45 – 0.79, p<0.001) for progression-free survival, and HR 0.39 (95% CI 0.25 – 0.60, p<0.001) for overall survival in the GOG patients. In total, 347/1915 (18%) OC patients carried pathogenic germline mutations in genes associated with OC risk. PALB2 and BARD1 are suspected OC genes and together with established OC genes (BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH2, MLH1, PMS2, and MSH6) bring the total number of genes suspected to cause hereditary OC to 11.