Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer.
Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer.
复制标题
DOI：
10.1001/jama.2011.1456
复制
发表时间：
2011-10-12
影响因子：
120.7
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
--
作者：
Yang, Da;Khan, Sofia;Sun, Yan;Hess, Kenneth;Shmulevich, Ilya;Sood, Anil K.;Zhang, Wei
确定BRCA1/2突变在卵巢癌（OvCa）中的临床意义的尝试产生了相互矛盾的结果。
为了确定BRCA1/2缺陷（即突变和启动子高甲基化）与卵巢癌的总生存期（OS）、无进展生存期（PFS）、化疗反应以及全外显子组突变率之间的关系。
对2009年至2010年通过癌症基因组图谱项目公开的316例高级别浆液性卵巢癌病例的多维基因组学和临床数据进行的观察性研究。
总生存期和无进展生存期率（主要结果）以及化疗反应（次要结果）。
BRCA2突变（29例）与显著更好的总生存期（校正风险比[HR]，0.33；95%置信区间，0.16 - 0.69，P = 0.003；BRCA2突变者5年总生存期为61%，而BRCA野生型[wt]病例为25%）和无进展生存期（校正HR，0.40；95%置信区间，0.22 - 0.74，P = 0.004；BRCA2突变者3年无进展生存期为44%，而BRCA野生型病例为16%）相关，而BRCA1突变（37例）和BRCA1甲基化（33例）均与预后无关。此外，BRCA2突变与显著更高的初始化疗敏感性率相关（BRCA2突变者为100%，而BRCA野生型和BRCA1突变病例分别为82%[P = 0.02]和80%[P = 0.05]）以及更长的无铂间期（中位无铂间期：BRCA2突变者为18.0个月，而BRCA野生型和BRCA1突变病例分别为11.7个月[P = 0.02]和12.5个月[P = 0.04]）。进一步研究显示，BRCA2突变而非BRCA1突变的病例呈现出“突变体表型”，在全外显子组中比BRCA野生型病例包含显著更多的突变（每个样本的中位突变数：BRCA2突变者为84个，而BRCA野生型病例为52个，错误发现率<0.1）。
与BRCA野生型相比，BRCA2突变而非BRCA1缺陷与生存期改善、化疗反应以及基因组不稳定性相关。
Attempts to determine the clinical significance of BRCA1/2 mutations in ovarian cancer (OvCa) have produced conflicting results. To determine the relationships between BRCA1/2 deficiency (i.e., mutation and promoter hypermethylation) and overall survival (OS), progression-free survival (PFS), chemotherapy response, and whole exome mutation rate in OvCa. Observational study of multidimensional genomics and clinical data on 316 high-grade serous OvCa cases that were made public between 2009 and 2010 via The Cancer Genome Atlas project. OS and PFS rates (primary outcomes) and chemotherapy response (secondary outcome). BRCA2 mutations (29 cases) were associated with significantly better OS (adjusted hazard ratio [HR], 0.33; 95% CI, 0.16–0.69, P=0.003; 5-year OS: 61% for BRCA2 mutated vs. 25% for BRCA wild-type [wt] cases) and PFS (adjusted HR, 0.40; 95% CI, 0.22–0.74, P=0.004; 3-year PFS: 44% for BRCA2 mutated vs. 16% for BRCA wt cases), whereas neither BRCA1 mutations (37 cases) nor BRCA1 methylation (33 cases) were associated with prognosis. Moreover, BRCA2 mutations were associated with a significantly higher primary chemotherapy sensitivity rate (100% for BRCA2 mutated vs. 82% [P=0.02] and 80% [P=0.05] for BRCA wt and BRCA1 mutated cases, respectively) and longer platinum-free duration (median platinum-free duration: 18.0 months for BRCA2 mutated vs. 11.7 [P=0.02] and 12.5 [P=0.04] months for BRCA wt and BRCA1 mutated cases, respectively). Further investigation revealed that BRCA2 mutated, but not BRCA1 mutated cases, exhibited a “mutator phenotype” by containing significantly more mutations than BRCA wt cases across the whole exome (median mutation number per sample: 84 for BRCA2 mutated vs. 52 for BRCA wt cases, false-discovery rate <0.1). BRCA2 mutation, but not BRCA1 deficiency, is associated with improved survival, chemotherapy response, and genome instability compared with BRCA wild-type.
登录
查看更多内容
影响因子：
16.8
作者：
Kim, Hongtae;Huang, Jun;Chen, Junjie
通讯作者：
Chen, Junjie
DOI：
10.1093/jnci/94.18.1365
发表时间：
2002-09-18
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Brose, MS;Rebbeck, TR;Weber, BL
通讯作者：
Weber, BL
影响因子：
16
作者：
Davies, AA;Masson, JY;West, SC
通讯作者：
West, SC
影响因子：
6.2
作者：
Cass, I;Baldwin, RL;Karlan, BY
通讯作者：
Karlan, BY
影响因子：
64.5
作者：
Joukov, Vladimir;Groen, Aaron C.;Livingston, David M.
通讯作者：
Livingston, David M.