Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
JAMA. 2011 Oct 12;306(14):1557-65. doi: 10.1001/jama.2011.1456.
CONTEXT: Attempts to determine the clinical significance of BRCA1/2 mutations in ovarian cancer have produced conflicting results. OBJECTIVE: To determine the relationships between BRCA1/2 deficiency (ie, mutation and promoter hypermethylation) and overall survival (OS), progression-free survival (PFS), chemotherapy response, and whole-exome mutation rate in ovarian cancer. DESIGN, SETTING, AND PATIENTS: Observational study of multidimensional genomics and clinical data on 316 high-grade serous ovarian cancer cases that were made public between 2009 and 2010 via The Cancer Genome Atlas project. MAIN OUTCOME MEASURES: OS and PFS rates (primary outcomes) and chemotherapy response (secondary outcome). RESULTS: BRCA2 mutations (29 cases) were associated with significantly better OS (adjusted hazard ratio [HR], 0.33; 95% CI, 0.16-0.69; P = .003 and 5-year OS, 61% for BRCA2-mutated vs 25% for BRCA wild-type cases) and PFS (adjusted HR, 0.40; 95% CI, 0.22-0.74; P = .004 and 3-year PFS, 44% for BRCA2-mutated vs 16% for BRCA wild-type cases), whereas neither BRCA1 mutations (37 cases) nor BRCA1 methylation (33 cases) was associated with prognosis. Moreover, BRCA2 mutations were associated with a significantly higher primary chemotherapy sensitivity rate (100% for BRCA2-mutated vs 82% [P = .02] and 80% [P = .05] for BRCA wild-type and BRCA1-mutated cases, respectively) and longer platinum-free duration (median platinum-free duration, 18.0 months for BRCA2-mutated vs 11.7 [P = .02] and 12.5 [P = .04] months for BRCA wild-type and BRCA1-mutated cases, respectively). BRCA2-mutated, but not BRCA1-mutated cases, exhibited a "mutator phenotype" by containing significantly more mutations than BRCA wild-type cases across the whole exome (median mutation number per sample, 84 for BRCA2-mutated vs 52 for BRCA wild-type cases, false discovery rate <0.1). CONCLUSION: Among women with high-grade serous ovarian cancer, BRCA2 mutation, but not BRCA1 deficiency, was associated with improved survival, improved chemotherapy response, and genome instability compared with BRCA wild-type.
背景：试图确定 BRCA1/2 突变在卵巢癌中的临床意义产生了相互矛盾的结果。
目的：确定 BRCA1/2 缺陷（即突变和启动子甲基化）与卵巢癌患者的总生存期（OS）、无进展生存期（PFS）、化疗反应和全外显子突变率之间的关系。
设计、地点和患者：通过癌症基因组图谱项目，对 2009 年至 2010 年间公开的 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观察性研究。
主要观察指标：OS 和 PFS 率（主要结局）和化疗反应（次要结局）。
结果：BRCA2 突变（29 例）与显著改善的 OS（调整后的危险比 [HR]，0.33；95%CI，0.16-0.69；P=0.003 和 5 年 OS，BRCA2 突变患者为 61%，BRCA 野生型患者为 25%）和 PFS（调整后的 HR，0.40；95%CI，0.22-0.74；P=0.004 和 3 年 PFS，BRCA2 突变患者为 44%，BRCA 野生型患者为 16%）相关，而 BRCA1 突变（37 例）或 BRCA1 甲基化（33 例）与预后无关。此外，BRCA2 突变与显著更高的原发性化疗敏感性率相关（BRCA2 突变患者为 100%，BRCA 野生型和 BRCA1 突变患者分别为 82%[P=0.02]和 80%[P=0.05]）和更长的铂无进展期（BRCA2 突变患者的中位铂无进展期为 18.0 个月，BRCA 野生型和 BRCA1 突变患者分别为 11.7[P=0.02]和 12.5[P=0.04]个月）。BRCA2 突变的卵巢癌患者（而非 BRCA1 突变的卵巢癌患者）与 BRCA 野生型患者相比，在整个外显子中表现出明显更多的突变，具有“突变体表型”（每个样本的中位突变数，BRCA2 突变患者为 84，BRCA 野生型患者为 52，假发现率<0.1）。
结论：在患有高级别浆液性卵巢癌的女性中，与 BRCA 野生型相比，BRCA2 突变与改善的生存、改善的化疗反应和基因组不稳定性相关，但 BRCA1 缺乏与生存改善无关。
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