Association of BRCA1 and BRCA2 Mutations With Survival, Chemotherapy Sensitivity, and Gene Mutator Phenotype in Patients With Ovarian Cancer

Department of Obstetrics and Gynaecology, University of Helsinki, Helsinki, Uusimaa, Finland
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 10/2011; 306(14):1557-65. DOI: 10.1001/jama.2011.1456
Source: PubMed


Attempts to determine the clinical significance of BRCA1/2 mutations in ovarian cancer have produced conflicting results.
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.
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.
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 = .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).
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.

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Available from: Ken Hess, Jul 22, 2014
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    • "The phenotype of BRCA-deficient ovarian cancers is of enhanced survival [20] [21] [22] [23], largely attributed to a better response to platinum chemotherapy. This phenotype of enhanced survival appears to also extend to ovarian cancers with deficiencies in other homologous recombination genes [24]. "
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    • "We then used drug-free survival analysis to evaluate the possibility of promoter methylation of lincRNAs as drug targets. The drug-free interval was defined as from the end of chemotherapeutic drug treatment to the date of progression or recurrence or last contact (censored) (56). XLOC_007617 was a lincRNA that showed positive correlation between its methylation and drug-free survival in UCEC (log-rank P = 0.013; Supplementary Figure S8). "
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