Abstract
Objective
Our objective was to determine the rate of BRCA1/2 deficiency in platinum-sensitive and platinum-resistant tumors from a cohort of unselect
patients with advanced epithelial ovarian cancer (EOH).
Methods
BRCA1/2 mutation analysis was performed in 29 patients with platinum-sensitive EOC and 24
patients with platinum-resistant disease. Germline DNA was analyzed in mutation carriers
when normal tissue was available. BRCA expression was ascertained by quantitative
rt-PCR. Associations between BRCA mutation status and expression levels and parameters of platinum response were analyzed.
Results
Fifteen of 53 (28.3%) EOC tumors had BRCA1/2 mutations. Twelve mutations were in BRCA1, while 3 involved BRCA2. Of the 12 mutation-carriers with normal tissue available for DNA analyses, 33.3%
of the mutations were found to be somatic. Three mutations were novel. The majority
of BRCA mutations (73%) were identified in patients with platinum-sensitive disease. In total,
38% of platinum-sensitive tumors were found to have a BRCA mutation, compared to 17% of the platinum-resistant patients. A statistical trend
toward platinum-sensitive disease was seen in BRCA mutation carriers (p=0.079). Nineteen (36%) study patients had some form of BRCA deficiency, and these patients were less likely to have platinum-resistant tumors
(OR=0.29; p value=0.048).
Conclusions
BRCA mutations occurred more frequently in platinum-sensitive EOC than platinum-resistant
disease. The high overall frequency of BRCA deficiency in EOC underscores the importance of tumor profiling as therapies targeting
the DNA repair pathway are being investigated.
Highlights
- BRCA mutations occur in a high percentage of advanced stage epithelial ovarian cancers.
- BRCA deficiency may define a patient population who will benefit from PARP therapy.
- Three novel BRCA mutations were discovered in this patient population.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Gynecologic OncologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cancer Statistics, 2010.CA Cancer J Clin. 2010; 60: 277-300
- Prognostic factors for stage II epithelial ovarian cancer: a gynecologic oncology group study.J Clin Oncol. 2007; 25: 3621-3627
- Phase III Trial of Carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a gynecologic oncology group study.J Clin Oncol. 2003; 21: 3194-3200
- Evaluation of new platinum-based treatment regimens in advanced-stage Ovarian Cancer: a phase III trial of the gynecologic cancer intergroup.J Clin Oncol. 2009; 27: 1419-1425
- Intraperitoneal cisplatin and paclitaxel in ovarian cancer.N Engl J Med. 2006; 354: 34-43
- Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada.J Natl Cancer Inst. 2006; 98: 1694-1706
- Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer.Am J Hum Genet. 2001; 68: 700-710
- Characterization of BRCA1 and BRCA2 mutations in a large United States sample.J Clin Oncol. 2006; 24: 863-871
- Contribution of BRCA1 and BRCA2 to Familial ovarian cancer: a gynecologic oncology group study.Gynecol Oncol. 2002; 85: 255-259
- BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases.Cancer. 2005; 102: 2807-2816
- Somatic mutations in BRCA1 and BRCA2 could expand the number if patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer.J Clin Oncol. 2010; 28: 3570-3576
- Effect of BRCA1/2 mutations on long tern survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer.J Clin Oncol. 2008; 26: 20-25
- Effect of BRCA mutations on the length of survival in epithelial ovarian tumors.J Clin Oncol. 2002; 20: 463-466
- BRCA1 expression in a large series of sporadic ovarian carcinomas: a Gynecologic Oncology Group study.Int J Gynecol Oncol. 2006; 16: 166-171
- The DNA repair proteins BRCA1 and ERCC1 as predictive markers in sporadic ovarian cancer.Int J Cancer. 2009; 124: 806-815
- Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer.JAMA. 2011; 306: 1557-1565
- Sporadic epithelial ovarian cancer: clinical relevance of the BRCA1 inhibition in the DNA damage and repair pathway.J Clin Oncol. 2008; 26: 3259-3267
- Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas.Mol Cancer. 2009; 8: 1-11
- Functions of BRCA1 and BRCA2 in the biological response to DNA damage.J Cell Sci. 2001; 114: 3591-3598
- Accumulation of p53 protein is frequent in ovarian cancers associated with BRCA1 and BRCA2 germline mutations.J Clin Pathol. 1999; 52: 372-375
- BRCA1 and p53 protein expression in cultured ovarian surface epithelial cells derived from women with and without BRCA1 germline mutation.Arch Gynecol Obstet. 2006; 274: 327-331
- Frequent loss of BRCA1 mRNA and protein expression in sporadic ovarian cancer.Int J Cancer. 2000; 87: 317-321
- BRCAness syndrome in ovarian cancer: a case control study describing clinical feature and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations.J Clin Oncol. 2008; 26: 5530-5536
- Gene espression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer.J Clin Oncol. 2010; 28: 3555-3561
- BRCA1 and implications for response to chemotherapy in ovarian cancer.Gynecol Oncol. 2009; 113: 134-142
- Secondary mutations of BRCA1/2 and drug resistance.Cancer Sci. 2011; 102: 663-669
- Epigenetic factors controlling BRCA1 and BRCA2 genes in sporadic ovarian cancer.Cancer Res. 2002; 62: 4151-4156
- Inhibition if poly(ADP-Ribose) polymerase in tumors from BRCA mutation carriers.N Engl J Med. 2009; 361: 123-134
- Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval.J Clin Oncol. 2010; 28: 2512-2519
- PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer.F1000 Biol Rep. 2010; 2: 1-4
- Integrated genomic analysis of ovarian carcinoma.Nature. 2011; 474: 609-615
- The molecular pathogenesis of hereditary ovarian carcinoma.Cancer. 2010; 116: 5261-5271
- High resolution analysis of BRCA1 promoter methylation in ovarian tumors.Cancer Genet Cytogenet. 2005; 159: 114-122
- COSMIC: mining complete cancer genomics in the Catalogue of Somatic Mutations in Cancer.Nucleic Acids Res. 2011; 39 (20): D945-D950
Article info
Publication history
Accepted:
March 5,
2012
Received:
November 22,
2011
Identification
Copyright
© 2012 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
