[HTML][HTML] Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas

B Norquist, KA Wurz, CC Pennil, R Garcia… - Journal of clinical …, 2011 - ncbi.nlm.nih.gov
B Norquist, KA Wurz, CC Pennil, R Garcia, J Gross, W Sakai, BY Karlan, T Taniguchi
Journal of clinical oncology, 2011ncbi.nlm.nih.gov
Purpose Secondary somatic BRCA1/2 mutations may restore BRCA1/2 protein in hereditary
ovarian carcinomas. In cell lines, BRCA2 restoration mediates resistance to platinum
chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. We assessed primary
and recurrent BRCA1/2-mutated ovarian carcinomas to define the frequency of secondary
mutations and correlate these changes with clinical outcomes. Methods Neoplastic cells
were isolated with laser capture microdissection, and DNA was sequenced at the site of the …
Abstract
Purpose
Secondary somatic BRCA1/2 mutations may restore BRCA1/2 protein in hereditary ovarian carcinomas. In cell lines, BRCA2 restoration mediates resistance to platinum chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. We assessed primary and recurrent BRCA1/2-mutated ovarian carcinomas to define the frequency of secondary mutations and correlate these changes with clinical outcomes.
Methods
Neoplastic cells were isolated with laser capture microdissection, and DNA was sequenced at the site of the known germline BRCA1/2 mutation. When secondary mutations were found that restored wild-type sequence, haplotyping was performed using single nucleotide polymorphisms in tumor and paired lymphocyte DNA to rule out retention of the wild-type allele.
Results
There were 64 primary and 46 recurrent ovarian carcinomas assessed. Thirteen (28.3%) of 46 (95% CI, 17.3% to 42.6%) recurrent carcinomas had a secondary mutation compared with two (3.1%) of 64 (95% CI, 1.0% to 10.7%) primary carcinomas (P=. 0003, Fisher's exact test). Twelve (46.2%) of 26 (95% CI, 28.7% to 64.7%) platinum-resistant recurrences had secondary mutations restoring BRCA1/2, compared with one (5.3%) of 19 (95% CI, 1.2% to 24.8%) platinum-sensitive recurrences (P=. 003, Fisher's exact test). Six (66.7%) of nine (95% CI, 34.8% to 87.8%) women with prior breast carcinoma had a recurrent carcinoma with a secondary mutation, compared with six (17.1%) of 35 (95% CI, 8.2% to 32.8%) with no history of breast carcinoma (P=. 007, Fisher's exact test).
Conclusion
Secondary somatic mutations that restore BRCA1/2 in carcinomas from women with germline BRCA1/2 mutations predict resistance to platinum chemotherapy and may also predict resistance to PARP inhibitors. These mutations were detectable only in ovarian carcinomas of women whom have had previous chemotherapy, either for ovarian or breast carcinoma.
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