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

Barbara Norquist1, Kaitlyn A Wurz, Christopher C Pennil

  • 1University of Washington Medical Center, Department of Obstetrics and Gynecology, Box 356460, Seattle, WA, USA.

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
|June 29, 2011
PubMed
Abstract

Insights

Secondary mutations restoring BRCA1/2 protein in ovarian cancer can emerge after chemotherapy, leading to resistance against platinum drugs and PARP inhibitors. These resistance mutations were observed in recurrent tumors, particularly in platinum-resistant cases.

Area of Science:

  • Oncology
  • Genetics
  • Cancer Research

Background:

  • Hereditary ovarian carcinomas often harbor germline mutations in BRCA1/2 genes.
  • Secondary somatic mutations can arise, potentially restoring BRCA1/2 protein function.
  • BRCA2 restoration in cell lines is linked to resistance against platinum chemotherapy and PARP inhibitors.

Purpose of the Study:

  • To determine the frequency of secondary BRCA1/2 mutations in primary and recurrent ovarian carcinomas.
  • To correlate these secondary mutations with clinical outcomes, including chemotherapy resistance.

Main Methods:

  • Laser capture microdissection was used to isolate neoplastic cells from tumors.
  • DNA sequencing was performed at the site of the germline BRCA1/2 mutation.
  • Haplotyping using single nucleotide polymorphisms differentiated secondary mutations from retained wild-type alleles.

Main Results:

  • Secondary mutations restoring BRCA1/2 were found in 28.3% of recurrent ovarian carcinomas versus 3.1% of primary ones.
  • Among platinum-resistant recurrences, 46.2% had secondary BRCA1/2-restoring mutations, compared to 5.3% in platinum-sensitive recurrences.
  • Women with a history of breast carcinoma were more likely to have recurrent ovarian carcinoma with secondary mutations (66.7% vs. 17.1%).

Conclusions:

  • Secondary somatic mutations restoring BRCA1/2 predict resistance to platinum chemotherapy and potentially PARP inhibitors in ovarian cancer.
  • These resistance-mediating mutations were primarily detected in ovarian carcinomas from patients with prior chemotherapy exposure.
  • The findings highlight a mechanism of acquired resistance in BRCA1/2-mutated ovarian cancers.

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