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Reversion of BRCA1/2 Germline Mutations Detected in Circulating Tumor DNA From Patients With High-Grade Serous Ovarian Cancer.
- Source :
-
Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2017 Apr 20; Vol. 35 (12), pp. 1274-1280. Date of Electronic Publication: 2017 Feb 13. - Publication Year :
- 2017
-
Abstract
- Purpose Germline BRCA1 or BRCA2 mutations in patients with high-grade serous ovarian cancer (HGSC) are associated with favorable responses to chemotherapy. However, secondary intragenic (reversion) mutations that restore protein function lead to clinically significant rates of acquired resistance. The goal of this study was to determine whether reversion mutations could be found in an unbiased manner in circulating cell-free DNA (cfDNA) to predict treatment response in HGSC. Patients and Methods Plasma and tumor samples were obtained from 30 patients with HGSC with either BRCA1 or BRCA2 germline mutation. Two cohorts were ascertained: patients with a malignancy before undergoing primary HGSC debulking surgery (n = 14) or patients at disease recurrence (n = 16). Paired tumor and plasma samples were available for most patients (24 of 30). Targeted amplicon, next-generation sequencing was performed using primers that flanked germline mutations, whose design did not rely on prior knowledge of reversion sequences. Results Five patients were identified with intragenic mutations predicted to restore BRCA1/2 open reading frames, including two patients with multiple independent reversion alleles. Reversion mutations were only detected in tumor samples from patients with recurrent disease (five of 16) and only in cfDNA from patients with a tumor-detected reversion (three of five). Findings from a rapid autopsy of a patient with multiple independent reversions indicated that reversion-allele frequency in metastatic sites is an important determinant of assay sensitivity. Abundance of tumor-derived DNA in total cell-free DNA, as measured by TP53 mutant allele frequency, also affected assay sensitivity. All patients with reversions detected in tumor-derived DNA were resistant to platin- or poly ADP ribose polymerase inhibitor-based chemotherapy. Conclusion Reversion mutations can be detected in an unbiased analysis of cfDNA, suggesting clinical utility for predicting chemotherapy response in recurrent HGSC.
- Subjects :
- Cohort Studies
Cystadenocarcinoma, Serous blood
Cystadenocarcinoma, Serous surgery
DNA, Neoplasm blood
Female
Humans
Neoplasm Grading
Neoplasm Recurrence, Local blood
Neoplasm Recurrence, Local genetics
Neoplasm Recurrence, Local pathology
Ovarian Neoplasms blood
Ovarian Neoplasms surgery
Cystadenocarcinoma, Serous genetics
DNA, Neoplasm genetics
Genes, BRCA1
Genes, BRCA2
Germ-Line Mutation
Ovarian Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1527-7755
- Volume :
- 35
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 28414925
- Full Text :
- https://doi.org/10.1200/JCO.2016.70.4627