Germline and Somatic Mutations in Homologous Recombination Genes Predict Platinum Response and Survival in Ovarian, Fallopian Tube, and Peritoneal Carcinomas

By K. Pennington, T. Walsh, M. Harrell, Ming K. Lee, C. Pennil, M. Rendi, A. Thornton, B. Norquist, S. Casadei, A. Nord and 6 more. Clinical Cancer Research, 2013

928 citations recorded by the source corpus.

Purpose: Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain. Experimental Design: Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway. Results: Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation. Conclusions: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials. Clin Cancer Res; 20(3); 764–75. ©2013 AACR.

Subfields: Genetics, Oncology, Reproductive Medicine

View Paper: https://www.semanticscholar.org/paper/ac62c6f1986b6638148dbd4998d0406fc54659e2

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Citations in the corpus

ESMO–ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease (2019, background): “[49] looked at somatic and germline mutations in 13 HR genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, RAD51D).”
Inherited Mutations in Women with Ovarian Carcinoma (2016, neutral): “RESULTS Overall, the median (range) age at diagnosis was 60 (28-91) years in patients recruited from UW and 61 (23-87) years in patients recruited from the GOG trials.”
ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease†. (2019, background): “successful in predicting platinum sensitivity at primary treatment than at relapse.(49) Other potentially important mutations include CDK12, loss of which may induce an HRD phenotype,(50) although”
The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded. (2016, background): “As previously noted, the subset of women with HGSCs called the SET variant may have a more favorable prognosis than women with the usual type of HGSC, because these tumors are more sensitive to chemotherapy, particularly PARP therapy.(104) The mechanism for this increase in chemosensitivity is thoug”
Homologous recombination deficiency: Exploiting the fundamental vulnerability of ovarian cancer (2015, background): “Although these alterations are most commonly encountered in high-grade serous histology, nonserous histologies, including clear-cell, endometrioid, and carcinosarcomas, have also been shown to harbor such alterations (22).”
Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer (2019, neutral): “Hypomagnesemia 98 (26) 10 (3) 94 (25) 5 (1) 84 (22) 3 (1)”