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Supp Table 4 from Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

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posted on 2023-04-03, 21:23 authored by Olga Kondrashova, Minh Nguyen, Kristy Shield-Artin, Anna V. Tinker, Nelson N.H. Teng, Maria I. Harrell, Michael J. Kuiper, Gwo-Yaw Ho, Holly Barker, Maria Jasin, Rohit Prakash, Elizabeth M. Kass, Meghan R. Sullivan, Gregory J. Brunette, Kara A. Bernstein, Robert L. Coleman, Anne Floquet, Michael Friedlander, Ganessan Kichenadasse, David M. O'Malley, Amit Oza, James Sun, Liliane Robillard, Lara Maloney, David Bowtell, Heidi Giordano, Matthew J. Wakefield, Scott H. Kaufmann, Andrew D. Simmons, Thomas C. Harding, Mitch Raponi, Iain A. McNeish, Elizabeth M. Swisher, Kevin K. Lin, Clare L. Scott

Copy number estimation by SNP array in the archival tumor tissue of the patient identified to have a germline RAD51C mutation (c.577C

Funding

NHMRC

Cancer Council Victoria

Victorian Cancer Agency

CRC

Stafford Fox Medical Research

National Institutes of Health

Wendy Feuer Ovarian Cancer Research

Australian Cancer Research Foundation

V Foundation for Cancer Research

Stand Up To Cancer

American Association for Cancer Research

NIH

Ovarian Cancer Research

Ovarian Cancer National Alliance

National Ovarian Cancer Coalition Dream Team Translational Research

Victorian Government

U.S. Army Medical Research and Materiel Command

Cancer Council Tasmania

National Health and Medical Research Council

History

ARTICLE ABSTRACT

High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in BRCA1, RAD51C, or RAD51D was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations.Significance: Analyses of primary and secondary mutations in RAD51C and RAD51D provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies. Cancer Discov; 7(9); 984–98. ©2017 AACR.See related commentary by Domchek, p. 937.See related article by Quigley et al., p. 999.See related article by Goodall et al., p. 1006.This article is highlighted in the In This Issue feature, p. 920

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Keywords

Carcinogenesis DNA damage and repair Oncogenes & Tumor Suppressors BRCA family

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