Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers

• DOI: 10.1038/s41467-022-34523-y
• Publication Date: 2022-11-08T00:04:18Z
• Authors: Jennifer B. Shah; Dana Pueschl; Bradley Wubbenhorst; Mengyao Fan; John Pluta; Kurt D’Andrea; Anna P. Hubert; Jake S. Shilan; Wenting Zhou; Adam A. Kraya; Alba Llop Guevara; Catherine Ruan; Violeta Serra; Judith Balmaña; Michael Feldman; Pat J. Morin; Anupma Nayak; Kara N. Maxwell; Susan M. Domchek; Katherine L. Nath...
• Keywords: Nonsense mutation; PARP1; BRCA Mutation; Primary tumor

Abstract Recurrence is a major cause of death among BRCA1/2 mutation carriers with breast (BrCa) and ovarian cancers (OvCa). Herein we perform multi-omic sequencing on 67 paired primary recurrent BrCa OvCa from 27 to identify potential recurrence-specific drivers. PARP1 amplifications are identified in recurrences (False Discovery Rate q = 0.05), significantly overexpressed across OvCa, independent amplification status. RNA analysis finds two BRCA2 isoforms, BRCA2-201/Long BRCA2-001/Short , respectively predicted be sensitive insensitive nonsense-mediated decay. expressed more frequently associated reduced overall survival cancer (87 vs. 121 months; Hazard Ratio 2.5 [1.18–5.5]). Loss heterozygosity (LOH) status discordant 25% patient’s tumors, switching between both LOH lack found. Our study reveals multiple drivers disease mutation-associated cancer, improving our understanding tumor evolution suggesting biomarkers.