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

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. Nathanson

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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

Original languageEnglish
Article number6728
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

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