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 and Katherine L. Nathanson ()
Additional contact information
Jennifer B. Shah: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania
Dana Pueschl: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania
Bradley Wubbenhorst: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania
Mengyao Fan: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania
John Pluta: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania
Kurt D’Andrea: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania
Anna P. Hubert: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania
Jake S. Shilan: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania
Wenting Zhou: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania
Adam A. Kraya: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania
Alba Llop Guevara: Vall d’Hebron Institut d’Oncologia
Catherine Ruan: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania
Violeta Serra: Vall d’Hebron Institut d’Oncologia
Judith Balmaña: Vall d’Hebron Institut d’Oncologia
Michael Feldman: Perelman School of Medicine at the University of Pennsylvania
Pat J. Morin: Perelman School of Medicine at the University of Pennsylvania
Anupma Nayak: Perelman School of Medicine at the University of Pennsylvania
Kara N. Maxwell: Perelman School of Medicine at the University of Pennsylvania
Susan M. Domchek: Perelman School of Medicine at the University of Pennsylvania
Katherine L. Nathanson: Department of Medicine, Perelman School of Medicine at the University of Pennsylvania

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34523-y

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