Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers
Shah, Jennifer B. (University of Pennsylvania)
Pueschl, Dana (University of Pennsylvania)
Wubbenhorst, Bradley (University of Pennsylvania)
Fan, Mengyao (University of Pennsylvania)
Pluta, John (University of Pennsylvania)
D'Andrea, Kurt (University of Pennsylvania)
Hubert, Anna P. (University of Pennsylvania)
Shilan, Jake S. (University of Pennsylvania)
Zhou, Wenting (University of Pennsylvania)
Kraya, Adam A. (University of Pennsylvania)
Llop Guevara, Alba (Vall d'Hebron Institut d'Oncologia)
Ruan, Catherine (University of Pennsylvania. Perelman School of Medicine)
Serra, Violeta (Vall d'Hebron Institut d'Oncologia)
Balmaña Gelpí, Judith (Vall d'Hebron Institut d'Oncologia)
Feldman, Michael (University of Pennsylvania)
Morin, Pat J. (University of Pennsylvania)
Nayak, Anupma (University of Pennsylvania)
Maxwell, Kara N. (University of Pennsylvania)
Domchek, Susan M. (University of Pennsylvania)
Nathanson, Katherine L. (University of Pennsylvania)
Universitat Autònoma de Barcelona

Data:	2022
Resum:	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. Carriers of pathogenic BRCA1/2 variants have a higher risk of breast and ovarian cancers, which recur frequently. Here, the authors sequence primary and recurrent tumours of BRCA1/2 mutation carriers, finding PARP1 amplifications, differential BRCA2 isoform usage, and discordant loss of heterozygosity that are associated with recurrence.
Ajuts:	Instituto de Salud Carlos III CPII19/00033
Nota:	Altres ajuts: U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) HG009495
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cancer genomics ; Cancer genetics ; Breast cancer ; RNA sequencing ; Ovarian cancer
Publicat a:	Nature communications, Vol. 13 (november 2022) , ISSN 2041-1723

DOI: 10.1038/s41467-022-34523-y
PMID: 36344544

19 p, 3.3 MB

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