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

Breast cancer; Cancer genetics; RNA sequencingCáncer de mama; Genética del cáncer; Secuenciación de ARNCàncer de mama; Genètica del càncer; Seqüenciació d'ARNRecurrence 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.This work was supported by the Tumor Tissue and Biospecimen Bank and the Next Generation Sequencing Core at the University of Pennsylvania (and in particular, we appreciated the help of Dr. Jonathan Schug). We would also like to thank Akoya Biosciences for their technical expertize regarding CODEX analyses. Lastly, the RNA sequencing pipeline used for this study was based on content from Dr. Dan Beiting’s DIY Transcriptomics class at the University of Pennsylvania (Spring 2021), for which we thank him as well. Figure 6 and Supplementary Fig. 15 were created using a licensed version of BioRender. This work was supported by the Basser Center for BRCA at the University of Pennsylvania (S.M.D., K.L.N.), the Gray Foundation Team Science Award (K.L.N.), the V Foundation for Cancer Research BRCA1/2 Convergence Team Award (K.L.N.), the Breast Cancer Research Foundation (S.M.D., K.L.N.) T32 HG009495 (A.K.), Miguel Servet Program (ISCIII) [CPII19/00033] (V.S.) and Asociación Española Contra el Cáncer (A.L.G.)