Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Experimental Therapeutics Group, Vall d'Hebron Institut d'Oncologia, Barcelona, Spain.
Nat Commun. 2022 Nov 7;13(1):6728. doi: 10.1038/s41467-022-34523-y.
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.
复发是 BRCA1/2 突变携带者乳腺癌 (BrCa) 和卵巢癌 (OvCa) 死亡的主要原因。在此，我们对 27 名 BRCA1/2 突变携带者的 67 对原发性和复发性 BrCa 和 OvCa 进行了多组学测序，以鉴定潜在的复发特异性驱动因素。在复发中鉴定到 PARP1 扩增（错误发现率 q = 0.05），并且 PARP1 在原发性 BrCa 和复发性 BrCa 和 OvCa 中均显著过表达，与扩增状态无关。RNA 测序分析发现了两种 BRCA2 异构体，BRCA2-201/Long 和 BRCA2-001/Short，分别预测对无义介导的衰变敏感和不敏感。BRCA2-001/Short 在复发性肿瘤中表达更频繁，与乳腺癌的总生存期缩短相关（87 与 121 个月；风险比 = 2.5 [1.18-5.5]）。在 25%的患者的原发性和复发性肿瘤中存在杂合性缺失 (LOH) 状态不一致，发现 LOH 和缺乏 LOH 之间的转换。我们的研究揭示了 BRCA1/2 突变相关癌症中复发性疾病的多个潜在驱动因素，提高了我们对肿瘤进化的理解，并提出了潜在的生物标志物。
