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PMID: 41040691 已发表 · epublish 英语

Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.

medRxiv : the preprint server for health sciences ·2025-09-22

Zwimpfer TA, Fereday S, Pandey A, Ariyaratne D, Jayawardana MW, Twomey L, Laumont CM, Kennedy CJ, Bolithon A, Meagher NS, Milne K, Hamilton P, Alsop J, Antoniou AC, Au-Yeung G, Beckmann MW, Berrington de Gonzalez A, Bisinotto C, Blome F, Bodelon C, Boros J, Brand AH, Carney ME, Cazorla-Jiménez A, Chiu DS, Christie EL, Chudecka-Głaz A, Coulson P, Cushing-Haugen KL, Cybulski C, Darcy KM, David C, Davidson T, Ekici AB, Elishaev E, Emons J, Engler T, Farrell R, Fischer A, García-Closas M, Gentry-Maharaj A, Ghatage P, Glasspool R, Harter P, Hartkopf AD, Hartmann A, Heikaus S, Hernandez BY, Hettiaratchi A, Heublein S, Huntsman DG, Jimenez-Linan M, Jones ME, Kang E, Kaznowska E, Kluz T, Kommoss FKF, Konecny G, Kruitwagen RFPM, Kwon J, Lambrechts D, Lee CH, Lester J, Leung SCY, Leung Y, Linder A, Lissowska J, Loverix L, Lubiński J, Mateoiu C, McNeish IA, Moubarak M, Nelson GS, Nevins N, Olawaiye AB, Olbrecht S, Orsulic S, Osorio A, Quinn CM, Mohan GR, Ray-Coquard I, Rodríguez-Antona C, Roxburgh P, Ruebner M, Salfinger SG, Samra S, Schoemaker MJ, Sinn HP, Sonke GS, Steele L, Stewart CJR, Talhouk A, Tan A, Tarney CM, Taylor SE, Van de Vijver KK, van der Aa MA, Van Gorp T, Van Nieuwenhuysen E, van-Wagensveld L, Wahner-Hendrickson AE, Walter C, Wang C, Welz J, Wentzensen N, Wilkens LR, Winham SJ, Winterhoff B, Anglesio MS, Berchuck A, Candido Dos Reis FJ, Cohen PA, Conrads TP, Crowe P, Doherty JA, Fasching PA, Fortner RT, García MJ, Gayther SA, Goodman MT, Gronwald J, Harris HR, Heitz F, Horlings HM, Karlan BY, Kelemen LE, Maxwell GL, Menon U, Modugno F, Neuhausen SL, Schildkraut JM, Staebler A, Sundfeldt K, Swerdlow AJ, Vergote I, Wu AH, Brenton JD, Pharoah PDP, Pearce CL, Pike MC, Goode EL, Ramus SJ, Köbel M, Nelson BH, DeFazio A, Friedlander ML, Bowtell DDL, Garsed DW

摘要

BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

文献信息
期刊
medRxiv : the preprint server for health sciences
期刊简称
medRxiv
发表日期
2025-09-22
语言
英语
国家/地区
United States
NLM ID
101767986
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