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

Research square ·2025-10-03

Garsed D, Zwimpfer T, Fereday S, Pandey A, Ariyaratne D, Jayawardana M, Twomey L, Laumont C, Kennedy C, Bolithon A, Meagher N, Milne K, Hamilton P, Alsop J, Antoniou A, Au-Yeung G, Beckmann M, de Gonzalez AB, Bisinotto C, Blome F, Bodelon C, Boros J, Brand A, Carney M, Cazorla-Jimenez A, Chiu D, Christie E, Chudecka-Glaz A, Coulson P, Cushing-Haugen K, Cybulski C, Darcy K, David C, Davidson T, Ekici A, Elishaev E, Emons J, Engler T, Farrell R, Fischer A, Garcia-Closas M, Gentry-Maharaj A, Ghatage P, Glasspool R, Harter P, Hartkopf A, Hartmann A, Heikaus S, Hernandez B, Hettiaratchi A, Heublein S, Huntsman D, Jimenez-Linan M, Jones M, Kang E, Kaznowska E, Kluz T, Kommoss F, Konecny GE, Kruitwagen R, Kwon J, Lambrechts D, Lee CH, Lester J, Leung S, Leung Y, Linder A, Lissowska J, Loverix L, Lubiński J, Mateoiu C, McNeish L, Moubarak M, Nelson G, Nevins N, Olawaiye A, Olbrecht S, Orsulic S, Osorio A, Quinn C, Mohan GR, Ray-Coquard I, Rodriguez-Antona C, Roxburgh P, Rübner M, Salfinger S, Samra S, Schoemaker M, Sinn HP, Sonke G, Steele L, Stewart C, Talhouk A, Tan A, Tarney C, Taylor S, Van de Vijver K, der Aa MA, Van Gorp T, Van Nieuwenhuysen E, van Wagensveld L, Wahner-Hendrickson A, Walter C, Wang C, Welz J, Wentzensen N, Wilkens L, Winham S, Winterhoff B, Anglesio M, Berchuck A, do Reis FC, Cohen P, Conrads T, Crowe P, Doherty J, Fasching P, Fortner R, Garcia M, Gayther S, Goodman M, Gronwald J, Harris H, Heitz F, Horlings H, Karlan B, Kelemen L, Maxwell G, Menon U, Modugno F, Neuhausen S, Schildkraut J, Staebler A, Sundfeldt K, Swedlow A, Vergote I, Wu A, Brenton J, Pharoah P, Pearce C, Pike M, Goode E, Ramus S, Köbel M, Nelson B, DeFazio A, Friedlander M, Bowtell D

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

Research square

期刊简称

Res Sq

ISSN

2693-5015

DOI

10.21203/rs.3.rs-7572112/v1

发表日期

2025-10-03

语言

英语

国家/地区

United States

NLM ID

101768035

外部链接

PubMed 原文 DOI: 10.21203/rs.3.rs-7572112/v1

分析服务

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

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