biostudies-literatureUnknownZwimpfer TANCRR NIH HHSNCI NIH HHS<i>BRCA</i>-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 <i>BRCA</i>-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with <i>BRCA</i>-deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one <i>BRCA</i>-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with <i>BRCA1</i>-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with <i>BRCA2</i>-deficient HGSC and loss of <i>NF1</i> survived twice as longmedRxiv : the preprint server for health sciences2025.09.17.25335919https://www.ebi.ac.uk/biostudies/studies/S-EPMC12486008biostudies-literatureBeyond <i>BRCA</i> deficiency: Clinical and molecular predictors of survival in patients with <i>BRCA</i>-deficient tubo-ovarian high-grade serous carcinoma.PMC12486008R21 CA267050R01 CA172404P50 CA136393R01 CA248288P30 CA015083K07 CA080668R01 CA168758M01 RR000056R01 CA095023Heitz FKaznowska EKobel MBoros JLubinski JCohen PAWelz JNelson BHGarsed DWOlbrecht SMohan GRGronwald Jvan-Wagensveld LAlsop JGentry-Maharaj AJones MESalfinger SGWalter CCrowe PEkici ABRodriguez-Antona CKonecny GChiu DSStaebler ADavid CVan Gorp TKelemen LEZwimpfer TAOrsulic SLester JFischer ABolithon AModugno FNeuhausen SLHeikaus SJimenez-Linan MPearce CLFortner RTKarlan BYHeublein SGayther SAFriedlander MLMeagher NSHamilton PRoxburgh PTalhouk ABowtell DDLWinterhoff BOlawaiye ABConrads TPHorlings HMSundfeldt KVan Nieuwenhuysen ELoverix LHuntsman DGSchildkraut JMCushing-Haugen KLCandido Dos Reis FJCoulson PKwon JGarcia MJGoodman MTWilkens LRLambrechts Dvan der Aa MAWentzensen NLee CHStewart CJRBodelon CBlome FWu AHLaumont CMTaylor SECybulski CSamra SGarcia-Closas MKennedy CJWang CEmons JAntoniou ACWahner-Hendrickson AEBisinotto CHartkopf ADEngler TLinder APharoah PDPKruitwagen RFPMKang EPike MCHarter PWinham SJSwerdlow AJTwomey LQuinn CMSinn HPSchoemaker MJDavidson TTarney CMFereday SMaxwell GLSteele LHettiaratchi AFasching PARay-Coquard ITan ANelson GSChristie ELNevins NCarney MEJayawardana MWVan de Vijver KKHernandez BYKommoss FKFKluz TBerchuck AMilne KFarrell RDarcy KMDoherty JALeung SCYGhatage PMenon UBrand AHMateoiu CBeckmann MWRamus SJHarris HRPandey ASonke GSMoubarak MAriyaratne DChudecka-Glaz ADeFazio ABerrington de Gonzalez AOsorio ACazorla-Jimenez AHartmann AVergote IRuebner MBrenton JDElishaev EGlasspool RAnglesio MSMcNeish IAAu-Yeung GLeung YLissowska JGoode ELfalseBeyond <i>BRCA</i> deficiency: Clinical and molecular predictors of survival in patients with <i>BRCA</i>-deficient tubo-ovarian high-grade serous carcinoma.<i>BRCA</i>-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 <i>BRCA</i>-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with <i>BRCA</i>-deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one <i>BRCA</i>-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with <i>BRCA1</i>-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with <i>BRCA2</i>-deficient HGSC and loss of <i>NF1</i> survived twice as long2025-01-01T00:00:00Z2025 Sep2026-06-10T03:09:44.145Z2026-06-10T03:07:14.804ZS-EPMC124860084104069110.1101/2025.09.17.25335919