Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival.

Autor: Kahn RM; Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Selenica P; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Boerner T; Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Roche KL; Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA., Xiao Y; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Sia TY; Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Maio A; Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Kemel Y; Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Sheehan M; Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Salo-Mullen E; Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Breen KE; Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Zhou Q; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Iasonos A; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Grisham RN; Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA., O'Cearbhaill RE; Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA., Chi DS; Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA., Berger MF; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Kundra R; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Schultz N; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Ellenson LH; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Stadler ZK; Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA., Offit K; Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA., Mandelker D; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Aghajanian C; Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA., Zamarin D; Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA., Sabbatini P; Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA., Weigelt B; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Liu YL; Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Electronic address: liuy3@mskcc.org.
Jazyk: angličtina
Zdroj: Gynecologic oncology [Gynecol Oncol] 2024 Jan; Vol. 180, pp. 35-43. Date of Electronic Publication: 2023 Dec 01.
DOI: 10.1016/j.ygyno.2023.11.019
Abstrakt: Objective: To define molecular features of ovarian cancer (OC) with germline pathogenic variants (PVs) in non-BRCA homologous recombination (HR) genes and analyze survival compared to BRCA1/2 and wildtype (WT) OC.
Methods: We included patients with OC undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015-12/31/2020, including germline assessment of BRCA1/2 and other HR genes ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D. Biallelic inactivation was assessed within tumors. Progression-free (PFS) and overall survival (OS) were calculated from pathologic diagnosis using the Kaplan-Meier method with left truncation. Whole-exome sequencing (WES) was performed in a subset.
Results: Of 882 patients with OC, 56 (6.3%) had germline PVs in non-BRCA HR genes; 95 (11%) had BRCA1-associated OC (58 germline, 37 somatic); and 59 (6.7%) had BRCA2-associated OC (40 germline, 19 somatic). High rates of biallelic alterations were observed among germline PVs in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10). In cases with WES (27/35), there was higher tumor mutational burden (TMB; median 2.5 [1.1-6.0] vs. 1.2 mut/Mb [0.6-2.6]) and enrichment of HR-deficient (HRD) mutational signatures in tumors associated with germline PALB2 and RAD51B/C/D compared with BRIP1 PVs (p < 0.01). Other features of HRD, including telomeric-allelic imbalance (TAI) and large-scale state transitions (LSTs), were similar. Although there was heterogeneity in PFS/OS by gene group, only BRCA1/2-associated OC had improved survival compared to WT OC (p < 0.01).
Conclusions: OCs associated with germline PVs in non-BRCA HR genes represent a heterogenous group, with PALB2 and RAD51B/C/D associated with an HRD phenotype.
Competing Interests: Declaration of Competing Interest YLL reports research funding from AstraZeneca, GSK and Repare Therapeutics outside of this work. KEB reports that an immediate family member is on the Scientific Advisory Board of Emendo Biotherapeutics, Karyopharm Therapeutics, Imago BioSciences, and DarwinHealth; is co-Founder of Isabl Technologies; and has equity interest in Imago BioSciences, Emendo Biotherapeutics and Isabl Technologies. BW reports research funding by Repare Theraputics. CA has received research grants from Abbvie, Clovis, Genentech, and Astra Zeneca and served on advisory boards for Abbvie, AstraZeneca/Merck, Eisai/Merck, Mersana Therapeutics, Repare Therapeutics, and Roche/Genentech. ZS reports an immediate family member who serves as a consultant in Ophthalmology for Adverum, Genentech, Gyroscope Therapeutics Limited, Neurogene, Optos Plc, Outlook Therapeutics, RegenexBio, and Regeneron. RO reports meeting/travel support from the Gynecologic Oncology Foundation, Curio, and Hitech Health; participation in the advisory boards of Tesaro/GlaxoSmithKline (GSK), Regeneron, Seattle Genetics, Fresenius Kabi, Bayer, and CarinaBiotech (non-compensated); non-compensated steering committee participation for Tesaro/GSK and AstraZeneca; and grant support paid to the institution from Bayer/Celgene/Juno, Tesaro/GSK, Merck, the Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Marker Therapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, KitePharma, and the Gynecologic Oncology Foundation. AI reports consulting fees from Mylan. RG reports honoraria from GSK, AstraZeneca, Natera, Springworks, Corcept, MJH, and PER. DC reports personal fees from Apyx Medical, Verthermia Inc., Biom ‘Up, and AstraZeneca, as well as recent or current stock/options ownership of Apyx Medical, Verthemia, Intuitive Surgical, Inc., TransEnterix, Inc., Doximity, Moderna, and BioNTech SE. KO is a founder and shareholder of AnaNeo Therapeutics Incorporated. MFB reports receiving research funding from GRAIL and advisory board activities for Eli Lilly, AstraZeneca, and PetDx. All other authors have no potential conflicts of interest to disclose.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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