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

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

Authors:	Kahn, R. M.; Selenica, P.; Boerner, T.; Roche, K. L.; Xiao, Y.; Sia, T. Y.; Maio, A.; Kemel, Y.; Sheehan, M.; Salo-Mullen, E.; Breen, K. E.; Zhou, Q.; Iasonos, A.; Grisham, R. N.; O'Cearbhaill, R. E.; Chi, D. S.; Berger, M. F.; Kundra, R.; Schultz, N.; Ellenson, L. H.; Stadler, Z. K.; Offit, K.; Mandelker, D.; Aghajanian, C.; Zamarin, D.; Sabbatini, P.; Weigelt, B.; Liu, Y. L.
Article Title:	Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival
Abstract:	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. © 2023 Elsevier Inc.
Keywords:	survival; adult; cancer survival; controlled study; human tissue; aged; unclassified drug; major clinical study; overall survival; single nucleotide polymorphism; somatic mutation; genetics; cancer patient; antineoplastic agent; ovarian cancer; phenotype; rad50 protein; allele; homologous recombination; progression free survival; ovary cancer; cohort analysis; brca1 protein; brca2 protein; wild type; carcinogenesis; nibrin; ovary carcinoma; atm protein; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; binding protein; neoadjuvant chemotherapy; rad51 protein; genetic heterogeneity; clinical outcome; fanconi anemia group c protein; brca1 associated ring domain protein 1; germline mutation; fanconi anemia group a protein; brca1/2; allelic imbalance; human; female; article; whole exome sequencing; rad51c protein; poly (adp-ribose) polymerase; tumor mutational burden; rad51d protein; partner and localizer of brca2; brca1 interacting protein 1; rad51b protein
Journal Title:	Gynecologic Oncology
Volume:	180
ISSN:	0090-8258
Publisher:	Elsevier Inc.
Date Published:	2024-01-01
Start Page:	35
End Page:	43
Language:	English
DOI:	10.1016/j.ygyno.2023.11.019
PUBMED:	38041901
PROVIDER:	scopus
PMCID:	PMC10922242
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85178130808&doi=10.1016%2fj.ygyno.2023.11.019&partnerID=40&md5=e96cca1557b414273e81f0d08bc7d62b
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Ying L. Liu -- Source: Scopus