Synapse - Germline drivers of gynecologic carcinosarcomas

Germline drivers of gynecologic carcinosarcomas Journal Article

Authors:	Sia, T. Y.; Gordhandas, S. B.; Birsoy, O.; Kemel, Y.; Maio, A.; Salo-Mullen, E.; Sheehan, M.; Hensley, M. L.; Rubinstein, M.; Makker, V.; Grisham, R. N.; O'Cearbhaill, R. E.; Roche, K. L.; Mueller, J. J.; Leitao, M. M. Jr; Sonoda, Y.; Chi, D. S.; Abu-Rustum, N. R.; Berger, M. F.; Ellenson, L. H.; Latham, A.; Stadler, Z.; Offit, K.; Aghajanian, C.; Weigelt, B.; Mandelker, D.; Liu, Y. L.
Article Title:	Germline drivers of gynecologic carcinosarcomas
Abstract:	Objectives: To describe the prevalence of germline pathogenic variants (gPVs) in endometrial and ovarian carcinosarcomas and determine if gPVs are drivers of carcinosarcoma. Methods: Patients with endometrial or ovarian carcinosarcomas who underwent clinical tumor-normal sequencing from 1/1/2015 to 6/1/2021 and consented to germline assessment of ≥76 cancer predisposition genes were included. In patients with gPVs, biallelic inactivation was identified through analysis of loss of heterozygosity and somatic pathogenic alterations. Results: Of 216 patients identified, 167 (77%) were diagnosed with endometrial carcinosarcoma and 49 (23%) with ovarian carcinosarcoma. Overall, 33 gPVs were observed in 29 patients (13%); 20 gPVs (61%) had biallelic loss in tumors. The rate of high-penetrance gPVs overall was 7% (16 of 216); 88% of high-penetrance gPVs had biallelic loss. In the endometrial carcinosarcoma cohort, 22 gPVs were found in 19 (11%) of 167 patients; 12 gPVs (55%) had biallelic loss in tumors, including 8 (89%) of 9 in high-penetrance gPVs. Among the ovarian carcinosarcoma cohort, 11 gPVs were found in 10 (20%) of 49 patients; 8 gPVs (73%) had biallelic loss in tumors, and all evaluable high-penetrance gPVs (n = 6) had biallelic loss. All gPVs in homologous recombination (BRCA1, BRCA2, RAD51C) and Lynch syndrome (MSH2, MSH6) genes had biallelic loss in tumors (n = 15). Conclusions: gPVs in genes affecting homologous recombination- or Lynch-associated mismatch repair exhibited biallelic inactivation within tumors, suggesting likely drivers of gynecologic carcinosarcoma. Our data support germline testing for patients with gynecologic carcinosarcomas, given implications for treatment and risk-reduction in patients and at-risk family members. © 2023 Elsevier Inc.
Keywords:	human tissue; aged; major clinical study; cancer patient; endometrium carcinoma; homologous recombination; cancer susceptibility; prevalence; cohort analysis; brca1 protein; brca2 protein; carcinogenesis; heterozygosity loss; lynch syndrome; protein msh6; genetic testing; rad51 protein; penetrance; carcinosarcoma; germline mutation; ovarian carcinosarcoma; human; female; article; endometrial carcinosarcoma; dna mismatch repair protein msh2; germline pathogenic variants; gynecologic carcinosarcomas
Journal Title:	Gynecologic Oncology
Volume:	174
ISSN:	0090-8258
Publisher:	Elsevier Inc.
Date Published:	2023-07-01
Start Page:	34
End Page:	41
Language:	English
DOI:	10.1016/j.ygyno.2023.04.024
PUBMED:	37149903
PROVIDER:	scopus
PMCID:	PMC10330315
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85156197143&doi=10.1016%2fj.ygyno.2023.04.024&partnerID=40&md5=cc39bf792f483cfb01062956dcb9e744
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Ying L. Liu -- Source: Scopus