Synapse - MAPK pathway genetic alterations are associated with prolonged overall survival in low-grade serous ovarian carcinoma

MAPK pathway genetic alterations are associated with prolonged overall survival in low-grade serous ovarian carcinoma Journal Article

Authors:	Manning-Geist, B.; Gordhandas, S.; Liu, Y. L.; Zhou, Q.; Iasonos, A.; Da Cruz Paula, A.; Mandelker, D.; Long Roche, K.; Zivanovic, O.; Maio, A.; Kemel, Y.; Chi, D. S.; O'Cearbhaill, R. E.; Aghajanian, C.; Weigelt, B.; Chui, M. H.; Grisham, R. N.
Article Title:	MAPK pathway genetic alterations are associated with prolonged overall survival in low-grade serous ovarian carcinoma
Abstract:	PURPOSE: To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSC). EXPERIMENTAL DESIGN: Patients with LGSC tumors who underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations; copy-number alterations; and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected. RESULTS: Following central pathology rereview, 119 patients with LGSC were identified for analysis. Of these, 110 (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; MAPK pathway alterations were found in 60% (n = 71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis more than 50 years (P = 0.02) and platinum-sensitive disease (P = 0.03). On multivariate analysis, MAPK pathway alterations (P = 0.02) and platinum sensitivity (P = 0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; seven pathogenic germline mutations were identified: MUTYH (n = 2), BAP1 (n = 1), RB1 (n = 1), CHEK2 (n = 1), APC (n = 1), and FANCA (n = 1). There were no germline BRCA1/2 mutations. One germline MUTYH-associated LGSC harbored loss-of-heterozygosity at the MUTYH locus, and the patient with the germline BAP1 mutation also harbored a somatic BAP1 frameshift mutation. CONCLUSIONS: This study showed that MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC. See related commentary by Veneziani and Oza, p. 4357. ©2022 American Association for Cancer Research.
Keywords:	genetics; mutation; ovarian neoplasms; peritoneal neoplasms; pathology; ovary tumor; cystadenocarcinoma, serous; protein p21; proto-oncogene proteins p21(ras); b raf kinase; germ-line mutation; peritoneum tumor; proto-oncogene proteins b-raf; cystadenocarcinoma; germline mutation; humans; human; female
Journal Title:	Clinical Cancer Research
Volume:	28
Issue:	20
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2022-10-15
Start Page:	4456
End Page:	4465
Language:	English
DOI:	10.1158/1078-0432.Ccr-21-4183
PUBMED:	35443055
PROVIDER:	scopus
PMCID:	PMC9582036
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85140144803&doi=10.1158%2f1078-0432.CCR-21-4183&partnerID=40&md5=14d984348452fdfec3f8e5c1a65f6a3f
Notes:	Article -- Export Date: 1 November 2022 -- Source: Scopus