Synapse - TERT promoter mutations and gene amplification in endometrial cancer

TERT promoter mutations and gene amplification in endometrial cancer Journal Article

Authors:	Praiss, A. M.; Marra, A.; Zhou, Q.; Rios-Doria, E.; Momeni-Boroujeni, A.; Iasonos, A.; Selenica, P.; Brown, D. N.; Aghajanian, C.; Abu-Rustum, N. R.; Ellenson, L. H.; Weigelt, B.
Article Title:	TERT promoter mutations and gene amplification in endometrial cancer
Abstract:	Objective: To assess the clinicopathologic, molecular profiles, and survival outcomes of patients with endometrial carcinomas (ECs) harboring telomerase reverse transcriptase (TERT) hotspot mutations or gene amplification. Methods: ECs harboring somatic TERT promoter hotspot mutations or gene amplification (TERT-altered) were identified from 1944 ECs that underwent clinical tumor-normal sequencing from 08/2016–12/2021. Clinicopathologic variables, somatic mutation profiles, and survival outcomes of TERT-alt and TERT-wild-type EC were assessed. Results: We identified 66 TERT-altered ECs (43 TERT-mutated and 23 TERT-amplified), representing 3% of the unselected ECs across histologic subtypes. Most TERT-altered ECs were of copy number (CN)-high/TP53abn molecular subtype (n = 40, 60%), followed by microsatellite-unstable (MSI-H) or CN-low/no specific molecular profile (NSMP)(n = 13, 20% each). TERT-amplified and TERT-mutated ECs were molecularly distinct, with TERT-amplified ECs being more genomically instable and more frequently harboring TP53 and PPP2R1A alterations (q < 0.1). Compared to TERT-wild-type ECs, TERT-altered ECs were more commonly of CN-H/TP53abn molecular subtype (31% vs 57%, p = 0.001), serous histology (10% vs 26%, p = 0.004), and were significantly enriched for TP53, CDKN2A/B, and DROSHA somatic genetic alterations (q < 0.1). Median progression-free survival was 18.7 months (95% CI 11.8–not estimable [NE]) for patients with TERT-altered EC and 80.9 months (65.8-NE) for patients with TERT-wild-type EC (HR 0.33, 95% CI 0.21–0.51, p < 0.001). Similarly, median overall survival was 46.7 months (95% CI 30-NE) for TERT-altered EC patients and not reached for TERT-wild-type EC patients (HR 0.24, 95% CI 0.13–0.44, p < 0.001). Conclusion: TERT-altered ECs, although rare, are enriched for CN-high/TP53abn tumors, TP53, CDKN2A/B and DROSHA somatic mutations, and independently predict worse survival outcomes. © 2023 Elsevier Inc.
Keywords:	endometrial cancer; outcome; molecular subtypes; molecular profiles; tert gene alterations
Journal Title:	Gynecologic Oncology
Volume:	179
ISSN:	0090-8258
Publisher:	Elsevier Inc.
Date Published:	2023-12-01
Start Page:	16
End Page:	23
Language:	English
DOI:	10.1016/j.ygyno.2023.10.007
PROVIDER:	scopus
PUBMED:	37890416
PMCID:	PMC10841990
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85174534876&doi=10.1016%2fj.ygyno.2023.10.007&partnerID=40&md5=5cddfa2b445a288a0f866020ed09e7f9
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Britta Weigelt -- Source: Scopus