Clinicopathologic and genomic analysis of TP53-mutated endometrial carcinomas

Amir Momeni-Boroujeni, Wissam Dahoud, Chad M. Vanderbilt, Sarah Chiang, Rajmohan Murali, Eric V. Rios-Doria, Kaled M. Alektiar, Carol Aghajanian, Nadeem R. Abu-Rustum, Marc Ladanyi, Lora H. Ellenson, Britta Weigelt, Robert A. Soslow

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Copy number-high endometrial carcinomas were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy-number alterations (CNA), low mutational burden (i.e., non-hypermutant), nearuniversal TP53 mutation, and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant TP53-altered endometrial carcinomas of four histologic types. Experimental Design: TP53-mutated endometrial carcinomas, defined as TP53-mutant tumors lacking microsatellite instability or pathogenic POLE mutations, were identified (n = 238) in a cohort of 1,239 endometrial carcinomas subjected to clinical massively parallel sequencing of 410-468 cancer-related genes. Somatic mutations and CNAs (n = 238), and clinicopathologic features were determined (n = 185, initial treatment planning at our institution). Results: TP53-mutated endometrial carcinomas encompassed uterine serous (n=102, 55.1%), high-grade endometrial carcinoma with ambiguous features/not otherwise specified (EC-NOS; n = 44, 23.8%), endometrioid carcinomas of all tumor grades (n = 28, 15.1%), and clear cell carcinomas (n = 11, 5.9%). PTEN mutations were significantly more frequent in endometrioid carcinomas, SPOP mutations in clear cell carcinomas, and CCNE1 amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. ERBB2 amplification was present at similar frequencies across TP53- mutated histologic types (7.7%-18.6%). Although overall survival was similar across histologic types, serous carcinomas presented more frequently at stage IV, had more persistent and/or recurrent disease, and reduced disease-free survival. Conclusions: TP53-mutated endometrial carcinomas display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of ERBB2 assessment in all TP53-mutated endometrial carcinomas. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.

Original languageEnglish (US)
Pages (from-to)2613-2623
Number of pages11
JournalClinical Cancer Research
Volume27
Issue number9
DOIs
StatePublished - May 1 2021
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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