Clinicopathologic and Genomic Analysis of <i>TP53</i>-Mutated Endometrial Carcinomas.

Abstract

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), near-universal <i>TP53</i> mutation, and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant <i>TP53</i>-altered endometrial carcinomas of four histologic types. <i>TP53</i>-mutated endometrial carcinomas, defined as <i>TP53</i>-mutant tumors lacking microsatellite instability or pathogenic <i>POLE</i> mutations, were identified (<i>n</i> = 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 (<i>n</i> = 238), and clinicopathologic features were determined (<i>n</i> = 185, initial treatment planning at our institution). <i>TP53</i>-mutated endometrial carcinomas encompassed uterine serous (<i>n</i> = 102, 55.1%), high-grade endometrial carcinoma with ambiguous features/not otherwise specified (EC-NOS; <i>n</i> = 44, 23.8%), endometrioid carcinomas of all tumor grades (<i>n</i> = 28, 15.1%), and clear cell carcinomas (<i>n</i> = 11, 5.9%). <i>PTEN</i> mutations were significantly more frequent in endometrioid carcinomas, <i>SPOP</i> mutations in clear cell carcinomas, and <i>CCNE1</i> amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. <i>ERBB2</i> amplification was present at similar frequencies across <i>TP53</i>-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. <i>TP53</i>-mutated endometrial carcinomas display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of <i>ERBB2</i> assessment in all <i>TP53</i>-mutated endometrial carcinomas. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.