Genetic and molecular subtype heterogeneity in newly diagnosed early- and advanced-stage endometrial cancer

Arnaud Da Cruz Paula, Deborah F. DeLair, Lorenzo Ferrando, Daniel J. Fix, Robert A. Soslow, Kay J. Park, Sarah Chiang, Jorge S. Reis-Filho, Ahmet Zehir, Mark T.A. Donoghue, Michelle Wu, David N. Brown, Rajmohan Murali, Claire F. Friedman, Dmitriy Zamarin, Vicky Makker, Jennifer J. Mueller, Mario M. Leitao, Nadeem R. Abu-Rustum, Carol AghajanianBritta Weigelt

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Objective: To characterize and compare the molecular subtypes and profiles of prospectively-accrued newly-diagnosed early- and advanced-stage endometrial cancers (ECs). Methods: EC patients consented to an IRB-approved protocol of massively parallel sequencing of 410–468 cancer-related genes; 175 ECs of 7 histologic types (n = 135 FIGO stages I/II, n = 40 FIGO stages III/IV) were included. Previously reported sequencing data from 99 additional advanced-stage ECs were retrieved for comparisons. Results: Irrespective of histologic type, all 175 ECs could be stratified into the molecular subtypes, with 75 (43%) being of p53 wild-type, 49 (28%) MMR-deficient, 39 (22%) p53 abnormal and 12 (7%) of POLE molecular subtypes. Subtype distribution, mutational and copy number profiles varied according to histologic type. In endometrioid ECs, genetic alterations varied according to histologic grade. Potential therapeutic targets, including high tumor mutational burden, ERBB2 amplification and PIK3CA hotspot mutations, were found across histologic types in 63% (n = 110) of all ECs. Compared to their early-stage counterparts, advanced-stage endometrioid ECs had a significantly higher fraction of genome altered (median 0.1% vs 12%, p < 0.001) and ARID1B mutations (0% vs 11%, p = 0.01), and advanced-stage serous ECs harbored more frequent ERBB2 amplification (18% vs 8%, p > 0.05) and PIK3CA mutations (46% vs 27%, p > 0.05). Whole-genome doubling was found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas. Conclusions: Our findings demonstrate the molecular heterogeneity within and across histologic types of EC and the increased genomic complexity of advanced-stage ECs. Molecular subtypes are present across EC histologic types and may help stratify EC patients for prognostic and therapeutic purposes.

Original languageEnglish
Pages (from-to)535-544
Number of pages10
JournalGynecologic Oncology
Volume161
Issue number2
DOIs
StatePublished - May 2021
Externally publishedYes

Keywords

  • Endometrial cancer
  • Massively parallel sequencing
  • Molecular subtypes
  • Whole-genome duplication

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