Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome

Robb Hollis, John Thomson, Barbara Stanley, Michael Churchman, Alison M Meynert, Tzyvia Rye, Clare Bartos, Yasushi Iida, Ian Croy, Melanie J Mackean, Fiona Nussey, Aikou Okamoto, Colin A Semple, Charlie Gourley, C Simon Herrington

Research output: Contribution to journalArticlepeer-review

Abstract

Endometrioid ovarian carcinoma (EnOC) demonstrates substantial clinical and molecular heterogeneity. Here, we report whole exome sequencing of 112 EnOC cases following rigorous pathological assessment. We detect a high frequency of mutation in CTNNB1(43%), PIK3CA(43%), ARID1A(36%), PTEN(29%), TP53(26%) and SOX8(19%), a recurrently-mutated gene previously unreported in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy is constructed, identifying clinically distinct EnOC subtypes: cases with TP53 mutation demonstrate greater genomic complexity, are commonly FIGO stage III/IV at diagnosis (48%), are frequently incompletely debulked (44%) and demonstrate inferior survival; conversely, cases with CTNNB1 mutation, which is mutually exclusive with TP53 mutation, demonstrate low genomic complexity and excellent clinical outcome, and are predominantly stage I/II at diagnosis (89%) and completely resected (87%). Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.
Original languageEnglish
Article number4995
JournalNature Communications
Volume11
Issue number10
Early online date5 Oct 2020
DOIs
Publication statusE-pub ahead of print - 5 Oct 2020

Keywords

  • cancer
  • ovarian carcinoma
  • endometrioid
  • molecular
  • genomic
  • stratificatioon
  • survival

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