Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome

Robert L. Hollis, John P. Thomson, Barbara Stanley, Michael Churchman, Alison M. Meynert, Tzyvia Rye, Clare Bartos, Yasushi Iida, Ian Croy, Melanie Mackean, Fiona Nussey, Aikou Okamoto, Colin A. Semple, Charlie Gourley and C. Simon Herrington ()
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Robert L. Hollis: University of Edinburgh
John P. Thomson: University of Edinburgh
Barbara Stanley: University of Edinburgh
Michael Churchman: University of Edinburgh
Alison M. Meynert: University of Edinburgh
Tzyvia Rye: University of Edinburgh
Clare Bartos: University of Edinburgh
Yasushi Iida: University of Edinburgh
Ian Croy: University of Edinburgh
Melanie Mackean: Western General Hospital
Fiona Nussey: Western General Hospital
Aikou Okamoto: The Jikei University School of Medicine
Colin A. Semple: University of Edinburgh
Charlie Gourley: University of Edinburgh
C. Simon Herrington: University of Edinburgh

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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%), KRAS (26%), 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.

Date: 2020
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DOI: 10.1038/s41467-020-18819-5

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