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.
Highlights
Endometrioid ovarian carcinoma (EnOC) demonstrates substantial clinical and molecular heterogeneity
Of 289 historically diagnosed EnOC cases identified with available tumour material, 112 WT1 negative cases were characterised by whole exome sequencing (WES) following rigorous pathology review (Fig. 1)
WT1 negativity has emerged as an important discriminator of high grade EnOC from high grade serous OC (HGSOC), which displays morphological similarities[4,24,25,26,27]
Summary
Endometrioid ovarian carcinoma (EnOC) demonstrates substantial clinical and molecular heterogeneity. 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. Ovarian carcinomas (OC) are a heterogeneous group of malignancies comprising five core histological types, each with distinct pathological characteristics, molecular landscapes and clinical behaviour[1,2]. Targeted sequencing approaches have identified PTEN, ARID1A, PIK3CA, KRAS, CTNNB1, and genes encoding mismatch repair (MMR) proteins as frequently mutated in relatively small cohorts of EnOC8–10, reminiscent of endometrioid endometrial carcinoma (EnEC)[11], with a TP53 mutation (TP53m) rate markedly lower than their high grade serous OC (HGSOC) counterparts[12]. Recent whole genome sequencing of a small EnOC case series has recapitulated these findings and identified a small proportion of EnOC with extensive copy number alterations (CNAs) more akin to the genomic instability demonstrated by HGSOC13
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