Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome

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.

How Does Endometriosis Lead to Ovarian Cancer? The Molecular Mechanism of Endometriosis-Associated Ovarian Cancer Development

“…Although these copy number alterations are potential molecular targets, a new treatment strategy based on copy number alterations has not been developed for CCC [ 43 ]. On the other hand, whole-exome sequencing studies have identified some EC samples with widespread copy number alterations, similar to the genomic instability demonstrated by HGSC [ 20 , 21 , 22 ]. As an example, Hollis et al reported that the copy number alteration burden of EC varies by molecular subgroup defined by the mutation status of TP53 and CTNNB [ 22 ].…”

“…On the other hand, whole-exome sequencing studies have identified some EC samples with widespread copy number alterations, similar to the genomic instability demonstrated by HGSC [ 20 , 21 , 22 ]. As an example, Hollis et al reported that the copy number alteration burden of EC varies by molecular subgroup defined by the mutation status of TP53 and CTNNB [ 22 ]. These authors showed that cases of TP53 mutation (26%) harbored a greater copy number alteration burden than cases of wild-type TP53 (74%).…”

“…With the improvement of sequencing technology, several studies focusing on genomic features or molecular targets in EAOC have been performed. Table 1 and Table 2 summarize the genomic alterations occurring in CCC [ 15 , 16 , 17 , 18 , 19 ] or endometrioid carcinoma (EC) [ 20 , 21 , 22 ] based on previously reported results of whole-exome sequencing, respectively. First, the ARID1A gene, which encodes a key component of the SWI/SNF complex that plays an important role in chromatin remodeling, is most frequently mutated in EAOC; indeed, 46–70% of CCCs and 19–36% of ECs harbor ARID1A mutations.…”

“…In another report, loss of ARID1A expression was more frequent in CCC cases with (54%) than in those without (30%) PI3K/AKT pathway activation ( p = 0.046) [ 25 ]. Several genomic studies based on next-generation sequencing data have demonstrated that ARID1A and PIK3CA mutations frequently coexist in both CCC (20–56%) [ 29 ] and EC (11–25%) [ 21 , 22 ]. In addition, Mabuchi et al conducted proteome analysis of 98 primary ovarian tumors (52 CCCs and 46 HGSCs) using a tissue microarray and showed that AKT, mTORC1, and mTORC2 are more frequently activated in the former than in the latter [ 30 ].…”

“…In addition, they reported that CTNNB mutation cases with wild-type TP53 had a lower copy number alteration burden than wild-type CTNNB cases with wild-type TP53 . Comparing the clinical behavior of the above three genomic subtypes of EC, the group with a high copy number alteration burden ( TP53 mutation group) had worse outcomes, whereas the group with the lowest burden ( CTNNB1 mutation group with wild-type TP53 ) had favorable outcomes [ 22 ].…”