An integrated molecular profile of endometrioid ovarian cancer

Endometrioid ovarian carcinoma (EOVC) is an uncommon subtype of epithelial ovarian carcinoma and its molecular characteristics have been incompletely described. Prior sequencing investigations have been limited to targeted gene panels. We performed whole-exome sequencing to build an unbiased genetic profile of molecular alterations in endometrioid ovarian tumors with a goal to better understand this disease in the context of epithelial ovarian cancer and endometrioid uterine cancers.

Whole-exome sequencing was performed on EOVC samples (n = 26) and matched normals (n = 15). Gene mutations, mutational signatures and copy number variations (CNVs) informed a multi-dimensional regression classifier allowing for comparison to endometrial carcinoma (UCEC) and high grade serous ovarian carcinoma (HGSC).

EOVC has a distinct and heterogeneous genomic profile. Identified significantly mutated genes in EOVC (PTEN, CTNNB1, PIK3CA, KMT2D, KMT2B, PIK3R1, ARID1A and TP53) occurred at similar frequencies in UCEC. Hypermutation, resulting from both mismatch repair deficiency (MMRd) and POLE mutation, was observed in EOVC at a frequency similar to UCEC. Like UCEC, a subset of EOVC cases closely resembled HGSC, harboring TP53 mutations, homologous recombination deficiency (HRd) mutation signatures and widespread CNVs. A machine-learning classifier confirmed the heterogeneous composition of EOVC. Potential therapeutic targets were identified in 62% of EOVC cases. We validated our findings in an orthogonal clinical sequencing registry of EOVC cases.

We identified that EOVC are a molecularly heterogeneous group of epithelial ovarian cancers with distinct mutational signatures. In an age of precision oncology, there is a pressing need to understand the unique molecular drivers in uncommon histologic subtypes to facilitate genomically driven oncologic treatments.