Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles

Abstract

Ovarian endometrioid carcinomas and endometrial endometrioid carcinomas share many histological and molecular alterations. These similarities are likely due to a common endometrial epithelial precursor cell of origin, with most ovarian endometrioid carcinomas arising from endometriosis. To directly compare the mutation profiles of two morphologically similar tumor types, endometrial endometrioid carcinomas (n=307) and ovarian endometrioid carcinomas (n=33), we performed select exon capture sequencing on a panel of genes: ARID1A, PTEN, PIK3CA, KRAS, CTNNB1, PPP2R1A, TP53. We found that PTEN mutations are more frequent in low-grade endometrial endometrioid carcinomas (67%) compared with low-grade ovarian endometrioid carcinomas (17%) (P<0.0001). By contrast, CTNNB1 mutations are significantly different in low-grade ovarian endometrioid carcinomas (53%) compared with low-grade endometrial endometrioid carcinomas (28%) (P<0.0057). This difference in CTNNB1 mutation frequency may be reflective of the distinct microenvironments; the epithelial cells lining an endometriotic cyst within the ovary are exposed to a highly oxidative environment that promotes tumorigenesis. Understanding the distinct mutation patterns found in the PI3K and Wnt pathways of ovarian and endometrial endometrioid carcinomas may provide future opportunities for stratifying patients for targeted therapeutics.

Figure 1. Low-grade ovarian and endometrial endometrioid mutation profiles

A. Low-grade endometrial endometrioid carcinomas (EEC) including grade 1 and 2 (n=276). B. Low-grade ovarian endometrioid carcinomas (OEC) including grade 1 and 2 (n=30). Individual columns designate one tumor case, and rows indicate genes. All colored boxes specify a genetic alteration such as missense, truncating, indels, splice site mutations and combinations of these mutations. Grey boxes indicate no mutation were identified by sequencing. These colors are specifically shown in the color legend.

Figure 2. PI3K/AKT and WNT signaling pathways

Theses two signaling pathways show convergence on GSK3β and β-catenin. Genetic alterations caused by mutations in both pathways can result in the transcription of cell growth and proliferation genes. Mutations are indicated by black stars and are found in both ovarian and endometrial endometrioid tumors.