Oncogenic Activation of the Wnt/β-Catenin Signaling Pathway in Signet Ring Stromal Cell Tumor of the Ovary

Abstract

Signet ring stromal cell tumor (SRSCT) of the ovary is a very rare benign ovarian neoplasm. To date, no underlying genetic mechanism has been identified. In this study, 50 oncogenes and tumor suppressor genes were evaluated for mutations in a typical SRSCT using the next-generation DNA sequencing approach. An in-frame deletion of 30 nucleotides in the glycogen serine kinase-3 beta phosphorylation region of the β-catenin gene (CTNNB1) was identified, and the finding was confirmed by Sanger sequencing. This deletion (c.68_97del) at the protein level would lead to a p.Ser23_Ser33delinsThr oncogenic-type mutation. Subsequent immunohistochemistry showed prominent nuclear accumulation of β-catenin and cyclin D1 in tumor cells. Thus, mutational activation of the Wnt/β-catenin pathway could be a crucial event in the molecular pathogenesis of SRSCT of the ovary. These findings may also assist in the diagnosis of this rare tumor.

FIGURE 1

A, Trabecular and nested growth patterns are evident in a low-power view of Signet ring stromal cell tumor of the ovary. B, The area with signet ring cell change and focal stromal luteinization. C and D, Areas with prominent signet ring cell change with cytoplasmic hyaline globules evident in PAS staining.

FIGURE 2

Tumor cells show strong nuclear and cytoplasmic labeling for β-catenin and strong nuclear labeling for cyclin D1. All tumor cells are positive for vimentin and SRC-1.

FIGURE 3

Integrative Genomics Viewer visualization of the p.Ser23_Ser33delinsThr CTNNB1 oncogenic mutation.

FIGURE 4

The Sanger DNA sequence of the CTNNB1 glycogen serine kinase-3 beta phosphorylation region. The beginning of the 30-nucleotide deletion (c.68_97del) is marked by an arrow.