Frequent Mutation and Nuclear Localization of β-Catenin in Sertoli Cell Tumors of the Testis

Abstract

The Sertoli cell tumor (SCT) of the testis is a sex cord stromal tumor, usually sporadic, rarely associated with genetic syndromes. Much remains unclear about the molecular genetic changes involved in SCT and its histogenesis. Recently, nuclear β-catenin immunostaining has been reported in a case of bilateral SCT, but the molecular basis of the aberrant nuclear β-catenin expression remains uncertain. In the present study, β-catenin immunohistochemical assay and mutational analysis of exon 3 of the CTNNB1 gene by direct sequencing were performed in 14 SCTs, 2 of which had an unfavorable clinical course. Immunohistochemical study showed that β-catenin was located in the cytoplasm of tumor cells in 4 cases (28.6%) and in both the nuclei and the cytoplasm in the remaining 10 cases (71.4%). β-Catenin mutations were detected in 10 of the 14 patients (71.4%) under evaluation. Ten of 10 mutation-carrying cases showed strong nuclear and diffuse cytoplasmic β-catenin immunoreactivity. Seven of the 8 CTNNB1-mutated tumors tested for cyclin D1 displayed diffuse immunoreactivity in the nuclei of tumor cells. We conclude that CTNNB1 exon 3 mutations are likely to be involved in the pathogenesis of male SCT with nuclear accumulation of β-catenin and affect the expression of cyclin D1.

Testicular and paratesticular tumors and tumor-like lesions in the first 2 decades

“…We have also recently seen in consultation a case of a histologically malignant Sertoli cell tumor in a 2-year-old boy. Recently mutation of the CTNNB1 gene that encodes β-catenin, with consequent nuclear staining for the protein, was found in a series of Sertoli cell tumors, including one in a 19-year old 146 ; this suggests a relationship of the tumor to familial adenomatous polyposis, as was proposed in a case report of an older patient with bilateral Sertoli cell tumors. 147 On gross examination the tumors are solid gray-white to yellow.…”

Intranodal Palisaded Myofibroblastoma

“…The stabilized beta-catenin protein accumulates in the cytoplasm and then translocates to the cell nucleus, where it forms bipartite complexes with, and activates T cell factor/lymphoid-enhancing factor (TCF/LEF) leading to up-regulation of TCF/LEF-responsive target genes, including CCND1 40,41,44,45 . This sequence of events results in Immunohistochemical overexpression of cyclin D1, which has been documented in a number of neoplastic processes exhibiting CTNNB1 mutations and nuclear expression of beta-catenin 46–56 .…”

The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes

“…Visinin-like 1 (VSNL1) is upregulated in aldosterone-producing adenomas (APAs) compared with normal adrenals23. CTNNB1 exon 3 mutations could be involved in APA formation due to accumulation of β-catenin and increased expression of Cyclin D124. The canonical (Wnt/β-catenin-mediated) signaling functionally interacts with GATA425, a marker of gonadal differentiation that is crucial in adrenal development26.…”