Aberrant expression and mutations of TGF-β receptor type II gene in endometrial cancer

Abstract

Objective. Transforming growth factor β (TGF-β) is a multifunctional cytokine that strongly inhibits epithelial cell growth. Disabling of TGF-β signaling is thought to be involved in development of a variety of tumors in which abnormal expression or function of TGF-β receptor plays critical roles. In the present study, we examined aberrant expression and mutation of the gene TGF-β receptor type II ( TβRII) in endometrial cancers of endometrioid subtype. Methods and results. Real-time PCR analysis using surgical tissue specimens of 27 endometrial cancers and 24 normal endometria revealed that endometrial cancers had significantly decreased levels of TβRII mRNA expression (mean level 2.44 ± 2.65), compared to normal endometria (mean level 7.23 ± 6.07) ( P < 0.001). Methylation status of TβRII promoter containing 30 CpGs was examined by bisulfite sequencing analysis, and 98% (51/52) of the patients were found to have unmethylated TβRII promoter, indicating that promoter hypermethylation is not the major cause of decreased expression of TβRII in endometrial cancers. Mutational analysis revealed that 15.1% (8/53) of endometrial cancers had frameshift mutations at polyadenine repeats in exon 3 of the TβRII gene. Notably, these mutations were preferentially accumulated in patients with MSI-H phenotype (7/19:37%) ( P < 0.001) or with those with methylated MLH1 promoters (6/16:38%) ( P < 0.01). Thus, it appears that the TβRII gene is a target of mismatch repair deficiency. Conclusion. Taken together, we found that the decreased expression of TβRII as well as frameshift mutation of TβRII via mismatch repair deficiency frequently occurs in this tumor type, possibly causing loss of receptor function and unresponsiveness of TGF-β signaling that may lead to endometrial carcinogenesis.