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

Objective. Transforming growth factor beta (TGF-beta) is a multifunctional cytokine that strongly inhibits epithelial cell growth. Disabling of TGF-beta signaling is thought to be involved in development of a variety of tumors in which abnormal expression or function of TGF-beta receptor plays critical roles. In the present study, we examined aberrant expression and mutation of the gene TGF-beta receptor type II (T beta RII) 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 T beta RII mRNA expression (mean level 2.44 +/- 2.65), compared to normal endometria (mean level 7.23 +/- 6.07) (P < 0.001). Methylation status of T beta RII promoter containing 30 CpGs was examined by bisulfite sequencing analysis, and 98% (51/52) of the patients were found to have unmethylated T beta RII promoter, indicating that promoter hypermethylation is not the major cause of decreased expression of T beta RII 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 T beta RII gene. Notably, these mutations were preferentially accumulated in patients with MSI-H phenotype (7/19:37%) (P < 0.001) or with those with methylated MLHI promoters (6/ 16:38%) (P < 0.01). Thus, it appears that the T beta RII gene is a target of mismatch repair deficiency. Conclusion. Taken together, we found that the decreased expression of T beta R11 as well as frameshift mutation of T beta RII via mismatch repair deficiency frequently occurs in this tumor type, possibly causing loss of receptor function and unresponsiveness of TGF-beta signaling that may lead to endometrial carcinogenesis. (c) 2005 Elsevier Inc. All rights reserved.