Aberrant expression and mutations of TGF-beta 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 (TbetaRII) in endometrial cancers of endometrioid subtype.


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 TbetaRII mRNA expression (mean level 2.44 +/- 2.65), compared to normal endometria (mean level 7.23 +/- 6.07) (P < 0.001). Methylation status of TbetaRII promoter containing 30 CpGs was examined by bisulfite sequencing analysis, and 98% (51/52) of the patients were found to have unmethylated TbetaRII promoter, indicating that promoter hypermethylation is not the major cause of decreased expression of TbetaRII 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 TbetaRII 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 TbetaRII gene is a target of mismatch repair deficiency.


CONCLUSIONS
Taken together, we found that the decreased expression of TbetaRII as well as frameshift mutation of TbetaRII 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.
Sakaguchi
Junko
J
Department of Obstetrics and Gynecology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
Kyo
Satoru
S
Kanaya
Taro
T
Maida
Yoshiko
Y
Hashimoto
Manabu
M
Nakamura
Mitsuhiro
M
Yamada
Kiyofumi
K
Inoue
Masaki
M
D000107:Acetylation; D000328:Adult; D000368:Aged; D020137:Base Pair Mismatch; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004260:DNA Repair; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D006657:Histones / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
D006657:Histones; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II