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マイクロサテライト不安定性陰性の遺伝性非腺腫症性大腸癌におけるTGF-β II型レセプター遺伝子の生殖細胞突然変異：陸世龍¹, 川畑正博², 今村健志², 秋山好光¹, 野水整³、宮園浩平², 湯浅保仁¹（¹東京医歯大・医・衛生, ²癌研・研・生化, ³星総合病・外）

HNPCC without microsatellite instability associated with germline mutation of the TGF-β type II receptor gene: Shi-Long LU¹, Masahiro KAWABATA², Takeshi IMAMURA², Yoshimitsu AKIYAMA¹, Tadashi NOMIZU³, Kohei MIYAZONO², Yasuhito YUASA¹ (¹Dept. Hygiene & Oncol., Tokyo Med. & Dent. Univ. Sch. Med., ²Dept. Biochem., Cancer Inst., ³ Dept. Surg., Hoshi General Hosp.)

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer predisposition syndrome associated with mutations in five DNA mismatch repair genes, i. e., hMSH2, hMLH1, hPMS1, hPMS2 and hMSH6. Germline mutations of these genes account for approximately 80% of kindreds with HNPCC fulfilling the Amsterdam criteria and showing microsatellite instability (MSI) in tumor DNA. However, the genes responsible for MSI(-) HNPCC are still unknown. Here we screened for germline mutations of the TGF-β type II receptor gene (RII) in five MSI(-) HNPCC kindreds. A substitution of methionine for threonine at codon 315 in the kinase domain of RII was found in one kindred. The patient and her two children exhibited a heterozygous state of the substitution. Loss of the wild type allele of RII was observed in a colorectal cancer of the proband, suggesting that loss of function of the gene play an essential role in the carcinogenesis of this tumor. Functional analysis of this mutant showed that it caused a defect in the growth inhibition in response to TGF-β .These data indicate that this germline mutation conferred the cancer predisposition in this family, and suggest that RII may be responsible for some HNPCC without MSI.