HNPCCと遺伝子異常

Genetic Analysis of HNPCC

要旨　HNPCCの発癌機構を解析するため，原因遺伝子であるhMSH2とhMLH1を日本人家系について調べた．現在までに6例でhMSH2の変異が，また1例でhMLH1の変異が検出された．すべてがナンセンス変異などの蛋白質が短くなる変異であった．今後これらの家系では，遺伝子診断が可能になった．これらの2つはミスマッチ修復遺伝子であり，異常の結果，短い繰り返し配列に変異が起こりやすくなる．TGF-β Ⅱ型レセプター遺伝子は短い繰り返し配列を持っているので，解析した結果HNPCCでは高率に変異が検出された．この遺伝子の異常によりHNPCCの発癌過程が始まる可能性が高い．

　Hereditary nonpolyposis colorectal cancer (HNPCC) is one of the cancer susceptible syndromes which are caused by the inheritance of mutations in the DNA mismatch repair genes, such as hMSH2, hMLH1, hPMS1 and hPMS2. To investigate the role of genetic alterations of hMSH2 and hMLH1 in HNPCC tumorigenesis, we analyzed Japanese kindreds with HNPCC. There were six HNPCC kindreds with germ line mutations of the hMSH2, and a HNPCC kindred with those of hMLH1. These results may identify presymptomatic patients with HNPCC.

　To determine the relation between the mutation of the TGF-β type Ⅱ receptor gene and the genomic instability in the tumorigenesis of HNPCC, we examined genomic DNA of tumors from patients with HNPCC. There were one or two A deletions in the (A)₁₀ repeat in 17 out of 24 (71%) genomic instability-positive HNPCC tumors, while there were no A deletions in 14 genomic instability-negative tumors. These deletions inactivated the receptor through a frameshift mutation which caused protein truncation. No mutations were detected in the corresponding normal cells from these cases, which indicated a somatic mutation. These results suggested that the TGF-β type Ⅱ receptor gene was a major target of genomic instability in HNPCC tomorigenesis.