HNPCCの概念と日本の現状

Current Concepts of HNPCC in Japan

要旨　HNPCC（hereditary nonpolyposis colorectal cancer）はLynch症候群あるいは家族性大腸癌とも言われている．第1例がWarthin（1913年）により報告され，後の後継者により更に追跡され集積された．その家系調査の解析の結果，Lynchにより優性遺伝性疾患であることが証明された．しかし，家族性大腸腺腫症のように多数の腺腫を発生するようなはっきりした形質発現がなく，その診断は家族構成員を含めての注意深い病歴の聴取によっていた．1994年，その原因遺伝子がクローニングされ本疾患の概念が明確となった．すなわち，酵母や大腸菌で既に知られているミスマッチ修復遺伝子mut HLS系のhuman homologueとしてhMLH2，hMLH1，hPMS1，hPMS2が相次いで発見され，これらが遺伝子群としてDNAミスマッチの修復を行い，染色体のstabilityの維持に役立っていることが判明した．これらの遺伝子に変異が起こるとミスマッチが修復されず遺伝子の変異が起こる確率が100～1,000倍増加すると考えられる．したがって第1癌が手術により治癒しても第2癌の発生のリスクが高いことも理解される．Lynch Ⅰ型は家系内に大腸癌のみ多発するもので，特に右側大腸癌が好発しsitespecific cancerとも言える．Lynch Ⅱ型は大腸癌のほかに他臓器の癌も発生するもので，わが国では第2癌として男性は胃癌，女性では子宮体部癌が多いことが第43回大腸癌研究会の調査で判明した．

　HNPCC (hereditary nonpolyposis colorectal cancer) is known as Lynch syndrome or familial colorectal cancer. The first kindred was reported by Dr. Warthin in 1937 which was subsequently followed by his successors. By analyzing this family tree, it was proved that HNPCC was a hereditary disease with dominant mode of inheritance by Dr. Lynch in 1973. However, because there was no specific phenotype such as polyps in familial adenomatous polyposis, the diagnosis of HNPCC mainly depended upon careful history taking. The category of HNPCC was well defined in 1994 when the causing genes of this disease were cloned as a human homologue of mutagenic gene of the yeast. They act as DNA repair genes, contributing to chromosomal stability. Various genes have been identified as follows hMSH2, hMSH1, hPMS1, hPMS2. These genes act as a unit to keep chromosomal stability, and their mutation increases the mutation rate of genes by 100 to 1,000 times. Therefore, even the primary colorectal cancer of HNPCC patient is surgically treated, there is a risk of developing another primary cancer in various organs. Lynch syndrome can be divided into Lynch-Ⅰ and Lynch-Ⅱ. Lynch-Ⅰ is characterized as a familial colon cancers which are predominantly located in the right side of the colon, and no cancer of the other organ is developed among the kindred. Lynch-Ⅱ is designated as familial cancers in various other organs besides the colon and rectum. In Japan, the stomach cancer in male and endometrial uterine cancer are most common second primary cancer in the cases of Lynch-Ⅱ, which was revealed by the survey of the 43rd Japanese society for the cancer of the colon and rectum.