内容紹介
A Novel Genetic Disorder of Lynch Syndrome―EPCAM Gene Deletion
Summary
Lynch syndrome, also known as hereditary non-polyposis colorectal cancer, HNPCC, is a cancer-predisposing autosomal-dominant hereditary disorder caused by defects of the mismatch repair(MMR)system during DNA replication. Not only colorectal cancer, but malignancies in various organs, e.g., endometrium, stomach, small intestine, and urinary tract, occur in people of a relatively young age and accumulate in the family; therefore, this syndrome is considered to be a very important clinical entity with regard to the cancer treatment strategy. Germline mutations of 4 MMR genes, e.g., MLH1, MSH2, MSH6 and PMS2, had been identified as the cause of this disease, however, a novel mechanism, epigenetic inactivation of MSH2 gene due to hypermethylation of promotor region by the deletion of 3′part of epithelial cell adhesion molecule(EPCAM)gene which is located upstream of the MSH2 gene, has been reported in recent years. Therefore, it should be kept in mind in genetic testing and/or counseling for Lynch syndrome case with MSH2 defect that there might be a deletion of the EPCAM gene. In this review, the significance of the EPCAM gene defect in the management for Lynch syndrome is briefly introduced.
要旨
Lynch syndrome(Lynch症候群)は,遺伝性非ポリポーシス大腸癌(hereditary non-polyposis colorectal cancer: HNPCC)とも呼ばれ,家族性大腸腺腫症(familial adenomatous polyposis: FAP)と並ぶ代表的な遺伝性大腸癌である。その定義は,ミスマッチ修復(mismatch repair: MMR)系の異常を背景とする常染色体優性遺伝形式の癌症候群であり,その原因としてMLH1,MSH2,MSH6,PMS2の4種のMMR遺伝子の生殖細胞変異germline mutationが知られていた。以前からこれらMMR遺伝子のメチル化による不活性化などが報告され,epigeneticな異常による新たな発癌機構として注目されたが,近年,MSH2遺伝子の不活性化の原因としてMSH2遺伝子の上流に位置するepithelial cell adhesion molecule(EPCAM)遺伝子の部分欠損の存在が明らかとなり,本疾患の遺伝子診断や遺伝カウンセリングに際しても留意する必要がある。 本稿では,Lynch症候群における新しい原因遺伝子異常として近年注目されているこのEPCAM遺伝子欠損について,その報告の経緯や臨床的意義などの概略を紹介することにする。
目次
Summary
Lynch syndrome, also known as hereditary non-polyposis colorectal cancer, HNPCC, is a cancer-predisposing autosomal-dominant hereditary disorder caused by defects of the mismatch repair(MMR)system during DNA replication. Not only colorectal cancer, but malignancies in various organs, e.g., endometrium, stomach, small intestine, and urinary tract, occur in people of a relatively young age and accumulate in the family; therefore, this syndrome is considered to be a very important clinical entity with regard to the cancer treatment strategy. Germline mutations of 4 MMR genes, e.g., MLH1, MSH2, MSH6 and PMS2, had been identified as the cause of this disease, however, a novel mechanism, epigenetic inactivation of MSH2 gene due to hypermethylation of promotor region by the deletion of 3′part of epithelial cell adhesion molecule(EPCAM)gene which is located upstream of the MSH2 gene, has been reported in recent years. Therefore, it should be kept in mind in genetic testing and/or counseling for Lynch syndrome case with MSH2 defect that there might be a deletion of the EPCAM gene. In this review, the significance of the EPCAM gene defect in the management for Lynch syndrome is briefly introduced.
要旨
Lynch syndrome(Lynch症候群)は,遺伝性非ポリポーシス大腸癌(hereditary non-polyposis colorectal cancer: HNPCC)とも呼ばれ,家族性大腸腺腫症(familial adenomatous polyposis: FAP)と並ぶ代表的な遺伝性大腸癌である。その定義は,ミスマッチ修復(mismatch repair: MMR)系の異常を背景とする常染色体優性遺伝形式の癌症候群であり,その原因としてMLH1,MSH2,MSH6,PMS2の4種のMMR遺伝子の生殖細胞変異germline mutationが知られていた。以前からこれらMMR遺伝子のメチル化による不活性化などが報告され,epigeneticな異常による新たな発癌機構として注目されたが,近年,MSH2遺伝子の不活性化の原因としてMSH2遺伝子の上流に位置するepithelial cell adhesion molecule(EPCAM)遺伝子の部分欠損の存在が明らかとなり,本疾患の遺伝子診断や遺伝カウンセリングに際しても留意する必要がある。 本稿では,Lynch症候群における新しい原因遺伝子異常として近年注目されているこのEPCAM遺伝子欠損について,その報告の経緯や臨床的意義などの概略を紹介することにする。