hMLH1プロモーター領域に胚細胞性メチル化を有する若年発症型MSI陽性大腸癌  [in Japanese] Early-onset MSI-H Colorectal Cancers with hMLH1 Promoter Germline Methylation  [in Japanese]

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    • 永井 秀雄 NAGAI H.
    • 自治医科大学外科学講座消化器外科部門 Department of Surgery, Jichi Medical University


MSIはゲノムDNAの単純な繰り返し配列の反復回数の異常でありHNPCCの90%に認められる. 一方, 非遺伝性大腸癌の10~15%でも認められ<i>hMLH1</i> プロモーターのメチル化が深く関与している. 最近, HNPCCに合致しない若年発症のMSI陽性大腸癌の報告が散見され, 胚細胞系列の<i>hMLH1</i> プロモーター領域のメチル化の関与が示唆されている. 今回, 現時点で報告されている8例の解析を行ったので報告する. 平均32歳と若年傾向を示し多重癌を4例に認めた. 6例にはHNPCC関連癌の家族歴を認めなかった. 末梢血リンパ球を含む正常細胞では, <i>hMLH1</i> プロモーターのメチル化が片側のアレルにのみ認められた. 子宮癌以外の癌組織では, <i>hMLH1</i> は片側アレルのメチル化と対側アレルのLOHのツーヒットで遺伝子発現を消失し発癌に関与していた. 両親, 子供, 兄弟にはメチル化は認めなかった. 若年発症型メチル化陽性MSI陽性大腸癌はMSI陽性大腸癌の特殊な一型であり, その個人において多重癌発症のリスクが高い可能性がある.

Microsatellite instability (MSI) can be detected as changes in the length of microsatellite repeats, which can be present in 90% of HNPCC and 10-15% of sporadic colorectal cancers (CRCs). Methylation of the <i>hMLH1</i> promoter region has been suggested to be the major mechanism for gene inactivation in sporadic MSI-H CRCs. Recently, germline methylation of the <i>hMLH1</i> promoter region was detected in early-onset MSI-H CRCs which did not meet criteria for HNPCC. So far, eight CRC patients have been reported. We review the clinical and genetic features of distinctive MSI-H category with germline methylation. All eight patients developed colon cancers at a young age and four of them developed multiple primary cancers. Six of them lacked familial predisposition to the HNPCC related cancers in their first-degree relatives. Methylation of the <i>hMLH1</i> promoter region occurred constitutively, for it was observed not only in peripheral blood lymphocytes, but also in miscellaneous organs. This methylation was hemiallelic in normal cells followed by inactivation of the other allele by chromosomal loss in cancers. Available affected individuals did not exhibit germline methylation. These findings suggest that constitutive hemiallelic methylation of the <i>hMLH1</i> promoter region is associated with carcinogenesis in sporadic early-onset MSI-H CRCs and may increase the risk of multiple primary cancers.


  • The Japanese journal of proctology  

    The Japanese journal of proctology 60(3), 130-135, 2007-03-01 

    The Japan Society of Coloproctology

References:  10

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