遺伝子背景からみた大腸癌の左右差

Molecular Mechanism Related to Tumor Site in Colorectal Cancer

要旨　近年の大腸癌の発癌機構に関する研究から，大腸癌の発生経路には，マイクロサテライト不安定性（microsatellite instability ; MSI）や染色体不安定性（chromosomal instability ; CIN）に加えて，エピゲノム異常が関与していることが明らかになってきた．MSI陽性大腸癌は，右側大腸に好発し予後良好である．一方，CIN陽性の大腸癌は，様々な遺伝子の変異が介在していることから，多様な臨床像を呈する．エピゲノム異常に起因する大腸癌のうちCIMP（CpG island methylator phenotype）は，右側結腸に好発し，BRAFの変異を伴う予後のよいCIMP1/CIMP-HとK-rasの変異を伴い予後の悪いCIMP2/CIMP-lowが存在する．さらに左側結腸のDNAメチル化異常は，主に加齢によりDNAメチル化の影響を受けやすい遺伝子がDNAメチル化していることが明らかとなった．これらのゲノム・エピゲノム異常が，左右大腸癌での異なる病理像や形態学，臨床経過に影響を及ぼしていると考える．

　Recent molecular analysis for CRCs（colorectal cancers）have revealed that at least three molecular pathways contribute to tumorigenesis ; MSI（microsatellite instability）, CIN（chromosomal instability）, and recently characterized epigenetic abnormalities. CRCs with MSI, which is characterized by the presence of frame-shift mutations in microsatellite repeats, tend to occur in the proximal colon and generally associate with good prognosis, while CRCs with CIN is characterized by the presence of aneuploidy and chromosomal alterations, and tend to occur in the distal colon. Another distinct pathway, CIMP（CpG island methylator phenotype）, which is characterized by excessive gene methylation, has been considerably studied recently. Further, a series of studies revealed that CIMP could be classified into two subgroups. CIMP1/CIMP-H CRCs occur in the proximal colon, have BRAF mutation, and are related to good prognosis, while CIMP2/CIMP-low CRCs frequently have K-ras mutation and show poor prognosis. These molecular mechanisms indicate that CRCs are no longer viewed as a single disease : CRCs in each pathway show distinct clinicopathological features including tumor location, with important implications for prevention, screening, and therapy.