| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2005: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Research Abstract |
There is increasing evidence that not only genetic but also epigenetic alterations are involved in many types of carcinogenesis. We have been studied molecular mechanisms of colorectal carcinogenesis using microsatellite, mutation and methylation analysis. Recently, we have found that the BRAF mutation was frequently seen in a subset of hyperplastic polyp (HP), termed as sessile serrated adenoma (SSA) and in sporadic colorectal cancer (CRC) showing high level microsatellite instability (MSI-H), both of which were associated with CpG island methylator phenotype (CIMP). We have first reported that sporadic MSI-H CRC may originate in SSA and not adenoma, and BRAF mutation and DNA methylation are early event in this "serrated neoplastic pathway" distinct from the accepted "adenoma-carcinoma-sequence" [Gut 53(8): 1137-1144, 2004]. Moreover, we have reported that promoter hypermethylation and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H CRC [Familiar C
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ancer 3(2): 101-107, 2004].
The colorectal polyps are classified into HP, mixed polyp, serrated adenoma (SA), villous adenoma and conventional adenoma using WHO criteria. Classifying HPs into microvesicular and goblet cell-type HP, and SAs into traditional SA and variant HP described as "SSA", we screened these precursor lesions and CRCs for activating mutation of oncogene KRAS and BRAF, inactivating mutation of tumor suppressor gene APC, and methylation status of CpG island. In contrast to well accepted multi-step model of mutation accumulation, we found that few CRC contained mutations in KRAS, BRAF and APC and almost CRC had mutation in only one of these genes. The most common combination of mutations was APC and KRAS (11.2%), whereas mutations in both APC and BRAF/KRAS were extremely rare (1.1%/0%). Similar mutational pattern was also observed in colon polyps. On the other hand, we confirmed that aberrant DNA methylation is only a disease of older individuals with MSI-H cancer but in associated with all subsets of colorectal cancers. These results suggest that multiple genetic pathways to CRC exist and that mutation in APC and CIMP negative was an early event in adenoma-carcinoma sequence, while mutation in KRAS/BRAF and CIMP-positive predispose to serrated neoplastic pathway. Less
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