Elucidation of carcinogenic mechanisms in ulcerative colitis

研究了溃疡性结肠炎（UC）相关肿瘤（UCAN）的基因改变状况，重点研究了微卫星不稳定性（microsatellite instability， MSI）在部分结直肠癌中的表现，以及发生在散发性结直肠肿瘤发生早期的大肠腺瘤性息肉病（adenomatous polyposis coli， APC）基因和K-ras基因的突变。我们调查了15例在我院行结直肠切除术的UC患者的31例UCAN。8例浸润性癌，15例高级别发育不良（HGD）， 8例低级别发育不良（LGD）。采用显微解剖法从每个肿瘤病变及相应的非肿瘤组织中提取DNA。检测了9个微卫星位点的MSI状态、APC位点杂合性缺失（LOH）和K-ras密码子12点突变。MSI: 4/31 (13%); UCAN: 1/8（13%）。HGD: 2/15（13%）。LGD: 1/8（13%）为msi高（3个或更多不稳定位点），12/31（39%）为UCAN(癌：3/8 (38%),HGD: 6/15 (40%), LGD: 3/8（38%）为msi低（1或2个不稳定位点）。在6例信息丰富（杂合）的UCAN中，9例APC位点未发现LOH。UCAN的K-ras突变率为3/31(9.7%)(癌：2/8 （25%),HGD: 1/15 (7%), LGD: 0/8）。MSI在UCAN中较为常见，存在于UCAN肿瘤发生的早期，APC基因和K-ras基因的遗传改变参与较少。MSI可能是UC肿瘤风险增加的机制之一，UCAN可能通过散发癌以外的其他致癌途径发展。

The status of genetic alterations in ulcerative colitis (UC)-associated neoplasia (UCAN) was investigated focusing on microsatellite instability (MSI) which is shown in a certain fraction of colorectal carcinomas, and adenomatous polyposis coli (APC) gene and K-ras gene, whose mutations occur in the early stage of sporadic colorectal tumorigenesis. Thirty-one UCAN from 15 UC patients who had undergone colorectal resection at our institution were investigated. There were 8 lesions of invasive carcinoma, 15 high-grade dysplasia (HGD) and 8 low-grade dysplasia (LGD). DNA was extracted from each neoplastic lesion and corresponding non-neoplastic tissue by microdissection method. MSI status at 9 microsatellite loci, loss of heterozygosity (LOH) at APC locus, and K-ras codon 12 point mutation were examined. As for MSI, 4/31 (13%) UCAN (carcinoma : 1/8 (13%). HGD : 2/15 (13%). LGD : 1/8 (13%) were MSI-high (3 or more unstable loci) and 12/31 (39%) UCAN (carcinoma : 3/8 (38%), HGD : 6/15 (40%), LGD : 3/8 (38%) were MSI-low (1 or 2 unstable loci). LOH at APC locus was not found in 9 UCAN from 6 informative (heterozygous) cases. K-ras mutation rate of UCAN was 3/31 (9.7%) (carcinoma : 2/8 (25%), HGD : 1/15 (7%) and LGD : 0/8). MSI is relatively common in UCAN and is present at the early stage of tumorigenesis of UCAN, and the involvement of genetic alterations of APC gene and K-ras gene is small. MSI may act as one of the mechanisms for the increased neoplastic risk in UC, and UCAN may develop through other carcinogenic pathway than sporadic carcinomas.