Elucidation of carcinogenic mechanisms in ulcerative colitis

本研究旨在探讨溃疡性结肠炎（UC）相关性肿瘤（UCAN）的遗传学改变，重点是在一定比例的大肠癌中出现的微卫星不稳定性（MSI），以及在散发性大肠肿瘤发生早期出现的结肠腺瘤性息肉病（APC）基因和K-ras基因的突变。我们研究了来自15名在我们机构接受结直肠切除术的UC患者的31例UCAN。浸润性癌8例，高度异型增生（HGD）15例，低度异型增生（LGD）8例。用显微切割法从每个肿瘤病灶和相应的非肿瘤组织中提取DNA。检测9个微卫星位点的MSI、APC位点的杂合性丢失（洛）和K-ras基因第12密码子点突变。MSI：UCAN：4/31（13%），癌：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%）UCAN（癌：38（38%），HGD：6/15（40%），LGD：38（38%）为MSI低（1或2个不稳定位点）。6例信息型（杂合子）UCAN中9例未发现APC位点洛。UCAN中K-ras突变率为9.7%（3/31），其中腺癌25%（2/8），HGD 7%（1/15），LGD 0/8。MSI在UCAN中较常见，且发生于UCAN肿瘤发生的早期阶段，APC基因和K-ras基因的遗传学改变所涉及的程度较小。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.