Chang Shih-Ching, Lin Jen-Kou, Lin Tzu-Chen, Liang Wen-Yih
Division of Colon and Rectal Surgery, Department of Surgery, Veterans General Hospital-Taipei, National Yang-Ming University, Taiwan, China.
World J Gastroenterol. 2005 Feb 14;11(6):778-84. doi: 10.3748/wjg.v11.i6.778.
Colorectal cancers result from the accumulation of several distinct genetic alterations. This study was to investigate the frequency and prognostic value of loss of heterozygosity (LOH) and microsatellite instability (MSI) at 14 genetic loci located near or within regions containing important genes implicated in colorectal tumorigenesis.
We studied colorectal cancers with corresponding normal mucosae in 207 patients (139 males and 68 females, mean age at the time of tumor resection 66.2+/-12.4 years, range 22-88 years). There were 37 right-sided colonic tumors, 85 left-sided colonic tumors and 85 rectal tumors. The distribution of tumor staging was stage I in 25, stage II in 73, stage III in 68, and stage IV in 41. We analyzed the LOH and MSI of HPC1, hMSH2, hMLH1, APC, MET, P53, NH23-H1, DCC, BAT25, BAT26, D17S250, MYCL1 and D8S254 with fluorescent polymerase chain reaction and denatured gel electrophoresis. High-frequency LOH was determined to be greater than three, or more than 50% of the informative marker with LOH. High-frequency MSI (MSI-H) was determined as more than four markers with instability (>30%). Correlations of LOH and MSI with clinical outcomes and pathological features were analyzed and compared.
The occurrence of MSI-H was 7.25%, located predominantly in the right colons (7/15) and had a higher frequency of poor differentiation (6/15) and mucin production (7/15). LOH in at least one genetic locus occurred in 78.7% of the tumors and was significantly associated with disease progression. Of the 166 potentially cured patients, 45 developed tumor recurrence within 36 mo of follow-up. Clinicopathological factors affecting 3-year disease-free survival (DFS) were TNM staging, grade of differentiation, preoperative CEA level, and high LOH status. Patients with high LOH tumors had a significantly lower DFS (50%) compared with patients with low LOH tumors (84%). Of the patients developing subsequent tumor recurrence, the number and percentage of LOH were 2.97 and 46.8% respectively, similar to the stage IV disease patients. TNM staging had the most significant impact on DFS, followed by high LOH status.
Clinical manifestations of LOH and MSI are different in colorectal cancer patients. High-frequency LOH is associated with high metastatic potential of colorectal cancers.
结直肠癌是由多种不同的基因改变累积所致。本研究旨在调查位于结直肠癌发生相关重要基因所在区域附近或内部的14个基因座处杂合性缺失（LOH）和微卫星不稳定性（MSI）的频率及预后价值。
我们研究了207例患者（139例男性和68例女性，肿瘤切除时的平均年龄为66.2±12.4岁，范围为22 - 88岁）的结直肠癌及其相应的正常黏膜。其中有37例右半结肠癌、85例左半结肠癌和85例直肠癌。肿瘤分期分布为：I期25例，II期73例，III期68例，IV期41例。我们采用荧光聚合酶链反应和变性凝胶电泳分析了HPC1、hMSH2、hMLH1、APC、MET、P53、NH23 - H1、DCC、BAT25、BAT26、D17S250、MYCL1和D8S254的LOH和MSI。高频LOH被定义为大于三个或超过50%的信息性标记出现LOH。高频MSI（MSI - H）被定义为超过四个标记出现不稳定性（>30%）。分析并比较了LOH和MSI与临床结局及病理特征的相关性。
MSI - H的发生率为7.25%，主要位于右半结肠（7/15），且低分化（6/15）和黏液产生（7/15）的频率较高。78.7%的肿瘤在至少一个基因座处发生LOH，且与疾病进展显著相关。在166例可能治愈的患者中，45例在随访的36个月内出现肿瘤复发。影响3年无病生存率（DFS）的临床病理因素为TNM分期、分化程度、术前癌胚抗原（CEA）水平和高LOH状态。与低LOH肿瘤患者（84%）相比，高LOH肿瘤患者的DFS显著更低（50%）。在出现后续肿瘤复发的患者中，LOH的数量和百分比分别为2.97和46.8%，与IV期疾病患者相似。TNM分期对DFS的影响最为显著，其次是高LOH状态。
结直肠癌患者中LOH和MSI的临床表现不同。高频LOH与结直肠癌的高转移潜能相关。
