Loss of heterozygosity: An independent prognostic factor of colorectal cancer
Loss of heterozygosity: An independent prognostic factor of colorectal cancer
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DOI：
10.3748/wjg.v11.i6.778
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发表时间：
2005-02-14
影响因子：
4.3
通讯作者：
Liang, Wen-Yih
中科院分区：
文献类型：
--
作者：
Chang, Shih-Ching;Lin, Jen-Kou;Liang, Wen-Yih
目的：结直肠癌是由几种不同的遗传变异累积而成。本研究旨在探讨位于大肠癌发生相关基因区域附近或区域内的14个基因位点的杂合性丢失（洛）和微卫星不稳定性（MSI）的频率及其预后价值。我们研究了207例结直肠癌患者的相应正常粘膜（139名男性和68名女性，肿瘤切除时的平均年龄为66.2 ± 12.4岁，范围为22-88岁）。右半结肠肿瘤37例，左半结肠肿瘤85例，直肠肿瘤85例。肿瘤分期分布为I期25例，II期73例，III期68例，IV期41例。应用荧光聚合酶链反应和变性凝胶电泳技术检测HPC 1、hMSH 2、hMLH 1、APC、MET、P53、NH 23-H1、DCC、BAT 25、BAT 26、D17 S250、MYCL 1和D8 S254的洛和不稳定性。高频率的洛被确定为大于3个，或大于50%的具有洛的信息标记。高频MSI（MSI-H）被确定为具有不稳定性（>30%）的4个以上标记物。结果：MSI-H的发生率为7.25%，主要发生在右半结肠（7/15），低分化（6/15）和粘蛋白生成（7/15）的发生率较高。78.7%的肿瘤发生至少一个基因位点的洛缺失，并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）的临床病理因素包括TNM分期、分化程度、术前CEA水平和高洛状态。高洛性肿瘤患者的DFS（50%）显著低于低洛性肿瘤患者（84%）。在肿瘤复发的患者中，洛缺失的数量和比例分别为2.97%和46.8%，与IV期患者相似。结论：结直肠癌患者洛和MSI的临床表现不同。高频率的洛缺失与大肠癌的高转移潜能有关。(C)2005年WJG出版社和Elsevier Inc. All rights reserved.
AIM: 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.METHODS: 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.RESULTS: 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.CONCLUSION: Clinical manifestations of LOH and MSI are different in colorectal cancer patients. High-frequency LOH is associated with high metastatic potential of colorectal cancers. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved.