Mathew R, Arora S, Mathur M, Chattopadhyay T K, Ralhan R
Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi.
J Cancer Res Clin Oncol. 2001 Oct;127(10):603-12. doi: 10.1007/s004320100249.
Microsatellite instability (MSI) as a determinant of propensity to esophageal squamous cell carcinoma (ESCC) at seven microsatellite markers at 2p (2p15-16), 3p (3p13, 3p14.1-3, 3p25, and 3p26) and 16q (16q12.1-3) was investigated to analyze their putative role as indicators of predisposition to esophageal malignancies.
Seven microsatellite loci were amplified by polymerase chain reaction, from surgically resected tumor tissues from 30 ESCC patients from Indian population, to assess the loss of heterozygosity (LOH) and replication error repeats (RER) and to correlate these alterations with aberrations in major cell cycle regulatory proteins and histopathological parameters.
LOH and RER analyses at these loci demonstrated moderate microsatellite alterations, suggesting the involvement of MSI in esophageal tumorigenesis in a subset of the Indian population. MSI, defined as RER in at least two or more of the loci studied, was observed in ten of 30 (33%) patients. Twenty-two of 30 patients (73%) showed LOH at one or more loci, while 17 of the 30 patients (60%) showed RER in at least one of the loci studied. RER-positive patients showed a trend towards better prognosis when compared to RER-negative patients. MSI demonstrated a significant association with concomitant loss of p16 and pRb (p16-/pRb- phenotype) (P=0.046). Interestingly, we observed an inverse correlation between MSI and p53 mutations (P=0.03) suggesting that MSI may provide a p53-independent pathway for esophageal tumorigenesis in RER+ patients. MSI showed a trend towards longer survival and absence of distant organ metastasis (P=0.06).
The present study demonstrates the probable role of MSI in esophageal squamous cell carcinoma in the Indian population. Instability associated with the repetitive sequences--the revealing marks of loss of DNA replication fidelity may serve as an indicator of predisposition to esophageal cancer.
研究微卫星不稳定性（MSI）作为食管鳞状细胞癌（ESCC）在2p（2p15 - 16）、3p（3p13、3p14.1 - 3、3p25和3p26）及16q（16q12.1 - 3）七个微卫星标记处易感性的决定因素，以分析其作为食管恶性肿瘤易感性指标的假定作用。
通过聚合酶链反应扩增来自印度人群30例ESCC患者手术切除肿瘤组织中的七个微卫星位点，以评估杂合性缺失（LOH）和复制错误重复序列（RER），并将这些改变与主要细胞周期调节蛋白的异常及组织病理学参数相关联。
这些位点的LOH和RER分析显示中度微卫星改变，提示MSI在部分印度人群的食管肿瘤发生中起作用。MSI定义为在所研究的至少两个或更多位点出现RER，在30例患者中有10例（33%）观察到。30例患者中有22例（73%）在一个或多个位点出现LOH，而30例患者中有17例（60%）在至少一个所研究位点出现RER。与RER阴性患者相比，RER阳性患者显示出预后较好的趋势。MSI与p16和pRb同时缺失（p16 - /pRb - 表型）显著相关（P = 0.046）。有趣的是，我们观察到MSI与p53突变呈负相关（P = 0.03），提示MSI可能为RER + 患者的食管肿瘤发生提供一条不依赖p53的途径。MSI显示出存活时间较长且无远处器官转移的趋势（P = 0.06）。
本研究证明了MSI在印度人群食管鳞状细胞癌中的可能作用。与重复序列相关的不稳定性——DNA复制保真度丧失的显著标志，可能作为食管癌易感性的指标。
