Jacoby R F, Marshall D J, Kailas S, Schlack S, Harms B, Love R
Division of Gastroenterology, University of Wisconsin, Madison, USA.
Gastroenterology. 1995 Jul;109(1):73-82. doi: 10.1016/0016-5085(95)90270-8.
BACKGROUND & AIMS: Genetic instability related to defective DNA mismatch repair genes may be involved in the pathogenesis of carcinoma in hereditary nonpolyposis colon cancer (HNPCC). However, nonneoplastic tissues from patients inheriting defects in human MSH2 or human MLH1 do not show significant genetic instability. The aim of this study was to determine whether acquisition of genetic instability at the adenoma stage promotes malignant transformation by studying adenoma-carcinoma progression in HNPCC.
Dinucleotide repeat loci were analyzed by polymerase chain reaction from microdissected adenoma and/or carcinoma stages from formalin-fixed paraffin-embedded HNPCC tumors.
Although genetic instability was observed at some loci in almost all cases, the proportion of microsatellite loci altered was significantly less (P < 0.01) in completely benign adenomas (24%) than in benign areas of adenomas with malignancy (54%). Molecular fingerprints indicated intratumor heterogeneity, with evolution of related subclones of neoplastic cells. However, in all cases of tumor progression, at least one subclone from the adenoma stage was closely related to the carcinoma.
Some genetic instability develops at the benign adenoma stage in most HNPCC tumors. Adenomas with a greater rate of genetic instability are more likely to progress to carcinoma. Topographic genotyping data provides evidence supporting the hypothesis of adenoma-carcinoma progression in HNPCC.
与DNA错配修复基因缺陷相关的基因不稳定可能参与遗传性非息肉病性结直肠癌（HNPCC）的癌变过程。然而，携带人类MSH2或人类MLH1缺陷的患者的非肿瘤组织并未显示出明显的基因不稳定。本研究的目的是通过研究HNPCC中腺瘤 - 癌的进展情况，确定腺瘤阶段基因不稳定的获得是否促进恶性转化。
通过聚合酶链反应对来自福尔马林固定石蜡包埋的HNPCC肿瘤的显微切割腺瘤和/或癌阶段的二核苷酸重复位点进行分析。
虽然几乎在所有病例的某些位点都观察到基因不稳定，但完全良性腺瘤（24%）中微卫星位点改变的比例明显低于伴有恶性的腺瘤的良性区域（54%）（P < 0.01）。分子指纹图谱显示肿瘤内存在异质性，肿瘤细胞相关亚克隆发生演变。然而，在所有肿瘤进展的病例中，至少有一个来自腺瘤阶段的亚克隆与癌密切相关。
大多数HNPCC肿瘤在良性腺瘤阶段会出现一些基因不稳定。基因不稳定率较高的腺瘤更有可能进展为癌。地形基因分型数据为支持HNPCC中腺瘤 - 癌进展假说提供了证据。
