Larson A A, Liao S Y, Stanbridge E J, Cavenee W K, Hampton G M
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla 92093, USA.
Cancer Res. 1997 Oct 1;57(19):4171-6.
Carcinomas of the uterine cervix are thought to arise from preinvasive dysplastic lesions, termed cervical intraepithelial neoplasias (CIN), grades I-III. Patients may present clinically with two or more distinct lesions of differing histological severity; however, the genesis of these multifocal lesions is unknown. Despite infection with high-risk human papilloma virus subtypes, which is a major etiological factor in disease pathogenesis, only a small and unpredictable number of dysplastic lesions progress to invasive cancer. Several lines of evidence suggest that additional somatic events, such as tumor suppressor gene inactivation, are required for malignant transformation. In support of this, loss of heterozygosity (LOH) analyses of invasive cervical carcinomas have identified several chromosomal arms likely to harbor tumor suppressor genes, of which regions on 3p, 4p, 4q, and 11q have been validated extensively. To evaluate the potential role of tumor suppressor gene inactivation in dysplastic progression, loci distributed on these four chromosomal regions were assessed for LOH in 42 CIN lesions of varying histological grade obtained from 17 patients. Analysis of at least 16 microsatellite loci in each lesion revealed allelic losses involving one or more of these chromosomal regions in 0% of CIN I lesions; 25% of CIN II lesions; and 88% of CIN III lesions, with 41% of CIN III lesions exhibiting LOH for three or more chromosomal regions. In addition, where LOH was scored for the same locus at a particular chromosomal region in all of the multiple lesions from a single patient, the same allele was lost at each locus, without exception. Statistical analysis of these allele-specific losses strongly suggests that topologically distinct lesions are related and likely arise from a common precursor cell.
子宫颈癌被认为起源于癌前发育异常病变，即宫颈上皮内瘤变（CIN），分为I - III级。患者临床上可能表现为两种或更多种不同组织学严重程度的明显病变；然而，这些多灶性病变的起源尚不清楚。尽管感染高危型人乳头瘤病毒亚型是疾病发病机制中的主要病因，但只有一小部分且不可预测数量的发育异常病变会发展为浸润性癌。有几条证据表明，恶性转化还需要其他体细胞事件，如肿瘤抑制基因失活。支持这一观点的是，对浸润性宫颈癌的杂合性缺失（LOH）分析已确定了几个可能含有肿瘤抑制基因的染色体臂，其中3p、4p、4q和11q区域已得到广泛验证。为了评估肿瘤抑制基因失活在发育异常进展中的潜在作用，对从17名患者获得的42个不同组织学分级的CIN病变，评估了分布在这四个染色体区域的基因座的LOH情况。对每个病变至少16个微卫星基因座的分析显示，CIN I级病变中0%出现涉及这些染色体区域中一个或多个区域的等位基因缺失；CIN II级病变中为25%；CIN III级病变中为88%，41%的CIN III级病变在三个或更多染色体区域表现出LOH。此外，在同一患者的所有多个病变中，对特定染色体区域的同一位点进行LOH评分时，每个位点无一例外都丢失了相同的等位基因。对这些等位基因特异性缺失的统计分析有力地表明，拓扑结构不同的病变是相关的，并且可能起源于一个共同的前体细胞。
