GENETIC ALTERATIONS ACCUMULATE DURING CERVICAL TUMORIGENESIS AND INDICATE A COMMON ORIGIN FOR MULTIFOCAL LESIONS

Carcinomas of the uterine cervix are thought to arise from preinvasive dysplastic lesions, termed cervical intraepithelial neoplasias (GIN), grades I-III, Patients may present clinically with two or more distin ct 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 i n disease pathogenesis, only a small and unpredictable number of dyspl astic lesions progress to invasive cancer, Several lines of evidence s uggest that additional somatic events, such as tumor suppressor gene i nactivation, are required for malignant transformation. In support of this, loss of heterozygosity (LOH) analyses of invasive cervical carci nomas have identified several chromosomal arms likely to harbor tumor suppressor genes, of which regions on 3p, 4p, 4q, and 11q have been va lidated extensively, To evaluate the potential role of tumor suppresso r gene inactivation in dysplastic progression, loci distributed on the se 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 in volving one or more of these chromosomal regions in 0% of CIN I lesion s; 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 a ddition, where LOH was scored for the same locus at a particular chrom osomal region in all of the multiple lesions from a single patient, th e same allele was lost at each locus, without exception, Statistical a nalysis of these allele-specific losses strongly suggests that topolog ically distinct lesions are related and likely arise from a common pre cursor cell.