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Genetic Alterations Accumulate during Cervical Tumorigenesis and Indicate a Common Origin for Multifocal Lesions¹

Ludwig Institute for Cancer Research [A. A. L., W. K. C., G. M. H.], Department of Medicine [W. K. C., G. M. H.], and Center for Molecular Genetics [W. K. C.], University of California at San Diego, La Jolla, California 92093; Department of Pathology, St. Joseph Hospital, Orange, California 92668 [S-Y. L.]; and Department of Microbiology and Molecular Genetics, University of California at Irvine, Irvine, California 92717 [E. J. S.]

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.

¹ This work was supported in part by Grant CA 19401 (to E. J. S.). A. A. L. was a Howard Hughes Medical Student Trainee during the course of this work.

² To whom requests for reprints should be addressed, at Genos Biosciences, Inc., 11099 North Torrey Pines Road, Suite 220, La Jolla, CA 92037. E-mail: garret_hampton@sequana.com.

Received 6/20/97. Accepted 8/13/97.

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