GENETIC ALTERATIONS AT 5P15 - A POTENTIAL MARKER FOR PROGRESSION OF PRECANCEROUS LESIONS OF THE UTERINE CERVIX

Background: Development of uterine cervical cancer is preceded by pren eoplastic proliferative changes in the cervical epithelium called ''in tra-epithelial neoplasia'' or ''dysplasia.'' The genetic basis of the origin and progression of such preneoplastic lesions is not known. By analysis of carcinomas for loss of constitutional heterozygosity (LOH) , we have previously shown a high frequency of allelic loss in the sho rt arm of chromosome 5 (5p), suggesting loss of a candidate tumor supp ressor gene located in 5p and associated with the development of this tumor. Purpose: To further understand the role of genetic alterations that affect 5p in cervical carcinogenesis, we evaluated the status of microsatellite polymorphisms at five loci mapped to 5p14-ter in precan cerous and cancerous lesions. Methods: Biopsy specimens from two group s of patients were analyzed for genetic alterations affecting 5p. One group comprised 14 cases of precancerous lesions (i.e., dysplasias) an d five cases of carcinoma in situ (CIS); the second group comprised 46 previously untreated patients with invasive carcinoma. Tumor and norm al DNAs were analyzed by polymerase chain reaction for genetic losses and instability at five polymorphic microsatellite loci (D5S392, D5S40 6, D5S208, D5S117, and D5S432) mapped to 5p. Results: LOH was observed in 25 (55.6%) of 45 informative invasive carcinomas, one (20%) of fiv e cases of CIS, and three (21%) of 14 precancerous lesions. Among the loci tested, D5S406 (5p15.1-15.2) exhibited LOH in 12 (48%) of 25 inva sive carcinomas, one (33%) of three cases of CIS, and three (60%) of f ive precancerous lesions, suggesting this to be the site in 5p of the novel candidate tumor suppressor gene. In addition, replication error- type alterations were noted in the 5p14-ter region in six (13%) of 46 invasive carcinomas, two (40%) of five cases of CIS, and three (21%) o f 14 precancerous lesions. Instability affected D5S406 in eight (66.7% ) of 12 instances that showed microsatellite instability, Conclusion: These observations suggest that allelic loss and microsatellite instab ility in the region of D5S406 may play a role early in the development of cervical carcinoma and identify the site of a candidate tumor supp ressor gene. These genetic markers (allelic loss and microsatellite in stability) may also define CIS and precancerous lesions at high risk f or progression to invasive cancer. Implications: The future molecular cloning of the candidate tumor suppressor gene at 5p15.1-15.2 may prov ide new insights into the genetic mechanisms of cervical carcinogenesi s. Analysis and clinical follow-up of a large cohort of prospectively ascertained cases of precancerous lesions would help to validate the u sefulness of these markers.