GENOMIC ALTERATIONS IN CERVICAL-CARCINOMA - LOSSES OF CHROMOSOME HETEROZYGOSITY AND HUMAN PAPILLOMA-VIRUS TUMOR STATUS

Specific human papilloma virus (HPV) types appear to be necessary etio logical factors for most cervical cancers, yet additional genetic alte rations seem to be required for their development and progression. The aim of this study is to determine the likely chromosomes location of tumorigenicity suppressor-like genes, the loss of function of which mi ght be important in the origin or progression of cervical carcinomas. PCR with primers for 75 highly polymorphic microsatellite loci located on the major autosome arms were used to estimate the incidence of los s of heterozygosity (LOH) in 38 tumors. The HPV status of the tumors w as also determined. LOH was found to involve 19 chromosome arms in 20- 43% of the tumors. Chromosome arms 6p, 3p, and 18q are most frequently involved in LOH in 43, 39, and 35% of the informative carcinomas, res pectively. The respective regions involved are 6p21.1-23, 3p13-25.3, a nd 18q12.2-21.2. LOH is generally limited to specific band segments wi thin these regions. Similar high incidences of LOH of the same 3p segm ents have been reported in cervical carcinomas from different parts of the world. The same 3p and 6p segments are involved in many types of common cancers, whereas 18q changes are less frequent in other cancers . Chromosome arms 1q, 2q, 3q, 4p, 4q, 5p, 5q, 6q, 7q, 8p, 8q, 11q, 13q , 16p, 18p, and 19p are involved in LOH in 20-33% of the cervical tumo rs. Chromosome 11 alterations are among the most frequently found in m any different types of neoplasias. In this study, 11p was involved in 16% of the tumors, and 11q was involved in 22%. Chromosome 17 alterati ons are found in more cancers than those of any other chromosome, freq uently involving the p53 gene on 17p. LOH of 17p was found in 5 (15%) cervical tumors; 2 of these were HPV negative and expressed mutant p53 . In such HPV-negative tumors, direct mutation of the wild-type p53 ap pears to replace the inactivation of the p53 product by oncogenic HPV types. Tumors with LOH at many loci were, on the average, at more adva nced stages, as were tumors with mutant p53. The higher overall incide nce of LOH in cervical carcinomas as compared to other cancers, and th e diversity of LOH patterns found, suggest that different cervical car cinomas probably arise and/or progress, in part, because of the loss o f function of different yet finite sets of tumorigenicity suppressor g enes and genes that are involved in tumor progression and metastasis. The findings also indicate that certain chromosome segments that are o ften altered in cervical carcinomas are also frequently altered in sev eral other types of cancers. It remains to be determined whether the s ame or different genes located within these segments are involved in t he different cancer types.