Loss of heterozygosity in clinical stage IB cervical carcinoma: relationship with clinical and histopathologic features.

Loss of heterozygosity (LOH) has been shown to be an important prognostic factor in a variety of malignant neoplasms. The relationship between LOH and established histopathological prognostic factors in cervical carcinoma has not been examined. We studied LOH in 58 FIGO stage IB cervical cancers treated by radical hysterectomy. In a randomly selected subset of 37 of these cases, LOH was examined using markers for all 41 chromosomal arms. Seventy-six percent of the 58 cases and 95% of the extensively studied cases showed LOH at one or more loci. The three most common sites of LOH were 3p21, 6p24-p23, and 11q23.3. In the extensively studied group, LOH on 11q was associated with extensive lymphvascular space invasion (P = .009) and less deeply invasive tumor (P = .042). There was a trend for tumors with LOH on 11q to recur, but this was not statistically significant. No correlation between the presence of LOH on 3p or 6p and lymphvascular space invasion or tumor depth was present. There was no correlation between the number of sites of LOH or between the presence of LOH on 3p, 6p, and 11q and the presence of metastatic tumor in regional lymph nodes, histologic type (squamous v nonsquamous), tumor differentiation, maximum tumor size, degree of inflammation, pattern of invasion, mitotic rate, or clinical recurrence. In summary, tumors with 11q LOH may behave in a more aggressive fashion. Future studies of LOH in cervical carcinoma should include histopathological prognostic information so that the relationship between LOH and these factors can be determined on larger numbers of patients.

Allelotyping of all chromosomal arms in invasive cervical cancer.

The best characterized factor in the development of cervical cancer is the integration, of human papillomavirus into cervical cell chromosomes. In addition to HPV integration, the neoplastic process probably requires the activation of cellular protooncogenes and loss of tumor suppressor gene function. Loss of heterozygosity analysis in a large sample is used to identify regions which harbor putative tumor suppressor genes (TSG) since the deletion of normal alleles unmask mutated alleles. We evaluated tumor tissue from invasive cervical carcinomas, carefully microdissected to eliminate normal stroma and lymphocytes, for LOH at all 41 chromosomal arms with 50 polymorphic markers. We have evaluated tumor and normal DNA pairs from 48 invasive cervical cancers of which 85% of the tumors are confined to the cervix. The mean loss for all chromosomal arms was 12%. Three regions exhibited LOH two standard deviations above the mean: 3p14.1-12 (40%), 11q23.3 (36%), and 6p22-21.3 (32%). Three regions showed loss one standard deviation above the mean: 19q13.4 (30%), 6q21-23.33 (25%), and 2q33-37 (24%). Our results indicate that a significant number of invasive cervical cancers have lost specific chromsomal regions, thereby suggesting that genes involved in the cell cycle regulation or the suppression of tumor development are located in these regions.