p53 null mutations are associated with a telomerase negative phenotype in ovarian carcinoma

Abstract

Telomerase activation and p53 dysfunction are important events in the development and progression of most cancers including ovarian cancer. However, many cancer cell lines and human tumors have been shown to lack telomerase, and maintain telomerase through the ALT (alternative lengthening of telomeres). It is not known whether specific types of p53 mutations are correlated with telomerase activity in human tumors. Invasive ovarian cancers (109) were analyzed for telomerase by ELISA and its subunits human telomerase RNA (hTR), and human telomerase reverse transcriptase (hTERT) by RT-PCR. p53 protein was analyzed in the same samples using immunohistochemistry, and p53 exons 2-11 were analyzed using SSCP and sequence analysis. Telomerase activity was detected in 80 (74%) of 109 tumors. The subunit hTR was consistently present in all ovarian cancer samples, and hTERT was expressed in 96 (88%) tumors. Thirteen (16%) tumors were negative for hTERT and none of these expressed telomerase. Fifty-seven (52%) tumors stained positive for p53, and there was no correlation with telomerase activity based on p53 staining (p = 0.08). Eighty-two (75%) tumors were found to have a p53 mutation, and 40 (36%) tumors contained a null mutation. Only 14% of the tumors with wild type or missense p53 were negative for telomerase activity. In contrast, 19 (48%) of 40 tumors with a p53 null mutation were negative for telomerase activity (p <0.001). There was no difference in the incidence of telomerase positivity between critical site versus non-critical site missense p53 mutations. Seventy-five percent of the tumors with a p53 mutation in the central region were telomerase positive. In contrast, only 47% of the tumors with a mutation in either the amino- or carboxy-terminus were telomerase positive (p = 0.03). Ovarian cancers with a p53 null mutation are more likely to lack telomerase activity. This may have implications for therapeutic approaches based on telomerase. ©2002 Landes Bioscience.