Genetic derangements in the tumor suppressor gene PTEN in endometrial precancers as prognostic markers for cancer development: a population-based study from northern Norway with long-term follow-up.

The purpose of the current study was to characterize the role of PTEN in malignant transformation and to evaluate the significance of mutated PTEN exons as prognostic markers in the carcinogenesis of endometrial hyperplasia. A comparison of PTEN mutations as prognostic markers with former investigated prognosticators was also intended. Histological material from 68 patients with endometrial hyperplasia and 10-20 years of follow-up of whom 18 later developed cancer was examined. PCR amplification and DNA sequencing were performed, screening the most frequently mutated exons 5a-8b of the PTEN gene. Mutations were demonstrated in 13.2% of the patients. Of the patients with cancer development, five showed to have PTEN mutations corresponding to 28%. Of the patients remaining without carcinoma, only 8% had PTEN mutations (P = 0.04). In total, there were three missense, three nonsense, and four frameshift mutations, and twice as many mutations leading to a truncated protein (six) than mutations altering one amino acid in the entire protein (three). Mutations were distributed in the following manner: three in exon 5a, two in exon 5b, two in exon 6, two in exon 7, and one in exon 8b. Only mutations in exons 6, 7, and 8a were connected with cancer development or coexisting cancer and six out of seven mutations within these exons were frameshift or nonsense mutations. Our results showed that mutations in the PTEN gene were statistically more frequent in cases with cancer development or coexisting cancer. Although the specificity was acceptable, the sensitivity of PTEN mutations was too low to make it suitable as a tumor marker (sensitivity of 27% and specificity of 91%) in clinical practice.