Somatic mutations of the PTEN/NMAC1 gene associated with frequent chromosomal loss detected using comparative genomic hybridization in endometrial cancer

Abstract

Objectives: We analyzed the mutational status of the transforming growth factor-beta type II receptor (TGF beta RII), BAX, and PTEN/MMAC1 genes as well as microsatellite instability (MI) in 29 consecutive cases of endometrial carcinoma operated on at the Cancer Institute Hospital (Tokyo, Japan). To identify chromosomal loss associated with significant somatic mutations, we conducted comparative genomic hybridization (CGH) analysis.

Methods: We conducted a direct sequence for mutational analysis of these genes. To examine copy number loss at the chromosomal regions bearing these genes, we used CGH analysis. CGH analysis may provides a genome-wide overview about tumor-associated genomic imbalances.

Results: Among nine tumors that showed the MI+ phenotype, four (44%) demonstrated a significant mutation with a definite amino acid change in the PTEN/MMAC1 gene. CGH analysis demonstrated that all four tumors (100%) showed chromosomal copy number loss around the locus of this gene, whereas four (57%) of seven tumors with PTEN/MMAC1 mutations showed chromosomal loss or double mutations in MI- carcinomas. The role of TGF beta RII and BAX genes is limited as a target gene of MI+ phenotype in endometrial cancer, because several mutations of these genes were detected but a chromosomal loss was demonstrated by CGH in only one tumor in MI+ endometrial cancers with mutation.

Conclusions: This report reveals, by using CGH, that most MI+ endometrial cancers with PTEN/MMAC1 mutations as well as MI- tumors showed inactivation of both alleles of this gene, which strongly suggested the involvement of this gene in carcinogenesis.