Recurrent Chromosome 10 Aberrations and Tp53 Mutations in Rat Endometrial Adenocarcinomas

摘要

Human genetic heterogeneity and differences in the environment and life style make analysis of complex diseases such as cancer difficult. By using inbred animal strains, the genetic variability can be minimized and the environmental factors can be reasonably controlled. Endometrial adenocarcinoma (EAC) is the most common gynecologic malignancy, ranking fourth in incidence among tumors in women. The inbred BDII rat strain is genetically prone to spontaneously develop hormone-related EAC, and can be used as a tool to investigate and characterize genetic changes in this tumor type. In the present project, BDII females were crossed to males from two nonsusceptible rat strains and Fl, F2, and backcross progeny were produced. Genetic and molecular genetic analysis of tumors showed that rat chromosome 10 (RNO10) was frequently involved in genetic changes. Our data indicate that often there was loss of chromosomal material in the proximal to middle part of the chromosome followed by gains in distal RNO10. This suggested that there is a tumor suppressor gene(s) in the proximal to middle part of RNO10 and an oncogene(s) in the distal part of the chromosome with potential significance in EAC development. The Tp53 gene, located at band RNO10q24-q25, was a strong candidate target for the observed aberrations affecting the middle part of the chromosome. However, our Tp53 gene mutation analyses suggested that a second gene situated very close to Tp53 might be the main target for the observed pattern of genetic changes.