Genetic imbalances in precursor lesions of endometrial cancer detected by comparative genomic hybridization

Endometrial hyperplasia is regarded as a precursor lesion of endometrioid a denocarcinomas of the endometrium, The genetic events involved in the multi step process from normal endometrial glandular tissue to invasive endometri al carcinomas are primarily unknown. We chose endometrial hyperplasia as a model for identifying chromosomal aberrations occurring: during carcinogene sis. Comparative genomic hybridization (CGH) was performed on 47 formalin-f ixed, paraffin-embedded specimens of endometrial hyperplasia using the micr odissection technique to increase the number of tumor cells in the samples and reduce contamination from normal cells. CGH analysis revealed that 24 o ut of 47 (51%) samples had detectable chromosomal imbalances, whereas 23 (4 9%) were in a genetically balanced state. The incidence of aberrant CGH pro files tended to parallel dysplasia grade, ranging from 22% aberrant profile s in simple hyperplasia to 67% in complex hyperplasia with atypia, The most frequent imbalances were 1p, 16p, and 20q underrepresentations and 4q over representations, Copy number changes in 1p were more frequent in atypical c omplex hyperplasia than in complex lesions without atypical cells or simple lesions (42% versus 20% and 0%), Our results show that endometrial hyperpl asia reveals recurrent chromosomal imbalances which tend to increase with t he presence of atypical cells. The most frequent aberrations in endometrial cancer, 1q and 8q overrepresentations, are not present or are rare in its precursor lesions. This analysis provides evidence that tumorigenesis proce eds through the accumulation of a series of genetic alterations and suggest s a stepwise mode of tumorigenesis.