Early molecular changes in endometrial cancer

Abstract

Endometrial carcinoma (EC) is currently divided into two major types, Type I and II, based on clinicopathological parameters. Type I carcinomas are associated with a hyperestrogenic state and account for approximately 85% of ECs. Type I carcinomas are low-grade, indolent tumors of endometrioid histology. In contrast, Type II tumors are estrogen independent and arise in the setting of atrophy. They are poorly differentiated tumors and most commonly demonstrate a serous morphology. Molecular genetic studies over the past decade have shown that the two tumor types evolve via distinct pathogenetic pathways(1). The most frequent early molecular genetic alterations in Type I tumors are mutations in the PTEN tumor suppressor gene and KRAS oncogene and microsatellite instability (MI). Molecular genetic studies have shown that PTEN and KRAS mutations are present in complex atypical hyperplasia (CAH), the direct precursor to endometrioid carcinoma. In addition, methylation of the hMLH1 gene, which is thought to result in MI, has also been documented in CAH. In addition, it has been consistently reported that there is a statistically significant association between PTEN mutations and MI in Type I tumors, however the biological significance of the association remains unclear(2). More recently mouse models have further supported a central and early role for the PTEN gene and MI in the development of Type I EC. One hundred percent of Pten heterozygous female mice spontaneously develop complex atypical hyperplasia. The lesions begin to develop at about 16 weeks and increase in number and size with age. By 10 months of age approximately 20% develop carcinoma. The invasive lesions are histologically very similar to well-differentiated endometrioid carcinoma often demonstrating mucinous and squamous metaplasia as seen in primary human endometrioid carcinoma. In order to explore the relationship of MI and PTEN mutations, Pten heterozygous, Mlh1 null mice were generated. Mice of this genotype have an accelerated onset of lesions and an increase in the frequency of invasion at a young age(3). This mouse model should provide a system in which the association of these two common molecular alterations can be studied and the relationship between genetic alterations and hormonal influences can be addressed. Although there have been fewer studies on Type II tumors, mutations in P53 have been found in 75% of endometrial intraepithelial carcinomas, the putative precursor to serous carcinoma, and in 90% of serous carcinomas. Additional studies are clearly needed to uncover the other common alterations in this uncommon, but aggressive, form of endometrial carcinoma.