This article reviews the main molecular alterations involved in endometrial carcinoma. Five molecular features (microsatellite instability, and mutations in the PTEN, k-RAS, PIK3CA and b-catenin genes) are characteristic of endometrioid carcinomas, whereas nonendometrioid carcinomas show alterations of p53, loss of heterozygosity (LOH) on several chromosomes, as well as other molecular alterations (STK15, p16, E-cadherin and C-erb B2). The review also covers the phenomenon of apoptosis resistance, as well as the results obtained from cDNA array studies, and the perspectives for targeted therapies. A group of practical applications of molecular pathology techniques are also mentioned: diagnosis of hereditary non-polyposis colon cancer syndrome in patients with endometrial carcinoma; evaluation of precursor lesions; prognosis; diagnosis, particularly for synchronous endometrioid carcinomas of the uterus and the ovaries; and targeted therapies. While OEC show microsatellite instability (MI), and mutations in the PTEN, k-RAS, PIK3CA and b-catenin genes, NOEC exhibit alterations of p53, loss of heterozygosity (LOH) on several chromosomes, as well as other molecular alterations (STK15, p16, E-cadherin and C-erb B2).
MOLECULAR PATHOLOGY OF ENDOMETRIOID CARCINOMASMicrosatellite instability (MI) is seen in cancers (colonic, endometrial and others) of patients with hereditary non-polyposis colon cancer (HNPCC), but is also seen in 25-30% of sporadic EC.
4-8HNPCC patients with EC have an inherited germ-line mutation in MLH-1, MSH-2, MSH-6 or PMS-2 (''first hit''); but EC develops only after the instauration of a deletion or mutation in the contralateral MLH-1,MSH-2, MSH-6 or PMS-2 allele (''second hit'') in endometrial cells. Once the two hits occur, the deficient mismatch repair role of the gene (MLH-1, MSH-2, MSH-6 or PMS-2) causes the acquisition of MI, and the development of the tumour. In sporadic EC, MLH-1 inactivation by promoter hypermethylation is the main cause of mismatch repair deficiency, 9 which usually occurs at the precursor (atypical hyperplasia) lesion.10 Thus, MLH-1 hypermethylation is an early event in the pathogenesis of OEC, which precedes the development of MI. The prognostic significance of MI is under debate, but there is some convincing evidence suggesting association with favourable outcome.The instauration of MI, the so-called mutator phenotype, leads to subsequent accumulation of myriads of mutations. Short-tandem repeats, like microsatellites, are particularly susceptible to mismatch repair alterations, but they are predominantly located in non-coding DNA sequences (fig 3); and the presence of subtle mutations (insertions or deletions) does not result in the production of abnormal proteins. However, some small short-tandem repeats, like mononucleotide repeats, are sometimes located within the coding sequence of some important genes (BAX, IGFIIR, hMSH3 and hMSH6). Mutations in these tracts are interpreted as secondary events in the mutator phenotype pathway in cancers with MI, probably...