more frequent in pre- and peri-menopausal women. Type 2 cancers account for 10 to 20% of cases, are estrogen-independent, arise in the background of atrophic endometrium and clinically follow a more aggressive course. Genetic alterations segregate with the cancer type and thus, different sets of altered pathways underlie their manifestation. In type 1, mutations in both alleles of PTEN lead to complete loss of function. A subsequently uncontrolled PI3K-AKT signaling results in aberrant cell growth and avoidance of apoptosis and in up-regulation of mTOR pathway. Mutations in one of the catalytic subunit of PI3K (PI3KCA) have also been reported; they are mostly found in tumors that also harbor PTEN mutation. Microsatellite instability (MSI) resulting from erroneous DNA mismatch repair (MMR) pathway is also a common feature of type 1 endometrial cancer and is mostly due to epigenetic inactivation of MLH1. Note that MSI and defective MMR are also associated with colorectal cancer and the epigenetic silencing of MLH1 appears to be common in both conditions. However, a larger subset of MMR genes that harbor mutations has been reported for colorectal cancer. In MSI associated endometrial cancer, mutations in the MSH6 gene involved in MMR have been observed although they are rare in endometrial cancers in general. Interestingly, in tumors with MSI, the mutation rates of PTEN are more than double compared to those in tumors without MSI. Gain-of-function mutations in beta-catenin, the core component of the canonical Wnt signaling pathway, have been reported; they do not appear to act in tandem with MSI and/or PTEN. Other mutations associated with type I endometrial cancer have implicated KRAS, a member of the Ras family of Ras superfamily of small monomeric G proteins that is a potent inducer of the Raf/Mek/Erk1 pathway. With respect to genetic alterations associated with type 2 endometrial cancers, the most common involves the tumor suppressor gene p53 resulting in altered signaling. Interestingly, it is thought that mutations in one allele take place earlier in the development of the disease whereas mutations in the second one occur later. Another pathway implicated in type 2 cancer is the epidermal growth factor signaling. Over-expression as well as gene amplification of Erbb2 receptor has been reported. It appears that all four receptors in the pathway are over-expressed in endometrial cancers. Genes important for the normal inflammatory and immune, and the angiogenic, cell cycle and apoptotic responses are targets of regulatory microRNAs. The expression of certain miRNAs is deregulated (up or down) in tumor samples when compared to normal endometrial tissues and is also different between different cancer types. To see the ontology report for annotations, GViewer and download click here
To see the Disease Ontology report for genes that in some fashon have been associated with endometrial neoplasms or suspected to confer susceptibility, click here
To link to the Cancer Disease Portal, click here
[click to see the associated KEGG map ¿ map05213]...(less)