Genetics of Endometrial Carcinoma

Endometrial cancer (EC) is the most common gynaecological malignancy in the western world and it comprises a heterogeneous group of tumours with distinct risk factors, clinical presentation, and histopathological features. Two main groups of EC exist, endometrioid endometrial carcinomas (EECs or type I) and non endometrioid endometrial carcinoma (NEECs or type II), which evolve via distinct molecular pathways. The most common molecular alterations associated with EECs affect the phosphoinositide 3-kinase (PI3K)/Akt pathway due to mutations in PTEN or PI3KCA. Other pathways, such as the RAS-RAF-MEK-ERK, FGF and WNT signalling pathways are also frequently affected by gene mutations or epigenetic changes. In addition, a group of sporadic EECs are characterized by microsatellite instability due to DNA mismatch repair (MMR) deficiency secondary to promoter hypermethylation of MLH1. In addition, EC is the second most frequent malignancy in hereditary Lynch syndrome. MMR deficiency in these patients is secondary to germline mutations in MLH1, MSH2 or MSH6. Finally, ARID1A mutations have been recently described in a subset of EECs.