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. Endometrial serous carcinoma is the most frequent histological type of NEEC and is characterized by alterations in TP53 with secondary chromosomal instability, which leads to multiple chromosomal gains and losses, including amplification of oncogenes and loss of important tumour suppressor genes. By contrast, the molecular alterations in clear cell carcinomas, another histological type of NEEC, are poorly defined. Differences in genetic and epigenetic alterations between EEC and NEEC tumours are reflected in distinct gene expression profiles observed amongst different EC types. In the near future, careful molecular characterization of ECs must be necessary in order to implement new directed targeted therapies. Endometrial carcinoma (EC) is a primary malignant epithelial tumour that arises in the endometrium and that can invade the myometrium in order to spread to distant sites [1]. In developed countries, EC is the most common malignant primary tumour of the female genital tract, and it represents the fourth and fifth most-frequently diagnosed cancer in women in Europe and the USA respectively, although this incidence is lower in Japan and developing countries. Moreover, while the incidence of EC among black women is approximately half that in white women, the proportion of EC-related deaths is greater in black than in white women for reasons that remain poorly understood [2]. The median age at which these tumours are diagnosed is 61 years, although some specific subtypes are diagnosed later, such as serous or clear cell carcinoma.Peer Reviewe