An intriguing journey into the hereditary syndromes predisposing to endometrial cancer: more than believed

Endometrial cancer (EC) is a gynecologic neoplasm with a constantly increasing incidence, especially in high-income countries. Obesity, diabetes, old age, and genetic predisposition account for the main risk factors. Genetic knowledge has steadily increased from the historical clinicopathological classification into two pathogenic types to the molecular subdivision into four groups, highlighting that EC is not a single entity, but rather the sum of different molecular diseases with different prognoses. About 5%-10% of ECs show a hereditary basis attributable to germline pathogenic variants (PVs) in different susceptibility genes, including MMR (MLH1, MSH2, MSH6, and PMS2), POLE/POLD1, PTEN, BRCA1/2, MUTYH, NTHL1, STK11, which confer an increased risk of developing an early onset EC. Lynch syndrome is the main inherited disorder predisposing to EC, followed by other hereditary conditions, including Cowden syndrome, polymerase proof-reading associated polyposis, NTHL1-associated syndrome, hereditary breast and ovarian cancer syndrome, MUTYH-associated polyposis, and Peutz-Jeghers syndrome. Genetics has been shown to affect several aspects of disease, including carcinogenesis, onset age, clinicopathological features, prognosis, and therapy response. In this review, we will investigate the impact of germline PVs in different genes on genetic susceptibility to the development of inherited EC, discussing the potential cancer risk in mutation carriers as well as prognostic implications and current therapeutic approaches, also evaluating the possibility of carrying out a more extensive routine genetic analysis for EC women, in order to increase the diagnostic power, improve prevention and surveillance strategies in genetically predisposed subjects, and implement tailored therapies.