Genetic Susceptibility to Endometrial Cancer: Risk Factors and Clinical Management

Abstract

Endometrial cancer (EC) is the most common cancer affecting the female reproductive organs in higher-income states. Apart from reproductive factors and excess weight, genetic predisposition is increasingly recognized as a major factor in endometrial cancer risk. Endometrial cancer is genetically heterogeneous: while a subgroup of patients belongs to cancer predisposition syndromes (most notably the Lynch Syndrome) with high to intermediate lifetime risks, there are also several common genomic polymorphisms contributing to the spectrum of germline predispositions. Germline variants and somatic events may act in concert to modulate the molecular evolution of the tumor, where mismatch-repair deficiency is common in endometrioid endometrial tumors whereas homologous recombinational repair deficiency has been described for non-endometrioid endometrial tumors. In this review, we will survey the currently known genomic predispositions for endometrial cancer and discuss their relevance for clinical management in terms of counseling, screening and novel treatments.

Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

“…12 Mutations in cancer susceptibility genes (CSGs) other than those associated with LS are thought to play a smaller role in EC risk. 13 Although multigene panel testing (MGPT) studies performed for women with EC have identified PVs in other CSGs, [14][15][16] the true burden of PVs in other CSGs remains unknown. The modest number of cases investigated (381 in the study by Ring et al, 14 156 in Cadoo et al, 15 and 98 in Samadder et al 16 ), coupled with the fact that the cohorts overrepresent women with nonendometrioid, high-grade, and higher-stage tumors, limits our understanding of how frequent PVs in other CSGs are in the general EC population.…”

The Role of Long Non-Coding RNAs (lncRNAs) in Female Oriented Cancers

“…EC is genetically heterogeneous, apart from a patient’s subgroup belonging to a cancer predisposition syndrome, i.e., Lynch Syndrome, triggered by the germline alterations of DNA mismatch repair genes such as MLH1, PMS2, MSH2, and MSH6. EC also exhibits a high frequency of several other germline mutations in cancer predisposition genes [ 31 ].…”

Contemporary Fertility-Sparing Management Options of Early Stage Endometrioid Endometrial Cancer in Young Nulliparous Patients

“…Endometrial cancer (EC) is a malignant disease of the uterine inner layer (endometrium) developing from the glandular epithelium covering the luminal surface [ 1 , 2 , 3 ]. Most endometrial cancers are adenocarcinomas [ 3 ].…”

“…Potential risk factors for EC are well-known: obesity, insulin resistance, hypertension, nulliparity, early menarche, sedentary lifestyle, and anovulation contribute to the development of EC, especially in young patients [ 6 , 10 , 12 , 21 , 22 ]. EC is the most strongly hormone-dependent and excess-weight-related cancer [ 2 ]. These factors are linked to each other as elevated estrogen levels, especially those derived through the extragonadal estrogen aromatization pathway, are associated with increased body weight [ 2 , 4 , 6 , 21 ].…”