Molecular Classification in Relation to Prevention of Endometrial Cancer Recurrence and Lifestyle Factors

Overview

Endometrial cancer (EC) is one of the most prevalent cancers in women worldwide with a significantly increasing incidence, especially in developed countries. One of the reasons for the increase in the incidence of this disease is the rising incidence of obesity as the biggest risk factor for the development of this disease. Other important risk factors are hypertension, diabetes mellitus and the general ageing of the population. These risk factors are not only associated with a higher risk of developing the disease, but also, for example, with post-operative complications affecting the quality of life of patients after surgery. The molecular classification of endometrial cancer, which has been introduced into clinical practice in recent years, is currently helping physicians to make treatment decisions for individual patients and predict prognosis. In this project, we would like to focus on the relationship of this molecular classification with genomic mutational signatures detected by whole-exome sequencing and their association with lifestyle risk factors for endometrial cancer (obesity - BMI, hypertension, diabetes mellitus), including the extent of staging lymphadenectomy. Identification and detailed analysis of dominant mutational profiles associated with a specific molecular subtype of EC and their influence on the presence of lifestyle risk factors may have a major impact on both disease development and prevention of disease recurrence. The possible relationship of the mutational profile with the extent of staging lymphadenectomy may help in deciding the extent of this surgical procedure, which subsequently affects the quality of life of patients, especially in patients with high BMI. Given the widespread prevalence of lifestyle risk factors in the developed world, a detailed understanding of the relationship between the genetic profile, its alterations and the prevalence of these risk factors, with potentially major implications for treatment success, is crutial.

The main goal of the project is to define specific mutational signatures of endometrial cancer (EC) patients using whole-exome sequencing technology. The relationship between mutational profiles and molecular classification of endometrial cancer will be analyzed in order to improve the stratification of these patients, especially those classified as having a non-specific molecular profile or p53 mutations. At the same time, the association between the dominant mutational profiles of EC patients with the prevalence of lifestyle risk factors such as obesity/BMI, hypertension and diabetes mellitus will be investigated and their incidence is becoming more prevalent in the modern population. Associations between the occurrence of specific mutation profiles with risk factors will be sought and their role in influencing the genetic profile of EC patients will be analyzed. Another aim of the project is to find relationships between specific mutational profiles of patients with the extent of staging lymphadenectomy, which could help to decide the extent of this surgery, which subsequently affects the quality of life of patients, especially in patients with high BMI. The final aim of the project is to establish a methodology to detect mutations arising from dominant specific mutational profiles in circulating tumor DNA (ctDNA) to monitor potential recurrence in patients at high risk of developing and recurrent disease. Overall, the main contribution of the project will be a detailed understanding of the relationship of the genetic profile of EC patients with their molecular subtype, the extent of staging lymphadenectomy and, most importantly, their impact related to the presence of lifestyle risk factors. These factors may be related to the presence of specific dominant mutational profiles subsequently serving as a tool for prognosis, prevention, risk of recurrence but also potential therapeutic targets in women with the presence of any of the lifestyle risk factors.