Insights into inflammation and implications for the pathogenesis and long-term outcomes of endometrial cancer: Genome-wide surveys and A clinical cohort study

Recently, a growing number of studies have shown a relationship between inflammation and the risk of endometrial cancer, but investigations of genetic associations and cohort studies of the impact of inflammation on the long-term outcome of endometrial cancer still need to be improved. The aim of our research is to explore the impact of inflammatory factors on the pathogenesis, progression and consequences of endometrial cancer. For genetic correlation analysis, the Mendelian randomization research method was applied to investigate the causal relationships between inflammation-related single nucleotide polymorphisms and endometrial cancer in samples from two different population-based GWAS databases. Our observational retrospective study enrolled patients who underwent surgery at the Cancer Hospital of Shantou University Medical College from January 2010 to October 2020 and were diagnosed with endometrial cancer (stages I to IV). Basic clinical information and preoperative peripheral blood inflammatory indicators were further collected. Multivariate Cox regression analysis was conducted on the inflammatory indicators, and Kaplan-Meier curves were generated to estimate the overall survival rate and progression-free survival rate during the follow-up period. Subsequently, two prognostic nomogram models were constructed based on inflammatory markers and other clinical and pathological parameters to predict 5-year and 10-year overall survival and progression-free survival. The correlation between inflammation-related genes and prognosis was analyzed through the TCGA endometrial cancer database. The two-sample Mendelian Randomization investigation showed the suggestive causal relationships between inflammatory cytokines and endometrial cancer, but it was not statistically significant. The cohort study included 780 cases (median age 55.0 years) diagnosed with endometrial cancer, with a average follow-up time of 6.8 years. Statistical analysis revealed that an increase in baseline inflammatory parameters was associated with a higher FIGO stage and risk of invasive endometrial cancer (OR 1.01 to 4.20). Multivariate Cox regression showed that multiple inflammatory indicators were markedly associated with overall survival and progression-free survival (P < 0.05). The C-index of the nomogram developed for overall survival and progression-free survival was 0.811 and 0.789, respectively. Finally, the LASSO regression for validation supports the predictive efficacy of inflammatory and clinical factors for long-term outcomes of endometrial cancer. The TCGA analysis found that the quantities of the inflammation-related gene CXCL9 expressed in the tissue cells of patients with endometrial cancer were significantly higher than in control tissues, and this was verified by qPCR analysis. Although genetic investigations have not suggested that inflammatory cytokines adversely affect the risk of endometrial cancer, it is clear from our cohort study that inflammation levels are associated with the progression and long-term consequences of endometrial cancer, and that the inflammatory-related gene CXCL9 may contribute to the pathogenesis of endometrial cancer. This evidence potentially could contribute to the development of new strategies aimed at reducing inflammation during endometrial cancer treatment.