Gene Expression Profiling of Peripheral Blood and Endometrial Cancer Risk Factors: Systems Epidemiology Approach in the NOWAC Postgenome Cohort Study

ntroduction: The increasing incidence of endometrial cancer (EC) requires an extensive search for novel preventive tools and early intervention approaches. However, the development of reliable predictive models is impossible without knowledge of genetic alterations prior to diagnosis. In this work, we aimed to establish whether known EC risk factors are associated with peripheral blood gene expression changes in a prospective design and whether such associations differ between women who later developed EC and matched controls. Methods: First, we selected variables (parity status, lifetime number of years of menstruation, coffee consumption, body mass index (BMI), age at menopause, use of oral contraceptives) that were shown to have an impact on EC risk in a large prospective cohort (165,000 women). Next, using BeadChip microarray technology, we tested the association between these variables and gene expression profiles in RNA extracted from mixed circulating immune cells in a nested case-control study (79 case-control pairs) of women from the NOWAC postgenome cohort. Lastly, we undertook a gene set enrichment analysis (GSEA). Results: At overall gene expression level, we found no difference between the EC cases and controls. The introduction of parity status into the statistical model revealed changes in the expression of 1,379 genes in the controls, while we did not observe any expression changes in the cases. Twenty-seven genes were associated with BMI increase in the controls, whereas there was no association observed between changes in BMI and gene expression in women with EC. In GSEA, 2,407 significantly enriched gene sets were attributed to a parity increase among cancer-free women. Conclusion: In this study, we found that an increased number of parities has a life-long effect on the gene expression profile in the peripheral blood of women who never developed cancer. In contrast, in women who were diagnosed with EC later in life, neither multiparity nor elevated BMI showed a significant association with gene expression patterns. However, given the modest sample size and exploratory nature of the study, these findings should be verified in larger cohorts.