Inflammation factors and endometrial cancer: a prospective study

  • Topic: Endometrial Cancer
  • Institution: DKFZ (German Cancer Research Centre)
  • Country: Germany
  • Status: Completed

Scientific abstract

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Background

Although a western lifestyle is a well-established risk factor for endometrial cancer, the mechanisms underlying this relationship still have been only partially resolved. In complement to the strongest hypothesis today -- the “unopposed estrogen” hypothesis, which states that high levels of bioavailable estrogens, when not counterbalanced by progesterone, increase endometrial cancer risk – it has been hypothesised that chronic, low-grade inflammation can act as an additional independent mechanism in endometrial cancer development.

Methods

We conducted a case-control study, nested within the European Prospective study into Cancer and Nutrition, to investigate the associations between prediagnostic levels of TNF-α, soluble TNF receptors, IL-1Ra, IL-6 and CRP with endometrial cancer risk. This is the first prospective study of its kind to date, comprising 342 incident cases of endometrial cancer, and 644 matched controls. We also conducted a factor analysis to delineate uncorrelated important components that summarise the variation explained by a set of different biomarkers in the steroid, insulin, inflammation and lipid pathways and to examine their association with endometrial cancer risk.

Serum and plasma levels of inflammatory markers were measured using highly sensitive enzyme-linked immunoassays (R&D Systems Europe) at IARC (France) and at the German Cancer Research Center (Germany). Other biomarkers (testosterone, androstenedione, dehydroepiandrosterone sulfate, SHBG, estrone, estradiol, C-peptide, IGF binding protein-1 and -2, adiponectin, HDL- and LDL-cholesterol, glucose, and triglycerides) have been previously measured on the same cases and controls as part of another project also funded by WCRF.

Results

Using conditional logistic regression models, we observed a significant increased risk of endometrial cancer with elevated levels of TNF-α (odds ratio (OR) for top versus bottom quartiles: 1.82, 95%CI:1.19-2.78, Ptrend=0.005), sTNFR1 (OR for top versus bottom quartiles: 1.96, 95%CI: 1.21-3.19, Ptrend=0.005), sTNFR2 (OR for top versus bottom quartiles: 1.67, 95%CI: 1.05 -2.65, Ptrend=0.01), CRP (OR for top versus bottom quartiles: 1.58, 95%CI: 1.03-2.41, Ptrend=0.02), IL-6 (OR for top versus bottom quartiles: 1.66, 95%CI: 1.08 -2.54, Ptrend=0.008) and IL-1Ra (OR for top versus bottom category: 1.82, 95%CI: 1.22-2.73, Ptrend=0.004). After adjustment for BMI, the ORs were strongly attenuated and became non-significant for CRP, IL-6 and IL-1Ra. Only the association with TNF-α and sTNFR2 remained statistically significant after BMI adjustment (OR for top versus bottom category: 1.73, 95% CI: 1.09-2.73, Ptrend=0.01 for TNF-α and 1.53, 95%CI: 0.92-2.55, Ptrend=0.03 for sTNFR2).

Factor analysis identified three uncorrelated components that seemed to be associated with endometrial cancer risk and could be labeled as the “insulin resistance/metabolic syndrome”, the “steroids”, and the “inflammation” factors. A fourth “lipids” component, apart from its contribution to the metabolic syndrome, was not significantly associated with endometrial cancer risk.

Conclusion

Besides the well-known associations of risk with endogenous sex hormones and insulin-regulated physiologic axes, our data support the hypothesis that inflammation factors play an additional role in endometrial carcinogenesis. Inflammation is a possible mediator of the association observed between obesity and endometrial cancer risk and could also be an independent risk factor for endometrial cancer. Further prospective studies are needed to confirm these observations.

Plain language abstract

Background

Although a western lifestyle is a well-established risk factor for endometrial cancer, the mechanisms underlying this relationship still have been only partially resolved. Besides the well-known role of estrogens, chronic, low-grade inflammation has been proposed as a possible mediator of endometrial cancer development.

Methods

We conducted a study, within the European EPIC cohort, to address this hypothesis by measuring pre-diagnostic inflammatory markers in blood samples from women who subsequently had a clinical diagnosis of endometrial cancer, and from women of comparable age who did not develop cancer.

Results

We observed that women with the highest levels of pre-diagnostic inflammatory markers had a 60% to 80% higher risk of developing endometrial cancer compared to women with the lowest levels. This increase seemed to be at least partly mediated by obesity.

Furthermore, a comprehensive analysis of hormonal, metabolic and inflammatory profiles related to a western lifestyle identified three independent axes that seemed to be associated with endometrial cancer risk and could be labelled as the “insulin resistance/metabolic syndrome”, the “steroids”, and the “inflammation” axes. A fourth “lipids”axis, apart from its contribution to the metabolic syndrome, was not significantly associated with endometrial cancer risk.

Conclusion

Besides the well-known associations of risk with endogenous sex hormones and insulin-regulated physiologic axes, our data support the hypothesis that inflammation factors play an additional role in endometrial carcinogenesis. Further prospective studies are needed to confirm these observations.

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