A prospective study of circulating C-reactive protein, interleukin-6, and tumor necrosis factor α receptor 2 levels and risk of ovarian cancer

Abstract

Chronic inflammation may play a role in ovarian carcinogenesis. We examined associations between 3 plasma biomarkers of inflammation-C-reactive protein (CRP), interleukin 6, and tumor necrosis factor α receptor 2-and risk of invasive epithelial ovarian cancer in prospectively collected samples from the Nurses' Health Study (NHS; 1989-2010), Nurses' Health Study II (NHS II; 1996-2009), and the Women's Health Study (WHS; 1992-2011) and performed a meta-analysis including data from previous publications. Associations with ovarian cancer risk were calculated using logistic regression (NHS/NHS II; n = 217 cases) or Cox proportional hazards regression (WHS; n = 159 cases). Study-specific results were combined using random-effects meta-analysis. In the NHS/NHS II and WHS, we observed a 53% increased risk of invasive ovarian cancer when comparing women in the fourth quartile of CRP with women in the first quartile (95% confidence interval (CI): 1.05, 2.23). A CRP level of >10 mg/L versus a level of ≤1 mg/L was associated with a 2.16-fold increased risk (95% CI: 1.23, 3.78). In a meta-analysis of published studies, women in the third tertile of CRP had a 35% increased risk (95% CI: 1.10, 1.67) compared with women in the first tertile. There were no significant associations between interleukin 6 or tumor necrosis factor α receptor 2 and risk in the NHS/NHS II. Our results support the hypothesis that higher levels of circulating CRP are associated with increased risk of ovarian cancer, indicating that the role of inflammation in ovarian cancer requires further elucidation.

Keywords: C-reactive protein; interleukin 6; ovarian cancer; tumor necrosis factor α receptor 2.

Figure 1.

Relative risk (RR) of ovarian cancer among women in the second tertile of C-reactive protein level in a meta-analysis of published studies and in the present study. Numbers of cases and controls shown reflect the total number in each study rather than the number in the second tertile. CLUE I, Campaign Against Cancer and Stroke; CLUE II, Campaign Against Cancer and Heart Disease; Columbia MO, Columbia, Missouri, Serum Bank; FMC, Finnish Maternity Cohort; Guernsey, Island of Guernsey Prospective Study; NHS, Nurses’ Health Study; NHS II, Nurses’ Health Study II; NSHDS, Northern Sweden Health and Disease Study; NYUWHS, New York University Women's Health Study; ORDET, Hormones and Diet in the Etiology of Breast Cancer; WHS, Women's Health Study. Bars, 95% confidence interval (CI).

Figure 2.

Relative risk (RR) of ovarian cancer among women in the third tertile of C-reactive protein level in a meta-analysis of published studies and in the present study. Numbers of cases and controls shown reflect the total number in each study rather than the number in the third tertile. CLUE I, Campaign Against Cancer and Stroke; CLUE II, Campaign Against Cancer and Heart Disease; Columbia MO, Columbia, Missouri, Serum Bank; FMC, Finnish Maternity Cohort; Guernsey, Island of Guernsey Prospective Study; NHS, Nurses’ Health Study; NHS II, Nurses’ Health Study II; NSHDS, Northern Sweden Health and Disease Study; NYUWHS, New York University Women's Health Study; ORDET, Hormones and Diet in the Etiology of Breast Cancer; WHS, Women's Health Study. Bars, 95% confidence interval (CI).

Figure 3.

Relative risk (RR) of ovarian cancer among women with a C-reactive protein level greater than 10 mg/L in a meta-analysis of published studies and in the present study. Numbers of cases and controls shown reflect the total number in each study rather than the number with a C-reactive protein level greater than 10 mg/L. CLUE I, Campaign Against Cancer and Stroke; CLUE II, Campaign Against Cancer and Heart Disease; Columbia MO, Columbia, Missouri, Serum Bank; FMC, Finnish Maternity Cohort; Guernsey, Island of Guernsey Prospective Study; NHS, Nurses’ Health Study; NHS II, Nurses’ Health Study II; NSHDS, Northern Sweden Health and Disease Study; NYUWHS, New York University Women's Health Study; ORDET, Hormones and Diet in the Etiology of Breast Cancer; WHS, Women's Health Study. Bars, 95% confidence interval (CI).