Livia Lamartina, Giorgio Grani, Emanuela Arvat, Alice Nervo, Maria Chiara Zatelli, Roberta Rossi, Efisio Puxeddu, Silvia Morelli, Massimo Torlontano, Michela Massa, Rocco Bellantone, Alfredo Pontecorvi, Teresa Montesano, Loredana Pagano, Lorenzo Daniele, Laura Fugazzola, Graziano Ceresini, Rocco Bruno, Ruth Rossetto, Salvatore Tumino, Marco Centanni, Domenico Meringolo, Maria Grazia Castagna, Domenico Salvatore, Antonio Nicolucci, Giuseppe Lucisano, Sebastiano Filetti, and Cosimo Durante
Laure Dossus, Sabina Rinaldi, Susen Becker, Annekatrin Lukanova, Anne Tjonneland, Anja Olsen, Jakob Stegger, Kim Overvad, Nathalie Chabbert-Buffet, Aida Jimenez-Corona, Francoise Clavel-Chapelon, Sabine Rohrmann, Birgit Teucher, Heiner Boeing, Madlen Schütze, Antonia Trichopoulou, Vassiliki Benetou, Pagona Lagiou, Domenico Palli, Franco Berrino, Salvatore Panico, Rosario Tumino, Carlotta Sacerdote, Maria-Luisa Redondo, Noémie Travier, Maria-Jose Sanchez, Jone M Altzibar, Maria-Dolores Chirlaque, Eva Ardanaz, H Bas Bueno-de-Mesquita, Fränzel J B van Duijnhoven, N Charlotte Onland-Moret, Petra H M Peeters, Goran Hallmans, Eva Lundin, Kay-Tee Khaw, Nicholas Wareham, Naomi Allen, Tim J Key, Nadia Slimani, Pierre Hainaut, Dora Romaguera, Teresa Norat, Elio Riboli, and Rudolf Kaaks
Obesity, a major risk factor for endometrial cancer, is a low-grade inflammatory state characterized by elevated concentrations of cytokines and acute phase reactants. The current study had two aims: first to investigate the associations of C-reactive protein (CRP), interleukin 6 (IL6), and IL1 receptor antagonist (IL1Ra) with endometrial cancer risk and second to examine to which extent these markers can influence the association between obesity and endometrial cancer. We conducted a case–control study, nested within the European Prospective Investigation into Cancer and Nutrition, which comprised 305 incident cases of endometrial cancer and 574 matched controls. CRP, IL6, and IL1Ra were measured in prospectively collected blood specimens by immunoassays. Data were analyzed using conditional logistic regression. All statistical tests were two-sided, and P values <0.05 were considered statistically significant. We observed a significant increase in risk of endometrial cancer with elevated levels of CRP (odds ratio (OR) for top versus bottom quartile: 1.58, 95% confidence interval (CI): 1.03–2.41, P trend=0.02), IL6 (OR for top versus bottom quartile: 1.66, 95% CI: 1.08–2.54, P trend=0.008), and IL1Ra (OR for top versus bottom quartile: 1.82, 95% CI: 1.22–2.73, P trend=0.004). After adjustment for body mass index (BMI), the estimates were strongly reduced and became non-significant. The association between BMI and endometrial cancer was also substantially attenuated (∼10–20%) after adjustment for inflammatory markers, even when the effects of C-peptide or estrone had already been taken into account. We provided epidemiological evidence that chronic inflammation might mediate the association between obesity and endometrial cancer and that endometrial carcinogenesis could be promoted by an inflammatory milieu.
Naomi E Allen, Timothy J Key, Laure Dossus, Sabina Rinaldi, Anne Cust, Annekatrin Lukanova, Petra H Peeters, N Charlotte Onland-Moret, Petra H Lahmann, Franco Berrino, Salvatore Panico, Nerea Larrañaga, Guillem Pera, Maria-José Tormo, Maria-José Sánchez, J Ramón Quirós, Eva Ardanaz, Anne Tjønneland, Anja Olsen, Jenny Chang-Claude, Jakob Linseisen, Mandy Schulz, Heiner Boeing, Eva Lundin, Domenico Palli, Kim Overvad, Françoise Clavel-Chapelon, Marie-Christine Boutron-Ruault, Sheila Bingham, Kay-Tee Khaw, H Bas Bueno-de-Mesquita, Antonia Trichopoulou, Dimitiros Trichopoulos, Androniki Naska, Rosario Tumino, Elio Riboli, and Rudolf Kaaks
Epidemiological data show that reproductive and hormonal factors are involved in the etiology of endometrial cancer, but there is little data on the association with endogenous sex hormone levels. We analyzed the association between prediagnostic serum concentrations of sex steroids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition using a nested case–control design of 247 incident endometrial cancer cases and 481 controls, matched on center, menopausal status, age, variables relating to blood collection, and, for premenopausal women, phase of menstrual cycle. Using conditional regression analysis, endometrial cancer risk among postmenopausal women was positively associated with increasing levels of total testosterone, free testosterone, estrone, total estradiol, and free estradiol. The odds ratios (ORs) for the highest versus lowest tertile were 2.66 (95% confidence interval (CI) 1.50–4.72; P=0.002 for a continuous linear trend) for estrone, 2.07 (95% CI 1.20–3.60; P=0.001) for estradiol, and 1.66 (95% CI 0.98–2.82; P=0.001) for free estradiol. For total and free testosterone, ORs for the highest versus lowest tertile were 1.44 (95% CI 0.88–2.36; P=0.05) and 2.05 (95% CI 1.23–3.42; P=0.005) respectively. Androstenedione and dehydroepiandrosterone sulfate were not associated with risk. Sex hormone-binding globulin was significantly inversely associated with risk (OR for the highest versus lowest tertile was 0.57, 95% CI 0.34–0.95; P=0.004). In premenopausal women, serum sex hormone concentrations were not clearly associated with endometrial cancer risk, but numbers were too small to draw firm conclusions. In conclusion, relatively high blood concentrations of estrogens and free testosterone are associated with an increased endometrial cancer risk in postmenopausal women.
Petra H M Peeters, Annekatrin Lukanova, Naomi Allen, Franco Berrino, Tim Key, Laure Dossus, Sabina Rinaldi, Carla H van Gils, H Bas Bueno-de-Mesquita, Heiner Boeing, Mandy Schulz, Jenny Chang-Claude, Jakob Linseisen, Salvatore Panico, Carlotta Sacerdote, Domenico Palli, Rosario Tumino, Antonia Trichopoulou, Dimitrios Trichopolos, Christina Bamia, Nerea Larranaga, Eva Ardanaz, Guillem Pera, J Ramón Quirós, Carmen Martínez-García, Carmen Navarro, Sheila A Bingham, Kay-Tee Khaw, Françoise Clavel, Anne Tjonneland, Anja Olsen, Kim Overvad, Mette S Tetsche, Eiliv Lund, Eva Lundin, Göran Berglund, Elio Riboli, and R Kaaks
We set out to study the relationship between circulating levels of IGF-I and its major binding protein (IGFBP-3) in relation to ovarian cancer risk. We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. Levels of IGF-I and IGFBP-3 were measured in prediagnostic serum samples of 214 women who subsequently developed ovarian cancer, and 388 matched control subjects. Conditional logistic regression models were used to estimate relative risks of ovarian cancer by tertiles of IGF-I and IGFBP-3 levels. For all women, there was no association between the circulating IGF-I or IGFBP-3 levels and the risk of ovarian cancer. However, among women diagnosed with ovarian cancer aged 55 or younger, the relative risk was higher in the middle or top tertiles of serum IGF-I, when compared with women in the lowest tertile (odds ratios (OR) = 1.8 (95%CI 0.7–4.3) and OR = 2.4 (95%CI 0.9–6.4); P trend = 0.08) respectively. These results were adjusted for body mass index, previous hormone use, fertility problems, and parity. Restricting the analysis to women who were premenopausal at blood donation, relative risks for ovarian cancer diagnosed before age 55 were higher (OR = 5.1 (95%CI 1.5–18.2) and OR = 5.6 (95%CI 1.5–20.8) respectively, for second and third tertiles; P trend = 0.02). Adjustment for serum IGFBP-3 levels only slightly attenuated relative risk estimates. Relations between IGFBP-3 and ovarian cancer before age 55 were in the same direction as for IGF-I, but less strong and statistically not significant. In women aged over 55, there was no association between serum IGF-I or IGFBP-3 and ovarian cancer risk. Our results suggest that the circulating levels of IGF-I may play a potentially important role in the development of ovarian cancer in women of a pre- or perimenopausal age.
Anne E Cust, Rudolf Kaaks, Christine Friedenreich, Fabrice Bonnet, Martine Laville, Anne Tjønneland, Anja Olsen, Kim Overvad, Marianne Uhre Jakobsen, Véronique Chajès, Françoise Clavel-Chapelon, Marie-Christine Boutron-Ruault, Jakob Linseisen, Annekatrin Lukanova, Heiner Boeing, Tobias Pischon, Antonia Trichopoulou, Bamia Christina, Dimitrios Trichopoulos, Domenico Palli, Franco Berrino, Salvatore Panico, Rosario Tumino, Carlotta Sacerdote, Inger Torhild Gram, Eiliv Lund, J R Quirós, Noémie Travier, Carmen Martínez-García, Nerea Larrañaga, María-Dolores Chirlaque, Eva Ardanaz, Göran Berglund, Eva Lundin, H Bas Bueno-de-Mesquita, Fränzel J B van Duijnhoven, Petra H M Peeters, Sheila Bingham, Kay-Tee Khaw, Naomi Allen, Tim Key, Pietro Ferrari, Sabina Rinaldi, Nadia Slimani, and Elio Riboli
To clarify the role of metabolic factors in endometrial carcinogenesis, we conducted a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), and examined the relation between prediagnostic plasma lipids, lipoproteins, and glucose, the metabolic syndrome (MetS; a cluster of metabolic factors) and endometrial cancer risk. Among pre- and postmenopausal women, 284 women developed endometrial cancer during follow-up. Using risk set sampling, 546 matched control subjects were selected. From conditional logistic regression models, high-density lipoprotein cholesterol (HDL-C) levels were inversely associated with risk body mass index (BMI)-adjusted relative risk (RR) for top versus bottom quartile 0.61 (95% confidence intervals (CI) 0.38–0.97), P trend = 0.02). Glucose levels were positively associated with risk (BMI-adjusted RR top versus bottom quartile 1.69 (95% CI 0.99–2.90), P trend = 0.03), which appeared stronger among postmenopausal women (BMI-adjusted RR top versus bottom tertile 2.61 (95% CI 1.46–4.66), P trend = 0.0006, P heterogeneity = 0.13) and never-users of exogenous hormones (P heterogeneity = 0.005 for oral contraceptive (OC) use and 0.05 for hormone replacement therapy-use). The associations of HDL-C and glucose with risk were no longer statistically significant after further adjustment for obesity-related hormones. Plasma total cholesterol, Low-density lipoprotein cholesterol (LDL-C), and triglycerides were not significantly related to overall risk. The presence of MetS was associated with risk (RR 2.12 (95% CI 1.51–2.97)), which increased with the number of MetS factors (P trend = 0.02). An increasing number of MetS factors other than waist circumference, however, was marginally significantly associated with risk only in women with waist circumference above the median (P interaction = 0.01). None of the associations differed significantly by fasting status. These findings suggest that metabolic abnormalities and obesity may act synergistically to increase endometrial cancer risk.