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Understanding obesity and endometrial cancer risk: opportunities for prevention

2011; Elsevier BV; Volume: 205; Issue: 6 Linguagem: Inglês

10.1016/j.ajog.2011.05.042

1097-6868

Rosemarie Schmandt, David A. Iglesias, Ngai Na Co, Karen H. Lu,

Cancer, Lipids, and Metabolism

Worldwide, obesity has become a major public health crisis. Overweight and obesity not only increase the risk of cardiovascular disease and type-2 diabetes mellitus but also are now known risk factors for a variety of cancer types. Among all cancers, increasing body mass index is associated most strongly with endometrial cancer incidence and death. The molecular mechanisms underlying how adipose tissue and obesity contribute to the pathogenesis of endometrial cancer are becoming better understood and have revealed a number of rational strategies, both behavioral and pharmaceutical, for the prevention of both primary and recurrent disease. Worldwide, obesity has become a major public health crisis. Overweight and obesity not only increase the risk of cardiovascular disease and type-2 diabetes mellitus but also are now known risk factors for a variety of cancer types. Among all cancers, increasing body mass index is associated most strongly with endometrial cancer incidence and death. The molecular mechanisms underlying how adipose tissue and obesity contribute to the pathogenesis of endometrial cancer are becoming better understood and have revealed a number of rational strategies, both behavioral and pharmaceutical, for the prevention of both primary and recurrent disease. Obesity is a well-established risk factor for the development of multiple types of cancer, cancer-related death, and all-cause death.1Reeves G.K. Pirie K. Beral V. Green J. Spencer E. Bull D. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study.BMJ. 2007; 335: 1134Crossref PubMed Scopus (1040) Google Scholar, 2Bessonova L. Marshall S.F. Ziogas A. et al.The association of body mass index with mortality in the California teachers study.Int J Cancer. 2011; (Epub ahead of print)PubMed Google Scholar Among all cancers, increasing body mass index (BMI) and obesity are associated most strongly with endometrial cancer incidence and death.1Reeves G.K. Pirie K. Beral V. Green J. Spencer E. Bull D. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study.BMJ. 2007; 335: 1134Crossref PubMed Scopus (1040) Google Scholar In a recent metaanalysis of 19 reviews and prospective studies, Renehan et al3Renehan A.G. Tyson M. Egger M. Heller R.F. Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.Lancet. 2008; 371: 569-578Abstract Full Text Full Text PDF PubMed Scopus (3641) Google Scholar found that each increase in BMI of 5 kg/m2 significantly increased a woman's risk of the development of endometrial cancer (relative risk, 1.59; 95% confidence interval [CI], 1.50–1.68). In the Million Women Study conducted in the United Kingdom, the investigators found that increasing BMI was associated with increased incidence of endometrial cancer (trend in relative risk per 10-units, 2.89; 95% CI, 2.62–3.18).1Reeves G.K. Pirie K. Beral V. Green J. Spencer E. Bull D. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study.BMJ. 2007; 335: 1134Crossref PubMed Scopus (1040) Google Scholar Endometrial cancer death is also impacted adversely by obesity. Calle et al,4Calle E.E. Rodriguez C. Walker-Thurmond K. Thun M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.N Engl J Med. 2003; 348: 1625-1638Crossref PubMed Scopus (5882) Google Scholar in a prospective study of >495,000 women who were observed for 16 years, showed a significantly increased risk of death in obese women with endometrial cancer. Even more striking was the trend that was associated with increasing BMI; the relative risk of uterine cancer-related death for women who were considered obese (BMI, 30-34.9 kg/m2) was 2.53; for morbidly obese women (BMI >40 kg/m2), the relative risk was 6.25. Not only does obesity impact cancer-related death, but through its association with other medical co-morbidities (such as diabetes mellitus and hypertension), it adversely impacts all-cause death. In a retrospective review of 380 patients with early endometrial cancer, the Gynecologic Oncology Group found that morbid obesity was associated with a higher mortality rate (hazard ratio, 2.77; 95% CI, 1.21–6.36) from causes other than endometrial cancer or disease recurrence.5von Gruenigen V.E. Tian C. Frasure H. Waggoner S. Keys H. Barakat R.R. Treatment effects, disease recurrence, and survival in obese women with early endometrial carcinoma: a Gynecologic Oncology Group study.Cancer. 2006; 107: 2786-2791Crossref PubMed Scopus (146) Google Scholar Further complicating matters, there is limited public knowledge of the relationship between obesity and cancer risk. A recent survey indicated that up to 58% of women were not aware that obesity increased endometrial cancer risk.6Soliman P.T. Bassett Jr, R.L. Wilson E.B. et al.Limited public knowledge of obesity and endometrial cancer risk: what women know.Obstet Gynecol. 2008; 112: 835-842Crossref PubMed Scopus (54) Google Scholar Although it has been presumed that excess estrogen because of the peripheral conversion of androstenedione to estrone accounts for the increased risk of endometrial cancer in obese women, new studies implicate other mechanisms by which obesity promotes endometrial cancer. This review will discuss the current understanding of what factors underlie the association of obesity and endometrial cancer and what strategies are available for both prevention and treatment (Figure 1) . Estrogen is a known endometrial growth factor. Although the ovaries are the primary source of estrogen in premenopausal women, peripheral tissues, which include adipose tissue, become the primary sources of circulating estrogen in postmenopausal women.7Calle E.E. Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms.Nat Rev Cancer. 2004; 4: 579-591Crossref PubMed Scopus (2688) Google Scholar, 8Boon W.C. Chow J.D. Simpson E.R. The multiple roles of estrogens and the enzyme aromatase.Prog Brain Res. 2010; 181: 209-232Crossref PubMed Scopus (123) Google Scholar, 9van Kruijsdijk R.C. van der Wall E. Visseren F.L. Obesity and cancer: the role of dysfunctional adipose tissue.Cancer Epidemiol Biomarkers Prev. 2009; 18: 2569-2578Crossref PubMed Scopus (525) Google Scholar Androgens are converted to estrone and estradiol by the enzyme aromatase in adipose tissue. Aromatase is produced by mesenchymal stromal cells, which include adipocyte stem cells, and to a lesser degree by mature adipocytes themselves. Aromatase levels increase as a function of age and obesity and are reflected by an increase in circulating estrogen levels with increasing BMI in postmenopausal women.10Cauley J.A. Gutai J.P. Kuller L.H. LeDonne D. Powell J.G. The epidemiology of serum sex hormones in postmenopausal women.Am J Epidemiol. 1989; 129: 1120-1131PubMed Google Scholar, 11Simpson E.R. Mendelson C.R. Effect of aging and obesity on aromatase activity of human adipose cells.Am J Clin Nutr. 1987; 45: 290-295PubMed Google Scholar Cauley et al10Cauley J.A. Gutai J.P. Kuller L.H. LeDonne D. Powell J.G. The epidemiology of serum sex hormones in postmenopausal women.Am J Epidemiol. 1989; 129: 1120-1131PubMed Google Scholar demonstrated >40% increases in both circulating estrone and estradiol in obese (BMI, >30 kg/m2) vs normal (BMI, 2-fold increased risk for endometrial cancer. Hyperinsulinemia and the insulin-resistant state are associated closely with obesity. Epidemiologically, a number of studies have shown a modest association of diabetes mellitus with endometrial cancer risk.24Shoff S.M. Newcomb P.A. Diabetes, body size, and risk of endometrial cancer.Am J Epidemiol. 1998; 148: 234-240Crossref PubMed Scopus (144) Google Scholar, 25Weiderpass E. Persson I. Adami H.O. Magnusson C. Lindgren A. Baron J.A. Body size in different periods of life, diabetes mellitus, hypertension, and risk of postmenopausal endometrial cancer (Sweden).Cancer Causes Control. 2000; 11: 185-192Crossref PubMed Scopus (232) Google Scholar, 26Anderson K.E. Anderson E. Mink P.J. et al.Diabetes and endometrial cancer in the Iowa women's health study.Cancer Epidemiol Biomarkers Prev. 2001; 10: 611-616PubMed Google Scholar, 27Salazar-Martinez E. Lazcano-Ponce E.C. Lira-Lira G.G. et al.Case-control study of diabetes, obesity, physical activity and risk of endometrial cancer among Mexican women.Cancer Causes Control. 2000; 11: 707-711Crossref PubMed Scopus (93) Google Scholar, 28Parazzini F. La Vecchia C. Negri E. et al.Diabetes and endometrial cancer: an Italian case-control study.Int J Cancer. 1999; 81: 539-542Crossref PubMed Scopus (73) Google Scholar Interestingly, in 3 studies the most significant risks were seen in women who were both obese and diabetic.24Shoff S.M. Newcomb P.A. Diabetes, body size, and risk of endometrial cancer.Am J Epidemiol. 1998; 148: 234-240Crossref PubMed Scopus (144) Google Scholar, 27Salazar-Martinez E. Lazcano-Ponce E.C. Lira-Lira G.G. et al.Case-control study of diabetes, obesity, physical activity and risk of endometrial cancer among Mexican women.Cancer Causes Control. 2000; 11: 707-711Crossref PubMed Scopus (93) Google Scholar, 29Friberg E. Mantzoros C.S. Wolk A. Diabetes and risk of endometrial cancer: a population-based prospective cohort study.Cancer Epidemiol Biomarkers Prev. 2007; 16: 276-280Crossref PubMed Scopus (133) Google Scholar A study by Troisi et al30Troisi R. Potischman N. Hoover R.N. Siiteri P. Brinton L.A. Insulin and endometrial cancer.Am J Epidemiol. 1997; 146: 476-482Crossref PubMed Scopus (87) Google Scholar examined insulin levels in women with endometrial cancer compared with control subjects to determine whether elevated insulin levels could explain the association of obesity and endometrial cancer. Although elevated serum insulin levels, as measured by C-peptide, were associated with increased risk of endometrial cancer, the elevation of serum insulin levels alone could not account for the association of obesity and endometrial cancer (Figure 2) . Several recent studies, including 1 by our group, demonstrate an association of insulin resistance with endometrial cancer risk with the use of adiponectin as surrogate marker for insulin resistance.31Soliman P.T. Wu D. Tortolero-Luna G. et al.Association between adiponectin, insulin resistance, and endometrial cancer.Cancer. 2006; 106: 2376-2381Crossref PubMed Scopus (193) Google Scholar, 32Dal Maso L. Augustin L.S. Karalis A. et al.Circulating adiponectin and endometrial cancer risk.J Clin Endocrinol Metab. 2004; 89: 1160-1163Crossref PubMed Scopus (249) Google Scholar, 33Petridou E. Mantzoros C. Dessypris N. et al.Plasma adiponectin concentrations in relation to endometrial cancer: a case-control study in Greece.J Clin Endocrinol Metab. 2003; 88: 993-997Crossref PubMed Scopus (200) Google Scholar, 34Cust A.E. Kaaks R. Friedenreich C. et al.Plasma adiponectin levels and endometrial cancer risk in pre- and postmenopausal women.J Clin Endocrinol Metab. 2007; 92: 255-263Crossref PubMed Scopus (169) Google Scholar This adipokine can be measured in serum or plasma and demonstrates levels that are inversely proportional to insulin resistance. Using a case-control study design, our group found that low adiponectin levels were associated highly with endometrial cancer risk, independent of BMI. Subsequently, a large prospective, nested case-control study that was sponsored by the World Health Organization, performed a study on adiponectin and endometrial cancer risk.34Cust A.E. Kaaks R. Friedenreich C. et al.Plasma adiponectin levels and endometrial cancer risk in pre- and postmenopausal women.J Clin Endocrinol Metab. 2007; 92: 255-263Crossref PubMed Scopus (169) Google Scholar All samples were collected prospectively; those samples that were used for analysis were from a time point before the onset of endometrial cancer. This study confirmed that low adiponectin levels were associated with endometrial cancer risk, again independent of BMI, which strongly suggested that insulin resistance is an independent risk factor for endometrial cancer. The specific effects of hyperinsulinemia on the pathogenesis of obesity-associated cancers are not well-defined. Our group has demonstrated that the proliferative effect of estrogen on the endometrium is enhanced in obese vs lean animals.35Zhang Q. Shen Q. Celestino J. et al.Enhanced estrogen-induced proliferation in obese rat endometrium.Am J Obstet Gynecol. 2009; 200: 186.e1-186.e8Abstract Full Text Full Text PDF Scopus (27) Google Scholar In the Zucker rat model of hyperinsulinemia, estrogen induced significantly higher expression of the proproliferative genes, cyclin A and c-myc, and in endometrium of obese rats, as compared with what had been observed in lean control animals. Conversely, the estrogen-induced suppression of the cell cycle inhibitor, p27Kip1, and the anti-proliferative genes sFRP4 and RALDH2 are more pronounced in the obese endometrium. Obesity therefore alters the balance between pro- and anti-proliferative signals to favor endometrial growth. Systemic levels of IGFs are also altered by obesity. Six IGF-binding proteins (IGFBPs) bind to and modulate IGF bioactivity by interfering with receptor binding. Although increased estrogen production directly increases IGF-1 synthesis,36Klotz D.M. Hewitt S.C. Ciana P. et al.Requirement of estrogen receptor-alpha in insulin-like growth factor-1 (IGF-1)-induced uterine responses and in vivo evidence for IGF-1/estrogen receptor cross-talk.J Biol Chem. 2002; 277: 8531-8537Crossref PubMed Scopus (244) Google Scholar, 37Hewitt S.C. Li Y. Li L. Korach K.S. Estrogen-mediated regulation of Igf1 transcription and uterine growth involves direct binding of estrogen receptor alpha to estrogen-responsive elements.J Biol Chem. 2010; 285: 2676-2685Crossref PubMed Scopus (97) Google Scholar sustained hyperinsulinemia results in the decreased synthesis of IGFBP1 and 2.7Calle E.E. Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms.Nat Rev Cancer. 2004; 4: 579-591Crossref PubMed Scopus (2688) Google Scholar IGFBP1 is most highly expressed by human endometrium.38Rutanen E.M. Insulin-like growth factors in endometrial function.Gynecol Endocrinol. 1998; 12: 399-406Crossref PubMed Scopus (108) Google Scholar, 39Rutanen E.M. Insulin-like growth factors and insulin-like growth factor binding proteins in the endometrium: effect of intrauterine levonorgestrel delivery.Hum Reprod. 2000; 15: 173-181Crossref PubMed Scopus (53) Google Scholar Therefore, obesity contributes to the simultaneous increase in circulating IGF and decrease in IGFBP1 and results in the net increase of bioavailable IGF-1.7Calle E.E. Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms.Nat Rev Cancer. 2004; 4: 579-591Crossref PubMed Scopus (2688) Google Scholar, 40Cust A.E. Allen N.E. Rinaldi S. et al.Serum levels of C-peptide, IGFBP-1 and IGFBP-2 and endometrial cancer risk; results from the European prospective investigation into cancer and nutrition.Int J Cancer. 2007; 120: 2656-2664Crossref PubMed Scopus (81) Google Scholar, 41Lukanova A. Zeleniuch-Jacquotte A. Lundin E. et al.Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer.Int J Cancer. 2004; 108: 262-268Crossref PubMed Scopus (147) Google Scholar Insulin and IGFs use common signaling mechanisms.42Pollak M. Insulin and insulin-like growth factor signalling in neoplasia.Nat Rev Cancer. 2008; 8: 915-928Crossref PubMed Scopus (1599) Google Scholar As illustrated in Figure 3, on ligand binding, receptor-mediated phosphorylation of the insulin receptor substrate 1 (IRS-1) scaffold protein results in the activation of both the phosphoinositide kinase 3 (PI3K)/AKT/mammalian target of rapamycin (mTOR) and MAPK signaling pathways, which promote cell survival and proliferation.42Pollak M. Insulin and insulin-like growth factor signalling in neoplasia.Nat Rev Cancer. 2008; 8: 915-928Crossref PubMed Scopus (1599) Google Scholar Hyperactivity of the PI3K/AKT/mTOR pathway is observed frequently in endometrial cancer. The ubiquitously expressed phosphatase and tensin homolog (PTEN) lipid/protein phosphatase dephosphorylates PI3K substrates and acts as a PI3K antagonist and tumor suppressor gene. PTEN inactivation or loss is observed in >40% of type I endometrial cancers. Therefore, coupled with elevated circulating IGF-1, the loss of PTEN promotes the hyperactivity of the PI3K/AKT/mTOR pathway and facilitates endometrial cancer growth in obese individuals. Furthermore, the insulin and IGF receptors simultaneously activate the MAPK signaling pathway, which is another mechanism that promotes mTOR signaling.42Pollak M. Insulin and insulin-like growth factor signalling in neoplasia.Nat Rev Cancer. 2008; 8: 915-928Crossref PubMed Scopus (1599) Google Scholar AMPK (5′ adenosine monophosphate-activated protein kinase) inhibits signaling through the PI3K/AKT/mTOR pathway by serving as a counterbalance to AKT and ERK activity. AMPK inactivation is commonly associated with obesity (energy/caloric excess) and insulin resistance. When phosphorylated by AMPK, the tuberous sclerosis complex 1/2 prevents mTOR-mediated endometrial proliferation. Inactivation of AMPK therefore represents an additional mechanism that contributes to the hyperactivity of mTOR and tumorigenesis in the endometrium. Adipose tissue is a complex endocrine organ that secretes a variety of both anti- and proinflammatory factors classified as "adipokines." The state of chronic systemic inflammation that is associated with obesity is linked increasingly to the development of insulin resistance and chronic hyperinsulinemia.43Shoelson S.E. Herrero L. Naaz A. Obesity, inflammation, and insulin resistance.Gastroenterology. 2007; 132: 2169-2180Abstract Full Text Full Text PDF PubMed Scopus (1308) Google Scholar, 44Nieto-Vazquez I. Fernandez-Veledo S. Kramer D.K. Vila-Bedmar R. Garcia-Guerra L. Lorenzo M. Insulin resistance associated to obesity: the link TNF-alpha.Arch Physiol Biochem. 2008; 114: 183-194Crossref PubMed Scopus (311) Google Scholar, 45Shaarawy M. Abdel-Aziz O. Serum tumour necrosis factor alpha levels in benign and malignant lesions of the endometrium in postmenopausal women: a preliminary study.Acta Oncol. 1992; 31: 417-420Crossref PubMed Scopus (12) Google Scholar, 46Cymbaluk A. Chudecka-Glaz A. Rzepka-Gorska I. Leptin levels in serum depending on body mass index in patients with endometrial hyperplasia and cancer.Eur J Obstet Gynecol Reprod Biol. 2008; 136: 74-77Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 47Ferdeghini M. Gadducci A. Prontera C. et al.Serum interleukin-6 levels in uterine malignancies: preliminary data.Anticancer Res. 1994; 14: 735-737PubMed Google Scholar, 48Hlavna M. Kohut L. Lipkova J. et al.Relationship of resistin levels with endometrial cancer risk.Neoplasma. 2011; 58: 124-128Crossref PubMed Scopus (46) Google Scholar, 49Long Y.C. Zierath J.R. AMP-activated protein kinase signaling in metabolic regulation.J Clin Invest. 2006; 116: 1776-1783Crossref PubMed Scopus (755) Google Scholar, 50Dossus L. Rinaldi S. Becker S. et al.Obesity, inflammatory markers, and endometrial cancer risk: a prospective case-control study.Endocr Relat Cancer. 2010; 17: 1007-1019Crossref PubMed Scopus (119) Google Scholar, 51Wang T. Rohan T.E. Gunter M.J. et al.A prospective study of inflammation markers and endometrial cancer risk in postmenopausal hormone non-users.Cancer Epidemiol Biomarkers Prev. 2011; 20: 971-977Crossref PubMed Scopus (81) Google Scholar, 52Wen W. Cai Q. Xiang Y.B. et al.The modifying effect of C-reactive protein gene polymorphisms on the association between central obesity and endometrial cancer risk.Cancer. 2008; 112: 2409-2416Crossref PubMed Scopus (24) Google Scholar For example, secretion of the adipokine, tumor necrosis factor alpha (TNFα), disrupts insulin receptor signaling by inducing the inhibitory phosphorylation of IRS proteins, thereby uncoupling insulin from downstream signaling cascades.44Nieto-Vazquez I. Fernandez-Veledo S. Kramer D.K. Vila-Bedmar R. Garcia-Guerra L. Lorenzo M. Insulin resistance associated to obesity: the link TNF-alpha.Arch Physiol Biochem. 2008; 114: 183-194Crossref PubMed Scopus (311) Google Scholar In addition to TNFα,45Shaarawy M. Abdel-Aziz O. Serum tumour necrosis factor alpha levels in benign and malignant lesions of the endometrium in postmenopausal women: a preliminary study.Acta Oncol. 1992; 31: 417-420Crossref PubMed Scopus (12) Google Scholar additional proinflammatory adipokines that are associated with endometrial cancer include leptin,46Cymbaluk A. Chudecka-Glaz A. Rzepka-Gorska I. Leptin levels in serum depending on body mass index in patients with endometrial hyperplasia and cancer.Eur J Obstet Gynecol Reprod Biol. 2008; 136: 74-77Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar interleukin-6 (IL-6),47Ferdeghini M. Gadducci A. Prontera C. et al.Serum interleukin-6 levels in uterine malignancies: preliminary data.Anticancer Res. 1994; 14: 735-737PubMed Google Scholar and resistin.48Hlavna M. Kohut L. Lipkova J. et al.Relationship of resistin levels with endometrial cancer risk.Neoplasma. 2011; 58: 124-128Crossref PubMed Scopus (46) Google Scholar In opposition to the proinflammatory adipokines, circulating levels of adiponectin are inversely proportional to BMI and insulin resistance and play a role in increasing insulin sensitivity and as an antiinflammatory. Adiponectin signals through its receptors (AdipoR1/2) to activate AMPK and inhibit PI3K/AKT/mTOR signaling49Long Y.C. Zierath J.R. AMP-activated protein kinase signaling in metabolic regulation.J Clin Invest. 2006; 116: 1776-1783Crossref PubMed Scopus (755) Google Scholar and should therefore inhibit tumor progression driven by the PI3K pathway. In support of this hypothesis, studies performed by our group and others confirm that adiponectin levels are independently and inversely associated with endometrial cancer risk.31Soliman P.T. Wu D. Tortolero-Luna G. et al.Association between adiponectin, insulin resistance, and endometrial cancer.Cancer. 2006; 106: 2376-2381Crossref PubMed Scopus (193) Google Scholar, 32Dal Maso L. Augustin L.S. Karalis A. et al.Circulating adiponectin and endometrial cancer risk.J Clin Endocrinol Metab. 2004; 89: 1160-1163Crossref PubMed Scopus (249) Google Scholar, 33Petridou E. Mantzoros C. Dessypris N. et al.Plasma adiponectin concentrations in relation to endometrial cancer: a case-control study in Greece.J Clin Endocrinol Metab. 2003; 88: 993-997Crossref PubMed Scopus (200) Google Scholar, 34Cust A.E. Kaaks R. Friedenreich C. et al.Plasma adiponectin levels and endometrial cancer risk in pre- and postmenopausal women.J Clin Endocrinol Metab. 2007; 92: 255-263Crossref PubMed Scopus (169) Google Scholar Adipokines and other inflammatory proteins that are associated with obesity, such as C-reactive protein, show promise as biomarkers of endometrial cancer risk50Dossus L. Rinaldi S. Becker S. et al.Obesity, inflammatory markers, and endometrial cancer risk: a prospective case-control study.Endocr Relat Cancer. 2010; 17: 1007-1019Crossref PubMed Scopus (119) Google Scholar, 51Wang T. Rohan T.E. Gunter M.J. et al.A prospective study of inflammation markers and endometrial cancer risk in postmenopausal hormone non-users.Cancer Epidemiol Biomarkers Prev. 2011; 20: 971-977Crossref PubMed Scopus (81) Google Scholar, 52Wen W. Cai Q. Xiang Y.B. et al.The modifying effect of C-reactive protein gene polymorphisms on the association between central obesity and endometrial cancer risk.