|Grant Number:||2R01CA082838-10A1 Interpret this number|
|Primary Investigator:||Devivo, Immaculata|
|Organization:||Brigham And Women'S Hospital|
|Project Title:||Molecular Pathoepidemiology of Endometrial Cancer Risk|
DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Despite high survival rates, survivors of early stage endometrial cancer continue to experience a lower quality of life many years after diagnosis and treatment compared to healthy controls. Lifestyle factors are strongly implicated in the etiology of Type I endometrial cancer and obesity may account for over one-third of incident endometrial cancer in high-income societies. Although a number of modifiable risk factors are well-established, the mechanisms behind endometrial carcinogenesis remain unclear. Endometrial cancer is considered a model of hormonal carcinogenesis as use of postmenopausal estrogen unopposed by progesterone, and obesity are the best-established risk factors. Recent findings suggest that in addition to the sex steroid pathway, altered hormone levels in energy balance pathways may play a substantial role in disease pathogenesis. Important details such as the degree to which each pathway mediates the effects of major risk factors on disease and the specific biomarkers involved in these processes have not been elucidated. To this end, in this competing renewal we propose to understand the molecular basis for several established and novel (i.e. insulin index) risk factors of endometrial cancer, with a focus on the roles of the sex steroid and energy balance pathways. By evaluating the expression of sex steroid and energy balance related markers in tumor tissue (and matched adjacent non-tumor tissue) in relation to reproductive and lifestyle exposures, we will provide considerable insight into the importance of each of these pathways. Finally, because several modifiable and relatively strong environmental and lifestyle risk factors for endometrial cancer are well-established, endometrial cancer is a particularly suitable cancer in which to examine the interplay of environment, germline genetics, and somatic genetics. In our study with up to 36 years of follow-up, we expect to have 722 Type I endometrial cancer cases with tumor tissue available for analysis. A large prospective cohort study is a powerful approach to elucidate the biological mechanisms involved in endometrial cancer pathogenesis and identify the existence of distinct etiological subtypes. A major strength of this proposal is that it will enhance our current mechanistic understanding behind endometrial cancer susceptibility by providing us with data on somatic molecular changes influenced by established and novel endometrial cancer risk factors. Such findings would refine endometrial cancer risk prediction, creating a basis for identifying women at highest risk that would most benefit from tailored and cost-effective lifestyle and/or chemopreventive intervention strategies. PUBLIC HEALTH RELEVANCE: Despite high survival rates, survivors of early stage endometrial cancer continue to experience a lower quality of life many years after diagnosis and treatment compared to healthy controls. Defining somatic molecular subtypes associated with established and novel endometrial cancer risk factors will provide us with a better mechanistic understanding into the etiology of this disease. Work resulting from this proposal will refine endometrial cancer risk prediction, creating a basis for identifying women at highest risk that would most benefit from tailored and cost-effective lifestyle and/or chemopreventive intervention strategies.
Healthy lifestyle and leukocyte telomere length in U.S. women.
Authors: Sun Q, Shi L, Prescott J, Chiuve SE, Hu FB, De Vivo I, Stampfer MJ, Franks PW, Manson JE, Rexrode KM
Source: PLoS One, 2012;7(5), p. e38374.
EPub date: 2012 May 31.
GSTM1 and GSTT1 copy number variation in population-based studies of endometrial cancer risk.
Authors: Karageorgi S, Prescott J, Wong JY, Lee IM, Buring JE, De Vivo I
Source: Cancer Epidemiol Biomarkers Prev, 2011 Jul;20(7), p. 1447-52.
EPub date: 2011 May 10.
Polymorphisms in genes hydroxysteroid-dehydrogenase-17b type 2 and type 4 and endometrial cancer risk.
Authors: Karageorgi S, McGrath M, Lee IM, Buring J, Kraft P, De Vivo I
Source: Gynecol Oncol, 2011 Apr;121(1), p. 54-8.
EPub date: 2010 Dec 3.
Common genetic variation within IGFI, IGFII, IGFBP-1, and IGFBP-3 and endometrial cancer risk.
Authors: McGrath M, Lee IM, Buring J, De Vivo I
Source: Gynecol Oncol, 2011 Feb;120(2), p. 174-8.
Associations between diet, lifestyle factors, and telomere length in women.
Authors: Cassidy A, De Vivo I, Liu Y, Han J, Prescott J, Hunter DJ, Rimm EB
Source: Am J Clin Nutr, 2010 May;91(5), p. 1273-80.
EPub date: 2010 Mar 10.
Genetic variation in CYP11A1 and StAR in relation to endometrial cancer risk.
Authors: Terry K, McGrath M, Lee IM, Buring J, De Vivo I
Source: Gynecol Oncol, 2010 May;117(2), p. 255-9.
EPub date: 2010 Mar 2.
Leukocyte telomere length in a population-based case-control study of ovarian cancer: a pilot study.
Authors: Mirabello L, Garcia-Closas M, Cawthon R, Lissowska J, Brinton LA, Pep?o?ska B, Sherman ME, Savage SA
Source: Cancer Causes Control, 2010 Jan;21(1), p. 77-82.
EPub date: 2009 Sep 27.
The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer.
Authors: Mirabello L, Huang WY, Wong JY, Chatterjee N, Reding D, Crawford ED, De Vivo I, Hayes RB, Savage SA
Source: Aging Cell, 2009 Aug;8(4), p. 405-13.
EPub date: 2009 Jun 1.
Genetic variations in UGT1A1 and UGT2B7 and endometrial cancer risk.
Authors: McGrath M, Lepine J, Lee IM, Villeneuve L, Buring J, Guillemette C, De Vivo I
Source: Pharmacogenet Genomics, 2009 Mar;19(3), p. 239-43.
Two estrogen-related variants in CYP19A1 and endometrial cancer risk: a pooled analysis in the Epidemiology of Endometrial Cancer Consortium.
Authors: Setiawan VW, Doherty JA, Shu XO, Akbari MR, Chen C, De Vivo I, Demichele A, Garcia-Closas M, Goodman MT, Haiman CA, Hankinson SE, Henderson BE, Horn-Ross PL, Lacey JV Jr, Le Marchand L, Levine DA, Liang X, Lissowska J, Lurie G, McGrath M, Narod SA, Rebbeck TR, Ursin G, Weiss NS, Xiang YB, Yang HP, Zheng W, Olson SH
Source: Cancer Epidemiol Biomarkers Prev, 2009 Jan;18(1), p. 242-7.
Novel breast cancer risk alleles and endometrial cancer risk.
Authors: McGrath M, Lee IM, Buring J, Hunter DJ, De Vivo I
Source: Int J Cancer, 2008 Dec 15;123(12), p. 2961-4.
Postmenopausal hormone therapy and stroke: role of time since menopause and age at initiation of hormone therapy.
Authors: Grodstein F, Manson JE, Stampfer MJ, Rexrode K
Source: Arch Intern Med, 2008 Apr 28;168(8), p. 861-6.
Cytochrome P450 1A1, cigarette smoking, and risk of endometrial cancer (United States).
Authors: McGrath M, Hankinson SE, De Vivo I
Source: Cancer Causes Control, 2007 Dec;18(10), p. 1123-30.
EPub date: 2007 Aug 24.
The p53 Arg72Pro and MDM2 -309 polymorphisms and risk of breast cancer in the nurses' health studies.
Authors: Cox DG, Deer D, Guo Q, Tworoger SS, Hankinson SE, Hunter DJ, De Vivo I
Source: Cancer Causes Control, 2007 Aug;18(6), p. 621-5.
EPub date: 2007 Mar 27.
CYP19 (aromatase) haplotypes and endometrial cancer risk.
Authors: Paynter RA, Hankinson SE, Colditz GA, Kraft P, Hunter DJ, De Vivo I
Source: Int J Cancer, 2005 Aug 20;116(2), p. 267-74.
Smoking and the risk of endometrial cancer: results from the Nurses' Health Study.
Authors: Viswanathan AN, Feskanich D, De Vivo I, Hunter DJ, Barbieri RL, Rosner B, Colditz GA, Hankinson SE
Source: Int J Cancer, 2005 May 10;114(6), p. 996-1001.
No evidence of a role for PPARgamma Pro12Ala polymorphism in endometrial cancer susceptibility.
Authors: Paynter RA, Hankinson SE, Colditz GA, Hunter DJ, De Vivo I
Source: Pharmacogenetics, 2004 Dec;14(12), p. 851-6.
The progesterone receptor Val660-->Leu polymorphism and breast cancer risk.
Authors: De Vivo I, Hankinson SE, Colditz GA, Hunter DJ
Source: Breast Cancer Res, 2004;6(6), p. R636-9.
EPub date: 2004 Sep 22.
Estrogen receptor beta (ESR2 ) polymorphisms and endometrial cancer (United States).
Authors: Setiawan VW, Hankinson SE, Colditz GA, Hunter DJ, De Vivo I
Source: Cancer Causes Control, 2004 Aug;15(6), p. 627-33.
A prospective study of folate intake and the risk of pancreatic cancer in men and women.
Authors: Skinner HG, Michaud DS, Giovannucci EL, Rimm EB, Stampfer MJ, Willett WC, Colditz GA, Fuchs CS
Source: Am J Epidemiol, 2004 Aug 1;160(3), p. 248-58.
No association between MTHFR 677 C->T or 1298 A->C polymorphisms and endometrial cancer risk.
Authors: Paynter RA, Hankinson SE, Hunter DJ, De Vivo I
Source: Cancer Epidemiol Biomarkers Prev, 2004 Jun;13(6), p. 1088-9.