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Grant Details

Grant Number: 5R01CA054419-15 Interpret this number
Primary Investigator: Cramer, Daniel
Organization: Brigham And Women'S Hosp., Inc.
Project Title: Genes, Hormones & Environment in an Ovarian Cancer Model
Fiscal Year: 2007
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Abstract

DESCRIPTION (provided by applicant): This New England-based case-control study has sought to identify risk factors for ovarian cancer mediated through depletion of ovarian germ cells and gonadotropin excess. New theories with a molecular basis and considering roles for ovarian steroids, inflammation, and certain genetic polymorphisms now need to be incorporated. In our new model, gonadotropins remain important with risk factors operating at the pituitary or hypothalamic level. Elements within the ovary include germ cells regulating pituitary feedback, stromal cells producing steroids and proteins, and epithelial cells responding to growth factors. Epithelial cells trapped in inclusion cysts or deriving from endometriosis may be more susceptible to local or circulating growth factors. Epithelial proliferation in the setting of reactive oxygen species (ROS), generated from catechol estrogen or inflammation, leads to DNA damage. Selection of cells destined to become cancer may occur when inherited DNA repair mechanisms are faulty and oncogenes or tumor suppressors are damaged. Other genetic factors include variants of genes in pathways for steroid production or xenobiotic metabolism, while a variety of exposures may impact on risk. In the continuation proposed, existing and new epidemiologic data and DNA from 1700 controls and 1800 cases with ovarian, fallopian tube, or primary peritoneal cancer (including a subset identified pre-operatively) will be used to examine how hormonal factors, genes, and environment interact in this model. Through pituitary effects, pregnancy and lactation protect better than pregnancy alone and opposed regimens of menopausal therapy protect better than unopposed regimens. As a marker for poor germ cell reserve, short cycle lengths in very early reproductive life increase risk for ovarian cancer. By affecting steroid production, genetic variants of 3 and 17betaHSD, CYP11A, CYP17, and CYP 19 may affect risk for ovarian cancer. Steroid production is also enhanced by caffeine use, a predicted risk factor interacting with dietary cholesterol or caffeine metabolism. Genetic polymorphisms affecting the production or clearance of catechol estrogen or ROS generated by inflammation also influence ovarian cancer risk, including Ahr, CYP1A1, COMT, MnSOD, GST, and NAT and may interact with exposures like genital talc. Protection from ovarian cancer is associated with a variety of antioxidants including lycopene, carotene, ginkgo, and indoles from Brassica vegetables as well as anti-inflammatory agents. Our continued goal is to identify modifiable risk factors and chemo preventive agents for a common and lethal cancer in women.

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Publications

Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis in the Ovarian Cancer Association Consortium.
Authors: Trabert B, Ness RB, Lo-Ciganic WH, Murphy MA, Goode EL, Poole EM, Brinton LA, Webb PM, Nagle CM, Jordan SJ, Australian Ovarian Cancer Study Group, Australian Cancer Study (Ovarian Cancer), Risch HA, Rossing MA, Doherty JA, Goodman MT, Lurie G, Kjær SK, Hogdall E, Jensen A, Cramer DW, Terry KL, Vitonis A, Bandera EV, Olson S, King MG, Chandran U, Anton-Culver H, Ziogas A, Menon U, Gayther SA, Ramus SJ, Gentry-Maharaj A, Wu AH, Pearce CL, Pike MC, Berchuck A, Schildkraut JM, Wentzensen N, Ovarian Cancer Association Consortium
Source: J Natl Cancer Inst, 2014 Feb;106(2), p. djt431.
PMID: 24503200
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ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: a comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas.
Authors: Johnatty SE, Beesley J, Gao B, Chen X, Lu Y, Law MH, Henderson MJ, Russell AJ, Hedditch EL, Emmanuel C, Fereday S, Webb PM, Australian Ovarian Cancer Study Group, Goode EL, Vierkant RA, Fridley BL, Cunningham JM, Fasching PA, Beckmann MW, Ekici AB, Hogdall E, Kjaer SK, Jensen A, Hogdall C, Brown R, Paul J, Lambrechts S, Despierre E, Vergote I, Lester J, Karlan BY, Heitz F, du Bois A, Harter P, Schwaab I, Bean Y, Pejovic T, Levine DA, Goodman MT, Camey ME, Thompson PJ, Lurie G, Shildkraut J, Berchuck A, Terry KL, Cramer DW, Norris MD, Haber M, MacGregor S, deFazio A, Chenevix-Trench G
Source: Gynecol Oncol, 2013 Oct;131(1), p. 8-14.
EPub date: 2013 Aug 1.
PMID: 23917080
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Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls.
Authors: Terry KL, Karageorgi S, Shvetsov YB, Merritt MA, Lurie G, Thompson PJ, Carney ME, Weber RP, Akushevich L, Lo-Ciganic WH, Cushing-Haugen K, Sieh W, Moysich K, Doherty JA, Nagle CM, Berchuck A, Pearce CL, Pike M, Ness RB, Webb PM, Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group, Rossing MA, Schildkraut J, Risch H, Goodman MT, Ovarian Cancer Association Consortium
Source: Cancer Prev Res (Phila), 2013 Aug;6(8), p. 811-21.
EPub date: 2013 Jun 12.
PMID: 23761272
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Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies.
Authors: Faber MT, Kjær SK, Dehlendorff C, Chang-Claude J, Andersen KK, Høgdall E, Webb PM, Jordan SJ, Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group, Rossing MA, Doherty JA, Lurie G, Thompson PJ, Carney ME, Goodman MT, Ness RB, Modugno F, Edwards RP, Bunker CH, Goode EL, Fridley BL, Vierkant RA, Larson MC, Schildkraut J, Cramer DW, Terry KL, Vitonis AF, Bandera EV, Olson SH, King M, Chandran U, Kiemeney LA, Massuger LF, van Altena AM, Vermeulen SH, Brinton L, Wentzensen N, Lissowska J, Yang HP, Moysich KB, Odunsi K, Kasza K, Odunsi-Akanji O, Song H, Pharaoh P, Shah M, Whittemore AS, McGuire V, Sieh W, Sutphen R, Menon U, Gayther SA, Ramus SJ, Gentry-Maharaj A, Pearce CL, Wu AH, Pike MC, Risch HA, Jensen A, Ovarian Cancer Association Consortium
Source: Cancer Causes Control, 2013 May;24(5), p. 989-1004.
EPub date: 2013 Mar 2.
PMID: 23456270
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ABO blood group and risk of epithelial ovarian cancer within the Ovarian Cancer Association Consortium.
Authors: Poole EM, Gates MA, High BA, Chanock SJ, Cramer DW, Cunningham JM, Fridley BL, Gayther SA, Goode EL, Iversen ES, Lissowska J, Palmieri Weber RT, Pharoah PD, Phelan CM, Ramus SJ, Schildkraut JM, Sutphen R, Tsai YY, Tyrer J, Vierkant RA, Wentzensen N, Yang HP, Terry KL, Tworoger SS
Source: Cancer Causes Control, 2012 Nov;23(11), p. 1805-10.
EPub date: 2012 Sep 8.
PMID: 22961099
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Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies.
Authors: Pearce CL, Templeman C, Rossing MA, Lee A, Near AM, Webb PM, Nagle CM, Doherty JA, Cushing-Haugen KL, Wicklund KG, Chang-Claude J, Hein R, Lurie G, Wilkens LR, Carney ME, Goodman MT, Moysich K, Kjaer SK, Hogdall E, Jensen A, Goode EL, Fridley BL, Larson MC, Schildkraut JM, Palmieri RT, Cramer DW, Terry KL, Vitonis AF, Titus LJ, Ziogas A, Brewster W, Anton-Culver H, Gentry-Maharaj A, Ramus SJ, Anderson AR, Brueggmann D, Fasching PA, Gayther SA, Huntsman DG, Menon U, Ness RB, Pike MC, Risch H, Wu AH, Berchuck A, Ovarian Cancer Association Consortium
Source: Lancet Oncol, 2012 Apr;13(4), p. 385-94.
EPub date: 2012 Feb 22.
PMID: 22361336
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Assessing ovarian cancer risk when considering elective oophorectomy at the time of hysterectomy.
Authors: Vitonis AF, Titus-Ernstoff L, Cramer DW
Source: Obstet Gynecol, 2011 May;117(5), p. 1042-50.
PMID: 21471855
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Prostate cancer susceptibility polymorphism rs2660753 is not associated with invasive ovarian cancer.
Authors: Amankwah EK, Kelemen LE, Wang Q, Song H, Chenevix-Trench G, Australian Ovarian Cancer Study Group, Beesley J, Webb PM, Australian Cancer Study (Ovarian Cancer), Pearce CL, Wu AH, Pike MC, Stram DO, Chang-Claude J, Wang-Gohrke S, Ness RB, Goode EL, Cunningham JM, Fridley BL, Vierkant RA, Tworoger SS, Whittemore AS, McGuire V, Sieh W, Gayther SA, Gentry-Maharaj A, Menon U, Ramus SJ, Rossing MA, Doherty JA, Goodman MT, Carney ME, Lurie G, Wilkens LR, Kjær SK, Høgdall E, Cramer DW, Terry KL, Garcia-Closas M, Yang H, Lissowska J, Anton-Culver H, Ziogas A, Schildkraut JM, Berchuck A, Pharoah PD, Ovarian Cancer Association Consortium
Source: Cancer Epidemiol Biomarkers Prev, 2011 May;20(5), p. 1028-31.
EPub date: 2011 Mar 17.
PMID: 21415361
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CA125 immune complexes in ovarian cancer patients with low CA125 concentrations.
Authors: Cramer DW, O'Rourke DJ, Vitonis AF, Matulonis UA, Dijohnson DA, Sluss PM, Crum CP, Liu BC
Source: Clin Chem, 2010 Dec;56(12), p. 1889-92.
EPub date: 2010 Oct 13.
PMID: 20943848
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Correlates of the preoperative level of CA125 at presentation of ovarian cancer.
Authors: Cramer DW, Vitonis AF, Welch WR, Terry KL, Goodman A, Rueda BR, Berkowitz RS
Source: Gynecol Oncol, 2010 Dec;119(3), p. 462-8.
EPub date: 2010 Sep 17.
PMID: 20850174
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Polymorphism in the GALNT1 gene and epithelial ovarian cancer in non-Hispanic white women: the Ovarian Cancer Association Consortium.
Authors: Phelan CM, Tsai YY, Goode EL, Vierkant RA, Fridley BL, Beesley J, Chen XQ, Webb PM, Chanock S, Cramer DW, Moysich K, Edwards RP, Chang-Claude J, Garcia-Closas M, Yang H, Wang-Gohrke S, Hein R, Green AC, Lissowska J, Carney ME, Lurie G, Wilkens LR, Ness RB, Pearce CL, Wu AH, Van Den Berg DJ, Stram DO, Terry KL, Whiteman DC, Whittemore AS, DiCioccio RA, McGuire V, Doherty JA, Rossing MA, Anton-Culver H, Ziogas A, Hogdall C, Hogdall E, Krüger Kjaer S, Blaakaer J, Quaye L, Ramus SJ, Jacobs I, Song H, Pharoah PD, Iversen ES, Marks JR, Pike MC, Gayther SA, Cunningham JM, Goodman MT, Schildkraut JM, Chenevix-Trench G, Berchuck A, Sellers TA, Ovarian Cancer Association Consortium, Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group
Source: Cancer Epidemiol Biomarkers Prev, 2010 Feb;19(2), p. 600-4.
PMID: 20142253
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ESR1/SYNE1 polymorphism and invasive epithelial ovarian cancer risk: an Ovarian Cancer Association Consortium study.
Authors: Doherty JA, Rossing MA, Cushing-Haugen KL, Chen C, Van Den Berg DJ, Wu AH, Pike MC, Ness RB, Moysich K, Chenevix-Trench G, Beesley J, Webb PM, Chang-Claude J, Wang-Gohrke S, Goodman MT, Lurie G, Thompson PJ, Carney ME, Hogdall E, Kjaer SK, Hogdall C, Goode EL, Cunningham JM, Fridley BL, Vierkant RA, Berchuck A, Moorman PG, Schildkraut JM, Palmieri RT, Cramer DW, Terry KL, Yang HP, Garcia-Closas M, Chanock S, Lissowska J, Song H, Pharoah PD, Shah M, Perkins B, McGuire V, Whittemore AS, Di Cioccio RA, Gentry-Maharaj A, Menon U, Gayther SA, Ramus SJ, Ziogas A, Brewster W, Anton-Culver H, Australian Ovarian Cancer Study Management Group, Australian Cancer Study (Ovarian Cancer), Pearce CL, Ovarian Cancer Association Consortium (OCAC)
Source: Cancer Epidemiol Biomarkers Prev, 2010 Jan;19(1), p. 245-50.
PMID: 20056644
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Common genetic variation in IGF1, IGFBP1 and IGFBP3 and ovarian cancer risk.
Authors: Terry KL, Tworoger SS, Gates MA, Cramer DW, Hankinson SE
Source: Carcinogenesis, 2009 Dec;30(12), p. 2042-6.
PMID: 19858071
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Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer.
Authors: Schildkraut JM, Goode EL, Clyde MA, Iversen ES, Moorman PG, Berchuck A, Marks JR, Lissowska J, Brinton L, Peplonska B, Cunningham JM, Vierkant RA, Rider DN, Chenevix-Trench G, Webb PM, Beesley J, Chen X, Phelan C, Sutphen R, Sellers TA, Pearce L, Wu AH, Van Den Berg D, Conti D, Elund CK, Anderson R, Goodman MT, Lurie G, Carney ME, Thompson PJ, Gayther SA, Ramus SJ, Jacobs I, Krüger Kjaer S, Hogdall E, Blaakaer J, Hogdall C, Easton DF, Song H, Pharoah PD, Whittemore AS, McGuire V, Quaye L, Anton-Culver H, Ziogas A, Terry KL, Cramer DW, Hankinson SE, Tworoger SS, Calingaert B, Chanock S, Sherman M, Garcia-Closas M, Australian Ovarian Cancer Study Group
Source: Cancer Res, 2009 Mar 15;69(6), p. 2349-57.
EPub date: 2009 Mar 10.
PMID: 19276375
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Activation of platelet-activating factor receptor and pleiotropic effects on tyrosine phospho-EGFR/Src/FAK/paxillin in ovarian cancer.
Authors: Aponte M, Jiang W, Lakkis M, Li MJ, Edwards D, Albitar L, Vitonis A, Mok SC, Cramer DW, Ye B
Source: Cancer Res, 2008 Jul 15;68(14), p. 5839-48.
PMID: 18632638
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Ovarian cancer risk in relation to medical visits, pelvic examinations and type of health care provider.
Authors: Abenhaim HA, Titus-Ernstoff L, Cramer DW
Source: CMAJ, 2007 Mar 27;176(7), p. 941-7.
PMID: 17389442
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Genetic variation in the progesterone receptor gene and ovarian cancer risk.
Authors: Terry KL, De Vivo I, Titus-Ernstoff L, Sluss PM, Cramer DW
Source: Am J Epidemiol, 2005 Mar 1;161(5), p. 442-51.
PMID: 15718480
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Reproductive factors and ovarian cancer risk in Jewish BRCA1 and BRCA2 mutation carriers (United States).
Authors: Modugno F, Moslehi R, Ness RB, Nelson DB, Belle S, Kant JA, Wheeler JE, Wonderlick A, Fishman D, Karlan B, Risch H, Cramer DW, Dube MP, Narod SA
Source: Cancer Causes Control, 2003 Jun;14(5), p. 439-46.
PMID: 12946038
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Risk of ovarian cancer in the United States in relation to anthropometric measures: does the association depend on menopausal status?
Authors: Kuper H, Cramer DW, Titus-Ernstoff L
Source: Cancer Causes Control, 2002 Jun;13(5), p. 455-63.
PMID: 12146850
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Carotenoids, antioxidants and ovarian cancer risk in pre- and postmenopausal women.
Authors: Cramer DW, Kuper H, Harlow BL, Titus-Ernstoff L
Source: Int J Cancer, 2001 Oct 1;94(1), p. 128-34.
PMID: 11668487
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