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Grant Details

Grant Number: 5R01CA122443-06 Interpret this number
Primary Investigator: Goode, Ellen
Organization: Mayo Clinic Rochester
Project Title: Genetic Variation in the Nf-Kappab Pathway and Ovarian Cancer Etiology
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): We will conduct a comprehensive molecular epidemiologic investigation of the role that genetic variation in the NF-kappaB pathway plays in ovarian cancer etiology. Substantial evidence suggests that inflammation, apoptosis, and immune response processes are linked to ovarian carcinogenesis. NF-kappaB is a family of transcription factors central to these processes which regulates the expression of numerous genes. We hypothesize that genetic variation in NF-kappaB subunits or NF-kappaB inhibitors and activators may modify the activity of NF-kappaB and lead to inter-individual differences in inflammation, apoptosis, and immune response. We will use a three-phase study design to examine whether this genetic variation (specifically, over 3,000 informative polymorphisms in 260 NF-kappaB-related genes) is associated with risk of ovarian cancer. The first two phases of this work will consist of a split-sample group sequential analysis of participants recruited in ongoing ovarian cancer studies at the Mayo Clinic in Rochester, MN and at Duke University in Durham, NC including 1,700 cases and 1,800 frequency-matched controls. The third phase of our study consists of external validation of approximately 50 polymorphisms using data from ongoing studies at the Queensland Institute of Medical Research, Australia, and the University of Cambridge, UK. This comprehensive pathway-based, multiple-phase, linkage disequilibrium-focused approach incorporates design elements at the forefront of epidemiologic methodology. In total, this study will provide excellent statistical power to detect moderately-increased odds ratios. Our goal is to identify the subset of genes which are most relevant to ovarian cancer from among 260 candidate genes encoding NF-kappaB subunits and regulatory molecules. The "shortlist" of genes and genetic variants showing replicated associations throughout each phase of the study will then be transitioned into downstream functional analysis by our transdisciplinary team for the identification of future preventive and therapeutic strategies.

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Publications

Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status.
Authors: Cunningham JM, Cicek MS, Larson NB, Davila J, Wang C, Larson MC, Song H, Dicks EM, Harrington P, Wick M, Winterhoff BJ, Hamidi H, Konecny GE, Chien J, Bibikova M, Fan JB, Kalli KR, Lindor NM, Fridley BL, Pharoah PP, Goode EL
Source: Sci Rep, 2014 Feb 7;4, p. 4026.
EPub date: 2014 Feb 7.
PMID: 24504028
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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, Kjr 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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Integrative genomic analysis identifies epigenetic marks that mediate genetic risk for epithelial ovarian cancer.
Authors: Koestler DC, Chalise P, Cicek MS, Cunningham JM, Armasu S, Larson MC, Chien J, Block M, Kalli KR, Sellers TA, Fridley BL, Goode EL
Source: BMC Med Genomics, 2014 Jan 30;7, p. 8.
EPub date: 2014 Jan 30.
PMID: 24479488
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Risk of ovarian cancer and the NF-?B pathway: genetic association with IL1A and TNFSF10.
Authors: Charbonneau B, Block MS, Bamlet WR, Vierkant RA, Kalli KR, Fogarty Z, Rider DN, Sellers TA, Tworoger SS, Poole E, Risch HA, Salvesen HB, Kiemeney LA, Baglietto L, Giles GG, Severi G, Trabert B, Wentzensen N, Chenevix-Trench G, for AOCS/ACS group, Whittemore AS, Sieh W, Chang-Claude J, Bandera EV, Orlow I, Terry K, Goodman MT, Thompson PJ, Cook LS, Rossing MA, Ness RB, Narod SA, Kupryjanczyk J, Lu K, Butzow R, Drk T, Pejovic T, Campbell I, Le ND, Bunker CH, Bogdanova N, Runnebaum IB, Eccles D, Paul J, Wu AH, Gayther SA, Hogdall E, Heitz F, Kaye SB, Karlan BY, Anton-Culver H, Gronwald J, Hogdall CK, Lambrechts D, Fasching PA, Menon U, Schildkraut J, Pearce CL, Levine DA, Kjaer SK, Cramer D, Flanagan JM, Phelan CM, Brown R, Massuger LF, Song H, Doherty JA, Krakstad C, Liang D, Odunsi K, Berchuck A, Jensen A, Lubinski J, Nevanlinna H, Bean YT, Lurie G, Ziogas A, Walsh C, Despierre E, Brinton L, Hein A, Rudolph A, Dansonka-Mieszkowska A, Olson SH, Harter P, Tyrer J, Vitonis AF, Brooks-Wilson A, Aben KK, Pike MC, Ramus SJ, Wik E, Cybulski C, Lin J, Sucheston L, Edwards R, McGuire V, Lester J, du Bois A, Lundvall L, Wang-Gohrke S, Szafron LM, Lambrechts S, Yang H, Beckmann MW, Pelttari LM, Van Altena AM, van den Berg D, Halle MK, Gentry-Maharaj A, Schwaab I, Chandran U, Menkiszak J, Ekici AB, Wilkens LR, Leminen A, Modugno F, Friel G, Rothstein JH, Vergote I, Garcia-Closas M, Hildebrandt MA, Sobiczewski P, Kelemen LE, Pharoah PD, Moysich K, Knutson KL, Cunningham JM, Fridley BL, Goode EL
Source: Cancer Res, 2014 Feb 1;74(3), p. 852-61.
EPub date: 2013 Nov 22.
PMID: 24272484
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The ratios of CD8+ T cells to CD4+CD25+ FOXP3+ and FOXP3- T cells correlate with poor clinical outcome in human serous ovarian cancer.
Authors: Preston CC, Maurer MJ, Oberg AL, Visscher DW, Kalli KR, Hartmann LC, Goode EL, Knutson KL
Source: PLoS One, 2013;8(11), p. e80063.
EPub date: 2013 Nov 14.
PMID: 24244610
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APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma.
Authors: Leonard B, Hart SN, Burns MB, Carpenter MA, Temiz NA, Rathore A, Vogel RI, Nikas JB, Law EK, Brown WL, Li Y, Zhang Y, Maurer MJ, Oberg AL, Cunningham JM, Shridhar V, Bell DA, April C, Bentley D, Bibikova M, Cheetham RK, Fan JB, Grocock R, Humphray S, Kingsbury Z, Peden J, Chien J, Swisher EM, Hartmann LC, Kalli KR, Goode EL, Sicotte H, Kaufmann SH, Harris RS
Source: Cancer Res, 2013 Dec 15;73(24), p. 7222-31.
EPub date: 2013 Oct 23.
PMID: 24154874
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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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Survival prediction based on inherited gene variation analysis.
Authors: Cicek MS, Maurer MJ, Goode EL
Source: Methods Mol Biol, 2013;1049, p. 53-64.
PMID: 23913208
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Toward understanding the genetics of regulatory T cells in ovarian cancer.
Authors: Derycke MS, Charbonneau B, Preston CC, Kalli KR, Knutson KL, Rider DN, Goode EL
Source: Oncoimmunology, 2013 Jun 1;2(6), p. e24535.
EPub date: 2013 Apr 16.
PMID: 23894717
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Biomarker-based ovarian carcinoma typing: a histologic investigation in the ovarian tumor tissue analysis consortium.
Authors: Kbel M, Kalloger SE, Lee S, Duggan MA, Kelemen LE, Prentice L, Kalli KR, Fridley BL, Visscher DW, Keeney GL, Vierkant RA, Cunningham JM, Chow C, Ness RB, Moysich K, Edwards R, Modugno F, Bunker C, Wozniak EL, Benjamin E, Gayther SA, Gentry-Maharaj A, Menon U, Gilks CB, Huntsman DG, Ramus SJ, Goode EL, Ovarian Tumor Tissue Analysis consortium
Source: Cancer Epidemiol Biomarkers Prev, 2013 Oct;22(10), p. 1677-86.
EPub date: 2013 Jul 23.
PMID: 23880734
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Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study.
Authors: Sieh W, Kbel M, Longacre TA, Bowtell DD, deFazio A, Goodman MT, Hgdall E, Deen S, Wentzensen N, Moysich KB, Brenton JD, Clarke BA, Menon U, Gilks CB, Kim A, Madore J, Fereday S, George J, Galletta L, Lurie G, Wilkens LR, Carney ME, Thompson PJ, Matsuno RK, Kjr SK, Jensen A, Hgdall C, Kalli KR, Fridley BL, Keeney GL, Vierkant RA, Cunningham JM, Brinton LA, Yang HP, Sherman ME, Garca-Closas M, Lissowska J, Odunsi K, Morrison C, Lele S, Bshara W, Sucheston L, Jimenez-Linan M, Driver K, Alsop J, Mack M, McGuire V, Rothstein JH, Rosen BP, Bernardini MQ, Mackay H, Oza A, Wozniak EL, Benjamin E, Gentry-Maharaj A, Gayther SA, Tinker AV, Prentice LM, Chow C, Anglesio MS, Johnatty SE, Chenevix-Trench G, Whittemore AS, Pharoah PD, Goode EL, Huntsman DG, Ramus SJ
Source: Lancet Oncol, 2013 Aug;14(9), p. 853-62.
EPub date: 2013 Jul 9.
PMID: 23845225
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Kernel canonical correlation analysis for assessing gene-gene interactions and application to ovarian cancer.
Authors: Larson NB, Jenkins GD, Larson MC, Vierkant RA, Sellers TA, Phelan CM, Schildkraut JM, Sutphen R, Pharoah PP, Gayther SA, Wentzensen N, Ovarian Cancer Association Consortium, Goode EL, Fridley BL
Source: Eur J Hum Genet, 2014 Jan;22(1), p. 126-31.
EPub date: 2013 Apr 17.
PMID: 23591404
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The immune system in the pathogenesis of ovarian cancer.
Authors: Charbonneau B, Goode EL, Kalli KR, Knutson KL, Derycke MS
Source: Crit Rev Immunol, 2013;33(2), p. 137-64.
PMID: 23582060
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Epigenome-wide ovarian cancer analysis identifies a methylation profile differentiating clear-cell histology with epigenetic silencing of the HERG K+ channel.
Authors: Cicek MS, Koestler DC, Fridley BL, Kalli KR, Armasu SM, Larson MC, Wang C, Winham SJ, Vierkant RA, Rider DN, Block MS, Klotzle B, Konecny G, Winterhoff BJ, Hamidi H, Shridhar V, Fan JB, Visscher DW, Olson JE, Hartmann LC, Bibikova M, Chien J, Cunningham JM, Goode EL
Source: Hum Mol Genet, 2013 Aug 1;22(15), p. 3038-47.
EPub date: 2013 Apr 9.
PMID: 23571109
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