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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

Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer.
Authors: Konecny GE, Wang C, Hamidi H, Winterhoff B, Kalli KR, Dering J, Ginther C, Chen HW, Dowdy S, Cliby W, Gostout B, Podratz KC, Keeney G, Wang HJ, Hartmann LC, Slamon DJ, Goode EL
Source: J Natl Cancer Inst, 2014 Oct;106(10), p. null.
EPub date: 2014 Sep 30.
PMID: 25269487
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Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.
Authors: Kelemen LE, Terry KL, Goodman MT, Webb PM, Bandera EV, McGuire V, Rossing MA, Wang Q, Dicks E, Tyrer JP, Song H, Kupryjanczyk J, Dansonka-Mieszkowska A, Plisiecka-Halasa J, Timorek A, Menon U, Gentry-Maharaj A, Gayther SA, Ramus SJ, Narod SA, Risch HA, McLaughlin JR, Siddiqui N, Glasspool R, Paul J, Carty K, Gronwald J, Lubi?ski J, Jakubowska A, Cybulski C, Kiemeney LA, Massuger LF, van Altena AM, Aben KK, Olson SH, Orlow I, Cramer DW, Levine DA, Bisogna M, Giles GG, Southey MC, Bruinsma F, Kjaer SK, Høgdall E, Jensen A, Høgdall CK, Lundvall L, Engelholm SA, Heitz F, du Bois A, Harter P, Schwaab I, Butzow R, Nevanlinna H, Pelttari LM, Leminen A, Thompson PJ, Lurie G, Wilkens LR, Lambrechts D, Van Nieuwenhuysen E, Lambrechts S, Vergote I, Beesley J, AOCS Study Group/ACS Investigators, Fasching PA, Beckmann MW, Hein A, Ekici AB, Doherty JA, Wu AH, Pearce CL, Pike MC, Stram D, Chang-Claude J, Rudolph A, Dörk T, Dürst M, Hillemanns P, Runnebaum IB, Bogdanova N, Antonenkova N, Odunsi K, Edwards RP, Kelley JL, Modugno F, Ness RB, Karlan BY, Walsh C, Lester J, Orsulic S, Fridley BL, Vierkant RA, Cunningham JM, Wu X, Lu K, Liang D, Hildebrandt MA, Weber RP, Iversen ES, Tworoger SS, Poole EM, Salvesen HB, Krakstad C, Bjorge L, Tangen IL, Pejovic T, Bean Y, Kellar M, Wentzensen N, Brinton LA, Lissowska J, Garcia-Closas M, Campbell IG, Eccles D, Whittemore AS, Sieh W, Rothstein JH, Anton-Culver H, Ziogas A, Phelan CM, Moysich KB, Goode EL, Schildkraut JM, Berchuck A, Pharoah PD, Sellers TA, Brooks-Wilson A, Cook LS, Le ND
Source: Mol Nutr Food Res, 2014 Oct;58(10), p. 2023-35.
EPub date: 2014 Jul 28.
PMID: 25066213
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A review of the application of inflammatory biomarkers in epidemiologic cancer research.
Authors: Brenner DR, Scherer D, Muir K, Schildkraut J, Boffetta P, Spitz MR, Le Marchand L, Chan AT, Goode EL, Ulrich CM, Hung RJ
Source: Cancer Epidemiol Biomarkers Prev, 2014 Sep;23(9), p. 1729-51.
EPub date: 2014 Jun 24.
PMID: 24962838
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ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.
Authors: Hedditch EL, Gao B, Russell AJ, Lu Y, Emmanuel C, Beesley J, Johnatty SE, Chen X, Harnett P, George J, Australian Ovarian Cancer Study Group, Williams RT, Flemming C, Lambrechts D, Despierre E, Lambrechts S, Vergote I, Karlan B, Lester J, Orsulic S, Walsh C, Fasching P, Beckmann MW, Ekici AB, Hein A, Matsuo K, Hosono S, Nakanishi T, Yatabe Y, Pejovic T, Bean Y, Heitz F, Harter P, du Bois A, Schwaab I, Hogdall E, Kjaer SK, Jensen A, Hogdall C, Lundvall L, Engelholm SA, Brown B, Flanagan J, Metcalf MD, Siddiqui N, Sellers T, Fridley B, Cunningham J, Schildkraut J, Iversen E, Weber RP, Berchuck A, Goode E, Bowtell DD, Chenevix-Trench G, deFazio A, Norris MD, MacGregor S, Haber M, Henderson MJ
Source: J Natl Cancer Inst, 2014 Jul;106(7), p. null.
EPub date: 2014 Jun 23.
PMID: 24957074
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Genome-wide investigation of regional blood-based DNA methylation adjusted for complete blood counts implicates BNC2 in ovarian cancer.
Authors: Winham SJ, Armasu SM, Cicek MS, Larson MC, Cunningham JM, Kalli KR, Fridley BL, Goode EL
Source: Genet Epidemiol, 2014 Jul;38(5), p. 457-66.
EPub date: 2014 May 22.
PMID: 24853948
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Methylation of leukocyte DNA and ovarian cancer: relationships with disease status and outcome.
Authors: Fridley BL, Armasu SM, Cicek MS, Larson MC, Wang C, Winham SJ, Kalli KR, Koestler DC, Rider DN, Shridhar V, Olson JE, Cunningham JM, Goode EL
Source: BMC Med Genomics, 2014 Apr 28;7, p. 21.
EPub date: 2014 Apr 28.
PMID: 24774302
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Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.
Authors: Charbonneau B, Moysich KB, Kalli KR, Oberg AL, Vierkant RA, Fogarty ZC, Block MS, Maurer MJ, Goergen KM, Fridley BL, Cunningham JM, Rider DN, Preston C, Hartmann LC, Lawrenson K, Wang C, Tyrer J, Song H, deFazio A, Johnatty SE, Doherty JA, Phelan CM, Sellers TA, Ramirez SM, Vitonis AF, Terry KL, Van Den Berg D, Pike MC, Wu AH, Berchuck A, Gentry-Maharaj A, Ramus SJ, Diergaarde B, Shen H, Jensen A, Menkiszak J, Cybulski C, Lubi?ski J, Ziogas A, Rothstein JH, McGuire V, Sieh W, Lester J, Walsh C, Vergote I, Lambrechts S, Despierre E, Garcia-Closas M, Yang H, Brinton LA, Spiewankiewicz B, Rzepecka IK, Dansonka-Mieszkowska A, Seibold P, Rudolph A, Paddock LE, Orlow I, Lundvall L, Olson SH, Hogdall CK, Schwaab I, du Bois A, Harter P, Flanagan JM, Brown R, Paul J, Ekici AB, Beckmann MW, Hein A, Eccles D, Lurie G, Hays LE, Bean YT, Pejovic T, Goodman MT, Campbell I, Fasching PA, Konecny G, Kaye SB, Heitz F, Hogdall E, Bandera EV, Chang-Claude J, Kupryjanczyk J, Wentzensen N, Lambrechts D, Karlan BY, Whittemore AS, Culver HA, Gronwald J, Levine DA, Kjaer SK, Menon U, Schildkraut JM, Pearce CL, Cramer DW, Rossing MA, Chenevix-Trench G, AOCS group, ACS, Pharoah PD, Gayther SA, Ness RB, Odunsi K, Sucheston LE, Knutson KL, Goode EL
Source: Cancer Immunol Res, 2014 Apr;2(4), p. 332-40.
EPub date: 2014 Jan 27.
PMID: 24764580
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Variation in NF-?B signaling pathways and survival in invasive epithelial ovarian cancer.
Authors: Block MS, Charbonneau B, Vierkant RA, Fogarty Z, Bamlet WR, Pharoah PD, Georgia Chenevix-Trench, for AOCS, /ACS Group, Rossing MA, Cramer D, Pearce CL, Schildkraut J, Menon U, Kjaer SK, Levine DA, Gronwald J, Culver HA, Whittemore AS, Karlan BY, Lambrechts D, Wentzensen N, Kupryjanczyk J, Chang-Claude J, Bandera EV, Hogdall E, Heitz F, Kaye SB, Fasching PA, Campbell I, Goodman MT, Pejovic T, Bean YT, Hays LE, Lurie G, Eccles D, Hein A, Beckmann MW, Ekici AB, Paul J, Brown R, Flanagan JM, Harter P, du Bois A, Schwaab I, Hogdall CK, Lundvall L, Olson SH, Orlow I, Paddock LE, Rudolph A, Eilber U, Dansonka-Mieszkowska A, Rzepecka IK, Ziolkowska-Seta I, Brinton LA, Yang H, Garcia-Closas M, Despierre E, Lambrechts S, Vergote I, Walsh CS, Lester J, Sieh W, McGuire V, Rothstein JH, Ziogas A, Lubi?ski J, Cybulski C, Menkiszak J, Jensen A, Gayther SA, Ramus SJ, Gentry-Maharaj A, Berchuck A, Wu AH, Pike MC, Van Den Berg D, Terry KL, Vitonis AF, Ramirez SM, Rider DN, Knutson KL, Sellers TA, Phelan CM, Doherty JA, Johnatty SE, deFazio A, Song H, Tyrer J, Kalli KR, Fridley BL, Cunningham JM, Goode EL
Source: Cancer Epidemiol Biomarkers Prev, 2014 Jul;23(7), p. 1421-7.
EPub date: 2014 Apr 16.
PMID: 24740199
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The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population.
Authors: Song H, Cicek MS, Dicks E, Harrington P, Ramus SJ, Cunningham JM, Fridley BL, Tyrer JP, Alsop J, Jimenez-Linan M, Gayther SA, Goode EL, Pharoah PD
Source: Hum Mol Genet, 2014 Sep 1;23(17), p. 4703-9.
EPub date: 2014 Apr 12.
PMID: 24728189
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Tumor hypomethylation at 6p21.3 associates with longer time to recurrence of high-grade serous epithelial ovarian cancer.
Authors: Wang C, Cicek MS, Charbonneau B, Kalli KR, Armasu SM, Larson MC, Konecny GE, Winterhoff B, Fan JB, Bibikova M, Chien J, Shridhar V, Block MS, Hartmann LC, Visscher DW, Cunningham JM, Knutson KL, Fridley BL, Goode EL
Source: Cancer Res, 2014 Jun 1;74(11), p. 3084-91.
EPub date: 2014 Apr 11.
PMID: 24728075
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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, 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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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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