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Grant Details

Grant Number: 5R01CA126841-04 Interpret this number
Primary Investigator: Moysich, Kirsten
Organization: Roswell Park Cancer Institute Corp
Project Title: Regulatory T Cell Function in Ovarian Cancer
Fiscal Year: 2012
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Abstract

Abstract Etiologic and prognostic factors in ovarian cancer remain poorly understood, although emerging evidence suggests that factors related to immune response play important roles in the development and clinical treatment of this disease. Recent evidence has revealed that a subset of T cells with immunosuppressive properties, referred to as regulatory T cells (Treg), are essential for the development and maintenance of self-tolerance. There is a very consistent body of literature that points to an important role of these Treg cells in human health. These studies have shown that lower peripheral Treg cells expression is associated with autoimmune disease, allergy, and adverse transplantation outcomes, indicating that insufficient Treg cell stimulated immune suppression might lead to the development of these auto reactive health conditions. On the other hand, elevated Treg cell expression has been consistently reported in patients with a wide variety of malignancies, suggesting that Treg cell-mediated suppression might interfere with an adequate immune response to tumor associated antigens. Our group and others also provided direct evidence linking elevated Treg cell expression to greater risk of ovarian cancer and poorer prognosis. Thus, the role of Treg cells in cancer etiology and prognosis is an area of emerging interest, as high Treg activity might a) prevent an adequate immune response at the time of cancer initiation and progression, b) prevent an adequate immune response after initial treatment of the tumor; and c) result in lower responsiveness to tumor immunotherapy. To date, we are unaware of any comprehensive epidemiological study that has focused on the role Treg cells in human cancer in general or ovarian carcinogenesis in particular. Thus, we propose to evaluate the role of Treg cell burden as well as a panel of candidate genetic polymorphisms, directly relevant to Treg cell activity, in the etiology and prognosis of ovarian cancer. We hypothesize in Aim 1 that women with ovarian cancer will have higher blood Treg cell levels than healthy controls. We also expect in Aim 2 that women with a genetically determined high activity Treg cell profile will be less effective in mounting an immune response toward tumor cells in the initiation and progression phase of ovarian carcinogenesis. We further hypothesize in Aim 3 that ovarian cancer patients with a genetically determined high activity Treg cell profile will be less effective in battling residual disease. We also seek to determine in Aim 4 if genetic variability in Treg cell function can predict Treg cell expression in ovarian tumors. We propose to utilize data and specimens from core resources at our institute and from a population-based case-control study of ovarian cancer. For Aim 1, we will newly recruit 100 ovarian cancer patients and 100 controls via our institute's Biorepository to collect fresh blood samples required for Treg cell measurements. In the case-control study we recently recruited over 900 ovarian cancer patients and 1800 community controls (Specific Aim 2) from the Buffalo, NY, Pittsburgh PA, and Cleveland, OH areas. We propose to follow-up the ovarian cancer patient group and assess relevant clinical outcomes (recurrence, survival; Specific Aim 3). We will also select 630 patients with advanced stage disease with available blood and tumor samples from our institute's Ovarian Cancer Specimen Bank (Specific Aim 4). For the laboratory analyses, we will utilize Illumina Golden Gate assays and flow-cytometry techniques for the genotype and Treg cell assessment, respectively. Our statistical and genetic analyses will be carried out by a trained genetic epidemiologist.

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Publications

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.
Authors: Chornokur G, Lin HY, Tyrer JP, Lawrenson K, Dennis J, Amankwah EK, Qu X, Tsai YY, Jim HS, Chen Z, Chen AY, Permuth-Wey J, Aben KK, Anton-Culver H, Antonenkova N, Bruinsma F, Bandera EV, Bean YT, Beckmann MW, Bisogna M, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bunker CH, Butzow R, Campbell IG, Carty K, Chang-Claude J, Cook LS, Cramer DW, Cunningham JM, Cybulski C, Dansonka-Mieszkowska A, du Bois A, Despierre E, Dicks E, Doherty JA, Dörk T, Dürst M, Easton DF, Eccles DM, Edwards RP, Ekici AB, Fasching PA, Fridley BL, Gao YT, Gentry-Maharaj A, Giles GG, Glasspool R, Goodman MT, Gronwald J, Harrington P, Harter P, Hein A, Heitz F, Hildebrandt MA, Hillemanns P, Hogdall CK, Hogdall E, Hosono S, Jakubowska A, Jensen A, Ji BT, Karlan BY, Kelemen LE, Kellar M, Kiemeney LA, Krakstad C, Kjaer SK, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lee AW, Lele S, Leminen A, Lester J, Levine DA, Liang D, Lim BK, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger LF, Matsuo K, McGuire V, McLaughlin JR, McNeish I, Menon U, Milne RL, Modugno F, Moysich KB, Ness RB, Nevanlinna H, Eilber U, Odunsi K, Olson SH, Orlow I, Orsulic S, Weber RP, Paul J, Pearce CL, Pejovic T, Pelttari LM, Pike MC, Poole EM, Risch HA, Rosen B, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Schernhammer E, Schwaab I, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Spiewankiewicz B, Sucheston L, Teo SH, Terry KL, Thompson PJ, Thomsen L, Tangen IL, Tworoger SS, van Altena AM, Vierkant RA, Vergote I, Walsh CS, Wang-Gohrke S, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Wu AH, Wu X, Woo YL, Yang H, Zheng W, Ziogas A, Hasmad HN, Berchuck A, Georgia Chenevix-Trench, AOCS management group, Iversen ES, Schildkraut JM, Ramus SJ, Goode EL, Monteiro AN, Gayther SA, Narod SA, Pharoah PD, Sellers TA, Phelan CM
Source: PLoS One, 2015;10(6), p. e0128106.
EPub date: 2015 Jun 19.
PMID: 26091520
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Genome-wide significant risk associations for mucinous ovarian carcinoma.
Authors: Ovarian Cancer Association Consortium, Australian Cancer Study, Australian Ovarian Cancer Study Group
Source: Nat Genet, 2015 Aug;47(8), p. 888-97.
EPub date: 2015 Jun 15.
PMID: 26075790
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Use of Common Analgesics Is Not Associated with Ovarian Cancer Survival.
Authors: Minlikeeva AN, Freudenheim JL, Lo-Ciganic WH, Eng KH, Friel G, Diergaarde B, Modugno F, Cannioto R, Gower E, Szender JB, Grzankowski K, Odunsi K, Ness RB, Moysich KB
Source: Cancer Epidemiol Biomarkers Prev, 2015 Aug;24(8), p. 1291-4.
EPub date: 2015 Jun 10.
PMID: 26063476
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Aspirin and Acetaminophen Use and the Risk of Cervical Cancer.
Authors: Friel G, Liu CS, Kolomeyevskaya NV, Hampras SS, Kruszka B, Schmitt K, Cannioto RA, Lele SB, Odunsi KO, Moysich KB
Source: J Low Genit Tract Dis, 2015 Jul;19(3), p. 189-93.
PMID: 25856123
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Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy.
Authors: Lei J, Rudolph A, Moysich KB, Rafiq S, Behrens S, Goode EL, Pharoah PP, Seibold P, Fasching PA, Andrulis IL, Kristensen VN, Couch FJ, Hamann U, Hooning MJ, Nevanlinna H, Eilber U, Bolla MK, Dennis J, Wang Q, Lindblom A, Mannermaa A, Lambrechts D, García-Closas M, Hall P, Chenevix-Trench G, Shah M, Luben R, Haeberle L, Ekici AB, Beckmann MW, Knight JA, Glendon G, Tchatchou S, Alnæs GI, Borresen-Dale AL, Nord S, Olson JE, Hallberg E, Vachon C, Torres D, Ulmer HU, Rüdiger T, Jager A, van Deurzen CH, Tilanus-Linthorst MM, Muranen TA, Aittomäki K, Blomqvist C, Margolin S, Kosma VM, Hartikainen JM, Kataja V, Hatse S, Wildiers H, Smeets A, Figueroa J, Chanock SJ, Lissowska J, Li J, Humphreys K, Phillips KA, kConFab Investigators, Linn S, Cornelissen S, van den Broek SA, Kang D, Choi JY, Park SK, Yoo KY, Hsiung CN, Wu PE, Hou MF, Shen CY, Teo SH, Taib NA, Yip CH, Ho GF, Matsuo K, Ito H, Iwata H, Tajima K, Dunning AM, Benitez J, Czene K, Sucheston LE, Maishman T, Tapper WJ, Eccles D, Easton DF, Schmidt MK, Chang-Claude J
Source: Breast Cancer Res, 2015 Feb 10;17, p. 18.
EPub date: 2015 Feb 10.
PMID: 25849327
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Epithelial ovarian cancer and recreational physical activity: A review of the epidemiological literature and implications for exercise prescription.
Authors: Cannioto RA, Moysich KB
Source: Gynecol Oncol, 2015 Jun;137(3), p. 559-73.
EPub date: 2015 Mar 20.
PMID: 25797080
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Population distribution of lifetime risk of ovarian cancer in the United States.
Authors: Pearce CL, Stram DO, Ness RB, Stram DA, Roman LD, Templeman C, Lee AW, Menon U, Fasching PA, McAlpine JN, Doherty JA, Modugno F, Schildkraut JM, Rossing MA, Huntsman DG, Wu AH, Berchuck A, Pike MC, Pharoah PD
Source: Cancer Epidemiol Biomarkers Prev, 2015 Apr;24(4), p. 671-6.
EPub date: 2015 Jan 26.
PMID: 25623732
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Identification of six new susceptibility loci for invasive epithelial ovarian cancer.
Authors: Kuchenbaecker KB, Ramus SJ, Tyrer J, Lee A, Shen HC, Beesley J, Lawrenson K, McGuffog L, Healey S, Lee JM, Spindler TJ, Lin YG, Pejovic T, Bean Y, Li Q, Coetzee S, Hazelett D, Miron A, Southey M, Terry MB, Goldgar DE, Buys SS, Janavicius R, Dorfling CM, van Rensburg EJ, Neuhausen SL, Ding YC, Hansen TV, Jønson L, Gerdes AM, Ejlertsen B, Barrowdale D, Dennis J, Benitez J, Osorio A, Garcia MJ, Komenaka I, Weitzel JN, Ganschow P, Peterlongo P, Bernard L, Viel A, Bonanni B, Peissel B, Manoukian S, Radice P, Papi L, Ottini L, Fostira F, Konstantopoulou I, Garber J, Frost D, Perkins J, Platte R, Ellis S, EMBRACE, Godwin AK, Schmutzler RK, Meindl A, Engel C, Sutter C, Sinilnikova OM, GEMO Study Collaborators, Damiola F, Mazoyer S, Stoppa-Lyonnet D, Claes K, De Leeneer K, Kirk J, Rodriguez GC, Piedmonte M, O'Malley DM, de la Hoya M, Caldes T, Aittomäki K, Nevanlinna H, Collée JM, Rookus MA, Oosterwijk JC, Breast Cancer Family Registry, Tihomirova L, Tung N, Hamann U, Isaccs C, Tischkowitz M, Imyanitov EN, Caligo MA, Campbell IG, Hogervorst FB, HEBON, Olah E, Diez O, Blanco I, Brunet J, Lazaro C, Pujana MA, Jakubowska A, Gronwald J, Lubinski J, Sukiennicki G, Barkardottir RB, Plante M, Simard J, Soucy P, Montagna M, Tognazzo S, Teixeira MR, KConFab Investigators, Pankratz VS, Wang X, Lindor N, Szabo CI, Kauff N, Vijai J, Aghajanian CA, Pfeiler G, Berger A, Singer CF, Tea MK, Phelan CM, Greene MH, Mai PL, Rennert G, Mulligan AM, Tchatchou S, Andrulis IL, Glendon G, Toland AE, Jensen UB, Kruse TA, Thomassen M, Bojesen A, Zidan J, Friedman E, Laitman Y, Soller M, Liljegren A, Arver B, Einbeigi Z, Stenmark-Askmalm M, Olopade OI, Nussbaum RL, Rebbeck TR, Nathanson KL, Domchek SM, Lu KH, Karlan BY, Walsh C, Lester J, Australian Cancer Study (Ovarian Cancer Investigators), Australian Ovarian Cancer Study Group, Hein A, Ekici AB, Beckmann MW, Fasching PA, Lambrechts D, Van Nieuwenhuysen E, Vergote I, Lambrechts S, Dicks E, Doherty JA, Wicklund KG, Rossing MA, Rudolph A, Chang-Claude J, Wang-Gohrke S, Eilber U, Moysich KB, Odunsi K, Sucheston L, Lele S, Wilkens LR, Goodman MT, Thompson PJ, Shvetsov YB, Runnebaum IB, Dürst M, Hillemanns P, Dörk T, Antonenkova N, Bogdanova N, Leminen A, Pelttari LM, Butzow R, Modugno F, Kelley JL, Edwards RP, Ness RB, du Bois A, Heitz F, Schwaab I, Harter P, Matsuo K, Hosono S, Orsulic S, Jensen A, Kjaer SK, Hogdall E, Hasmad HN, Azmi MA, Teo SH, Woo YL, Fridley BL, Goode EL, Cunningham JM, Vierkant RA, Bruinsma F, Giles GG, Liang D, Hildebrandt MA, Wu X, Levine DA, Bisogna M, Berchuck A, Iversen ES, Schildkraut JM, Concannon P, Weber RP, Cramer DW, Terry KL, Poole EM, Tworoger SS, Bandera EV, Orlow I, Olson SH, Krakstad C, Salvesen HB, Tangen IL, Bjorge L, van Altena AM, Aben KK, Kiemeney LA, Massuger LF, Kellar M, Brooks-Wilson A, Kelemen LE, Cook LS, Le ND, Cybulski C, Yang H, Lissowska J, Brinton LA, Wentzensen N, Hogdall C, Lundvall L, Nedergaard L, Baker H, Song H, Eccles D, McNeish I, Paul J, Carty K, Siddiqui N, Glasspool R, Whittemore AS, Rothstein JH, McGuire V, Sieh W, Ji BT, Zheng W, Shu XO, Gao YT, Rosen B, Risch HA, McLaughlin JR, Narod SA, Monteiro AN, Chen A, Lin HY, Permuth-Wey J, Sellers TA, Tsai YY, Chen Z, Ziogas A, Anton-Culver H, Gentry-Maharaj A, Menon U, Harrington P, Lee AW, Wu AH, Pearce CL, Coetzee G, Pike MC, Dansonka-Mieszkowska A, Timorek A, Rzepecka IK, Kupryjanczyk J, Freedman M, Noushmehr H, Easton DF, Offit K, Couch FJ, Gayther S, Pharoah PP, Antoniou AC, Chenevix-Trench G, Consortium of Investigators of Modifiers of BRCA1 and BRCA2
Source: Nat Genet, 2015 Feb;47(2), p. 164-71.
EPub date: 2015 Jan 12.
PMID: 25581431
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Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.
Authors: Lee AW, Tyrer JP, Doherty JA, Stram DA, Kupryjanczyk J, Dansonka-Mieszkowska A, Plisiecka-Halasa J, Spiewankiewicz B, Myers EJ, Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group, Chenevix-Trench G, Fasching PA, Beckmann MW, Ekici AB, Hein A, Vergote I, Van Nieuwenhuysen E, Lambrechts D, Wicklund KG, Eilber U, Wang-Gohrke S, Chang-Claude J, Rudolph A, Sucheston-Campbell L, Odunsi K, Moysich KB, Shvetsov YB, Thompson PJ, Goodman MT, Wilkens LR, Dörk T, Hillemanns P, Dürst M, Runnebaum IB, Bogdanova N, Pelttari LM, Nevanlinna H, Leminen A, Edwards RP, Kelley JL, Harter P, Schwaab I, Heitz F, du Bois A, Orsulic S, Lester J, Walsh C, Karlan BY, Hogdall E, Kjaer SK, Jensen A, Vierkant RA, Cunningham JM, Goode EL, Fridley BL, Southey MC, Giles GG, Bruinsma F, Wu X, Hildebrandt MA, Lu K, Liang D, Bisogna M, Levine DA, Weber RP, Schildkraut JM, Iversen ES, Berchuck A, Terry KL, Cramer DW, Tworoger SS, Poole EM, Olson SH, Orlow I, Bandera EV, Bjorge L, Tangen IL, Salvesen HB, Krakstad C, Massuger LF, Kiemeney LA, Aben KK, van Altena AM, Bean Y, Pejovic T, Kellar M, Le ND, Cook LS, Kelemen LE, Brooks-Wilson A, Lubinski J, Gronwald J, Cybulski C, Jakubowska A, Wentzensen N, Brinton LA, Lissowska J, Yang H, Nedergaard L, Lundvall L, Hogdall C, Song H, Campbell IG, Eccles D, Glasspool R, Siddiqui N, Carty K, Paul J, McNeish IA, Sieh W, McGuire V, Rothstein JH, Whittemore AS, McLaughlin JR, Risch HA, Phelan CM, Anton-Culver H, Ziogas A, Menon U, Ramus SJ, Gentry-Maharaj A, Harrington P, Pike MC, Modugno F, Rossing MA, Ness RB, Pharoah PD, Stram DO, Wu AH, Pearce CL
Source: Gynecol Oncol, 2015 Mar;136(3), p. 542-8.
EPub date: 2014 Dec 17.
PMID: 25528498
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Prognosis and conditional disease-free survival among patients with ovarian cancer.
Authors: Kurta ML, Edwards RP, Moysich KB, McDonough K, Bertolet M, Weissfeld JL, Catov JM, Modugno F, Bunker CH, Ness RB, Diergaarde B
Source: J Clin Oncol, 2014 Dec 20;32(36), p. 4102-12.
EPub date: 2014 Nov 17.
PMID: 25403208
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Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.
Authors: Candido-dos-Reis FJ, Song H, Goode EL, Cunningham JM, Fridley BL, Larson MC, Alsop K, Dicks E, Harrington P, Ramus SJ, de Fazio A, Mitchell G, Fereday S, Bolton KL, Gourley C, Michie C, Karlan B, Lester J, Walsh C, Cass I, Olsson H, Gore M, Benitez JJ, Garcia MJ, Andrulis I, Mulligan AM, Glendon G, Blanco I, Lazaro C, Whittemore AS, McGuire V, Sieh W, Montagna M, Alducci E, Sadetzki S, Chetrit A, Kwong A, Kjaer SK, Jensen A, Høgdall E, Neuhausen S, Nussbaum R, Daly M, Greene MH, Mai PL, Loud JT, Moysich K, Toland AE, Lambrechts D, Ellis S, Frost D, Brenton JD, Tischkowitz M, Easton DF, Antoniou A, Chenevix-Trench G, Gayther SA, Bowtell D, Pharoah PD, for EMBRACE, kConFab Investigators, Australian Ovarian Cancer Study Group
Source: Clin Cancer Res, 2015 Feb 1;21(3), p. 652-7.
EPub date: 2014 Nov 14.
PMID: 25398451
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Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study.
Authors: Köbel M, Madore J, Ramus SJ, Clarke BA, Pharoah PD, Deen S, Bowtell DD, Odunsi K, Menon U, Morrison C, Lele S, Bshara W, Sucheston L, Beckmann MW, Hein A, Thiel FC, Hartmann A, Wachter DL, Anglesio MS, Høgdall E, Jensen A, Høgdall C, Kalli KR, Fridley BL, Keeney GL, Fogarty ZC, Vierkant RA, Liu S, Cho S, Nelson G, Ghatage P, Gentry-Maharaj A, Gayther SA, Benjamin E, Widschwendter M, Intermaggio MP, Rosen B, Bernardini MQ, Mackay H, Oza A, Shaw P, Jimenez-Linan M, Driver KE, Alsop J, Mack M, Koziak JM, Steed H, Ewanowich C, DeFazio A, Chenevix-Trench G, Fereday S, Gao B, Johnatty SE, George J, Galletta L, AOCS Study Group, Goode EL, Kjær SK, Huntsman DG, Fasching PA, Moysich KB, Brenton JD, Kelemen LE
Source: Br J Cancer, 2014 Dec 9;111(12), p. 2297-307.
EPub date: 2014 Oct 30.
PMID: 25349970
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