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Grant Details

Grant Number: 5R01CA127219-06 Interpret this number
Primary Investigator: Spitz, Margaret
Organization: Baylor College Of Medicine
Project Title: Inflammation Genes and Lung Cancer Risk
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): There is accumulating evidence that chronic injury and inflammation in the respiratory tract, such as that caused by cigarette smoking, predispose to lung cancer. We therefore propose to conduct an in depth pathway-based analysis of gene variants in the inflammatory pathway using test and validation sets of cases and controls. This proposal builds on a well-annotated specimen repository of lung cancer cases and controls enrolled in an ongoing risk factor study (CA55769, Spitz, PI). Cases are frequency-matched to controls on age, gender, ethnicity and smoking status recruited from a multi-specialty physician practice. Data collected include smoking history, dietary intake, cancer family history, specific occupational exposures (e.g., asbestos, dust), and previous medical history including chronic obstructive airway disease, asthma and hay fever. Genomic DNA and rich candidate genotype and phenotype data are available. Aim 1: To identify novel genetic variants influencing lung cancer risk in a test set of 1500 cases with non-small cell lung cancer and 1500 matched controls (all Caucasian), using the Illumina iSelect Infinium chip with 8.5 to 9K SNP's. Aim 2: In a replication set of an additional 1000 cases and 1000 controls, using a GoldenGate assay, we will evaluate the top 1500 SNPs identified from Aim1 as meeting the P<0.1 criterion, or selected by a rational prioritizing approach that incorporates published results, type of SNP, evolutionary biology, physico-chemical properties and haplotype tagging SNPs. Aim 3: To perform fine mapping in the flanking regions of 50 SNPs selected by the same approach as in Aim 2, combining prior information with in silico approaches for predicting functionality. For each of these 50 SNPs, we will select an average of 10 additional SNPs per gene region to regenotype in all 2500 cases and 2500 controls. Aim 4. To extend our epidemiologic risk prediction model by incorporating established epidemiologic risk factor and gene variant data. We will apply machine-learning tools to identify gene-environment and gene-gene interactions. Covariates will include prior emphysema, asthma, hay fever, dust and asbestos exposure, smoking characteristics, family history of cancer, and anti-inflammatory drug use. The International Lung Cancer Consortium will perform external validation in a proposal to be developed. Our approach to comprehensively evaluate variants in a candidate pathway in a large well- powered study will be applicable to a variety of other cancer sites where inflammation plays an important etiologic role, as well as in non-neoplastic diseases with a strong inflammatory component such as emphysema. The public health potential of a useful risk prediction modes for lung cancer is substantial.

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Publications

Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer.
Authors: Wang Y, McKay JD, Rafnar T, Wang Z, Timofeeva MN, Broderick P, Zong X, Laplana M, Wei Y, Han Y, Lloyd A, Delahaye-Sourdeix M, Chubb D, Gaborieau V, Wheeler W, Chatterjee N, Thorleifsson G, Sulem P, Liu G, Kaaks R, Henrion M, Kinnersley B, Vallée M, LeCalvez-Kelm F, Stevens VL, Gapstur SM, Chen WV, Zaridze D, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Krokan HE, Gabrielsen ME, Skorpen F, Vatten L, Njølstad I, Chen C, Goodman G, Benhamou S, Vooder T, Välk K, Nelis M, Metspalu A, Lener M, Lubi?ski J, Johansson M, Vineis P, Agudo A, Clavel-Chapelon F, Bueno-de-Mesquita HB, Trichopoulos D, Khaw KT, Johansson M, Weiderpass E, Tjønneland A, Riboli E, Lathrop M, Scelo G, Albanes D, Caporaso NE, Ye Y, Gu J, Wu X, Spitz MR, Dienemann H, Rosenberger A, Su L, Matakidou A, Eisen T, Stefansson K, Risch A, Chanock SJ, Christiani DC, Hung RJ, Brennan P, Landi MT, Houlston RS, Amos CI
Source: Nat Genet, 2014 Jul;46(7), p. 736-41.
EPub date: 2014 Jun 1.
PMID: 24880342
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Inflammation-related genetic variations and survival in patients with advanced non-small cell lung cancer receiving first-line chemotherapy.
Authors: Pu X, Hildebrandt MA, Lu C, Roth JA, Stewart DJ, Zhao Y, Heist RS, Ye Y, Chang DW, Su L, Minna JD, Lippman SM, Spitz MR, Christiani DC, Wu X
Source: Clin Pharmacol Ther, 2014 Sep;96(3), p. 360-9.
EPub date: 2014 Apr 22.
PMID: 24755914
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Associations of menthol use with motivation and confidence to quit smoking.
Authors: Reitzel LR, Etzel CJ, Cao Y, Okuyemi KS, Ahluwalia JS
Source: Am J Health Behav, 2013 Sep;37(5), p. 629-34.
PMID: 23985285
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Symptom clusters of pain, depressed mood, and fatigue in lung cancer: assessing the role of cytokine genes.
Authors: Reyes-Gibby CC, Swartz MD, Yu X, Wu X, Yennurajalingam S, Anderson KO, Spitz MR, Shete S
Source: Support Care Cancer, 2013 Nov;21(11), p. 3117-25.
EPub date: 2013 Jul 13.
PMID: 23852407
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Association between a rare novel TP53 variant (rs78378222) and melanoma, squamous cell carcinoma of head and neck and lung cancer susceptibility in non-Hispanic Whites.
Authors: Guan X, Wang LE, Liu Z, Sturgis EM, Wei Q
Source: J Cell Mol Med, 2013 Jul;17(7), p. 873-8.
EPub date: 2013 Jun 7.
PMID: 23742673
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Pilot Study of CYP2B6 Genetic Variation to Explore the Contribution of Nitrosamine Activation to Lung Carcinogenesis.
Authors: Wassenaar CA, Dong Q, Amos CI, Spitz MR, Tyndale RF
Source: Int J Mol Sci, 2013 Apr 16;14(4), p. 8381-92.
EPub date: 2013 Apr 16.
PMID: 23591849
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A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.
Authors: Monda KL, Chen GK, Taylor KC, Palmer C, Edwards TL, Lange LA, Ng MC, Adeyemo AA, Allison MA, Bielak LF, Chen G, Graff M, Irvin MR, Rhie SK, Li G, Liu Y, Liu Y, Lu Y, Nalls MA, Sun YV, Wojczynski MK, Yanek LR, Aldrich MC, Ademola A, Amos CI, Bandera EV, Bock CH, Britton A, Broeckel U, Cai Q, Caporaso NE, Carlson CS, Carpten J, Casey G, Chen WM, Chen F, Chen YD, Chiang CW, Coetzee GA, Demerath E, Deming-Halverson SL, Driver RW, Dubbert P, Feitosa MF, Feng Y, Freedman BI, Gillanders EM, Gottesman O, Guo X, Haritunians T, Harris T, Harris CC, Hennis AJ, Hernandez DG, McNeill LH, Howard TD, Howard BV, Howard VJ, Johnson KC, Kang SJ, Keating BJ, Kolb S, Kuller LH, Kutlar A, Langefeld CD, Lettre G, Lohman K, Lotay V, Lyon H, Manson JE, Maixner W, Meng YA, Monroe KR, Morhason-Bello I, Murphy AB, Mychaleckyj JC, Nadukuru R, Nathanson KL, Nayak U, N'diaye A, Nemesure B, Wu SY, Leske MC, Neslund-Dudas C, Neuhouser M, Nyante S, Ochs-Balcom H, Ogunniyi A, Ogundiran TO, Ojengbede O, Olopade OI, Palmer JR, Ruiz-Narvaez EA, Palmer ND, Press MF, Rampersaud E, Rasmussen-Torvik LJ, Rodriguez-Gil JL, Salako B, Schadt EE, Schwartz AG, Shriner DA, Siscovick D, Smith SB, Wassertheil-Smoller S, Speliotes EK, Spitz MR, Sucheston L, Taylor H, Tayo BO, Tucker MA, Van Den Berg DJ, Edwards DR, Wang Z, Wiencke JK, Winkler TW, Witte JS, Wrensch M, Wu X, Yang JJ, Levin AM, Young TR, Zakai NA, Cushman M, Zanetti KA, Zhao JH, Zhao W, Zheng Y, Zhou J, Ziegler RG, Zmuda JM, Fernandes JK, Gilkeson GS, Kamen DL, Hunt KJ, Spruill IJ, Ambrosone CB, Ambs S, Arnett DK, Atwood L, Becker DM, Berndt SI, Bernstein L, Blot WJ, Borecki IB, Bottinger EP, Bowden DW, Burke G, Chanock SJ, Cooper RS, Ding J, Duggan D, Evans MK, Fox C, Garvey WT, Bradfield JP, Hakonarson H, Grant SF, Hsing A, Chu L, Hu JJ, Huo D, Ingles SA, John EM, Jordan JM, Kabagambe EK, Kardia SL, Kittles RA, Goodman PJ, Klein EA, Kolonel LN, Le Marchand L, Liu S, McKnight B, Millikan RC, Mosley TH, Padhukasahasram B, Williams LK, Patel SR, Peters U, Pettaway CA, Peyser PA, Psaty BM, Redline S, Rotimi CN, Rybicki BA, Sale MM, Schreiner PJ, Signorello LB, Singleton AB, Stanford JL, Strom SS, Thun MJ, Vitolins M, Zheng W, Moore JH, Williams SM, Ketkar S, Zhu X, Zonderman AB, NABEC Consortium, UKBEC Consortium, BioBank Japan Project, AGEN Consortium, Kooperberg C, Papanicolaou GJ, Henderson BE, Reiner AP, Hirschhorn JN, Loos RJ, North KE, Haiman CA
Source: Nat Genet, 2013 Jun;45(6), p. 690-6.
EPub date: 2013 Apr 14.
PMID: 23583978
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Role of selected genetic variants in lung cancer risk in African Americans.
Authors: Spitz MR, Amos CI, Land S, Wu X, Dong Q, Wenzlaff AS, Schwartz AG
Source: J Thorac Oncol, 2013 Apr;8(4), p. 391-7.
PMID: 23454887
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Associations between dietary intake of choline and betaine and lung cancer risk.
Authors: Ying J, Rahbar MH, Hallman DM, Hernandez LM, Spitz MR, Forman MR, Gorlova OY
Source: PLoS One, 2013;8(2), p. e54561.
EPub date: 2013 Feb 1.
PMID: 23383301
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Energy balance, polymorphisms in the mTOR pathway, and renal cell carcinoma risk.
Authors: Shu X, Lin J, Wood CG, Tannir NM, Wu X
Source: J Natl Cancer Inst, 2013 Mar 20;105(6), p. 424-32.
EPub date: 2013 Feb 2.
PMID: 23378641
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