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Grant Details

Grant Number: 5R01CA055769-18 Interpret this number
Primary Investigator: Spitz, Margaret
Organization: University Of Tx Md Anderson Can Ctr
Project Title: Adenocarcinoma of the Lung: Role of Nnk Susceptibility
Fiscal Year: 2008
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Abstract

DESCRIPTION (provided by applicant): To date our research on susceptibility to tobacco carcinogenesis has focused on the polycyclic hydrocarbon, benzo[a]pyrene, as an in vitro mutagen challenge for functional assays of DNA damage and repair. The tobacco-specific nitrosamine, NNK, is a selective inducer of adenocarcinoma (AC) of the lung, now the leading histologic subtype in the US. We therefore propose to build upon the infrastructure created from our parent grant, "Ecogenetics Study of Lung Cancer" to extend our research to a detailed assessment of susceptibility to NNK, incorporating functional assays of DNA damage and repair and specific polymorphisms in NNK-relevant metabolic and repair pathways. We will enroll 500 patients with newly diagnosed, previously untreated AC of the lung, from M. D. Anderson Cancer Center who are residents of Harris County, Texas, or the seven contiguous counties. Controls (n=500) will be frequency-matched to the cases on age, gender, ethnicity and smoking status (never, former and current) identified from Houston's largest private multi-specialty physician group encompassing a network of 23 clinics. By following the same design for data collection and control selection in the renewal, we can combine previously recruited AC cases (n= 600) and controls (n=600) from the parent grant with this renewal study for epidemiologic and genotype analyses, and thereby achieve time and cost efficiency and statistical power. Epidemiologic analyses will focus on smoking, diet (micronutrients such as isothiocyanates and folate intake), and family history. We propose to apply a panel of functional assays of DNA damage and repair, using activated NNK acetate (NNKOAc) as the in vitro challenge mutagen in the host cell reactivation, comet and micronucleus assays. We will evaluate frequencies of polymorphisms in genes involved in the following carefully selected pathways: metabolic activation and detoxification of NNK; repair via the alkyltransferase pathway; methylation genes; and p53. In a subgroup of cases for whom tumor tissue is available (estimated 300 patients), we will evaluate genetic (mutations in K-ras) and epigenetic changes (CpG island methylation in the promoter region of select genes). Analyses will focus on diet-gene, gene-environment, genotype/phenotype and surrogate tissue/target tissue genetic and epigenetic correlations. The unifying theme is that susceptibility to the genotoxic effects of NNK is an important determinant of lung AC risk. Identification of high risk smokers has potential for primary and secondary preventive initiatives. This research is also applicable to other sites since tobacco-specific nitrosamines are causative agents in esophagus, pancreas and oral cavity cancers, and are the most prevalent carcinogen in snuff products.

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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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Modeling the natural history and detection of lung cancer based on smoking behavior.
Authors: Chen X, Foy M, Kimmel M, Gorlova OY
Source: PLoS One, 2014;9(4), p. e93430.
EPub date: 2014 Apr 4.
PMID: 24705368
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Pathway-based serum microRNA profiling and survival in patients with advanced stage non-small cell lung cancer.
Authors: Wang Y, Gu J, Roth JA, Hildebrandt MA, Lippman SM, Ye Y, Minna JD, Wu X
Source: Cancer Res, 2013 Aug 1;73(15), p. 4801-9.
EPub date: 2013 Jun 17.
PMID: 23774211
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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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Integrative cancer epidemiology--the next generation.
Authors: Spitz MR, Caporaso NE, Sellers TA
Source: Cancer Discov, 2012 Dec;2(12), p. 1087-90.
PMID: 23230187
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Use of the cytokinesis-blocked micronucleus assay to detect gender differences and genetic instability in a lung cancer case-control study.
Authors: McHugh MK, Lopez MS, Ho CH, Spitz MR, Etzel CJ, El-Zein RA
Source: Cancer Epidemiol Biomarkers Prev, 2013 Jan;22(1), p. 135-45.
EPub date: 2012 Nov 29.
PMID: 23195992
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Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls.
Authors: Timofeeva MN, Hung RJ, Rafnar T, Christiani DC, Field JK, Bickeböller H, Risch A, McKay JD, Wang Y, Dai J, Gaborieau V, McLaughlin J, Brenner D, Narod SA, Caporaso NE, Albanes D, Thun M, Eisen T, Wichmann HE, Rosenberger A, Han Y, Chen W, Zhu D, Spitz M, Wu X, Pande M, Zhao Y, 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, Lathrop M, Benhamou S, Vooder T, Välk K, Nelis M, Metspalu A, Raji O, Chen Y, Gosney J, Liloglou T, Muley T, Dienemann H, Thorleifsson G, Shen H, Stefansson K, Brennan P, Amos CI, Houlston R, Landi MT, Transdisciplinary Research in Cancer of the Lung (TRICL) Research Team
Source: Hum Mol Genet, 2012 Nov 15;21(22), p. 4980-95.
EPub date: 2012 Aug 16.
PMID: 22899653
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Self-reported prior lung diseases as risk factors for non-small cell lung cancer in Mexican Americans.
Authors: McHugh MK, Schabath MB, Ho CH, Liu M, D'Amelio AM Jr, Greisinger AJ, Delclos GL, Spitz MR, Etzel CJ
Source: J Immigr Minor Health, 2013 Oct;15(5), p. 910-7.
PMID: 22847640
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Systematic evaluation of apoptotic pathway gene polymorphisms and lung cancer risk.
Authors: Lin J, Lu C, Stewart DJ, Gu J, Huang M, Chang DW, Lippman SM, Wu X
Source: Carcinogenesis, 2012 Sep;33(9), p. 1699-706.
EPub date: 2012 Jun 4.
PMID: 22665367
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Variants in inflammation genes are implicated in risk of lung cancer in never smokers exposed to second-hand smoke.
Authors: Spitz MR, Gorlov IP, Amos CI, Dong Q, Chen W, Etzel CJ, Gorlova OY, Chang DW, Pu X, Zhang D, Wang L, Cunningham JM, Yang P, Wu X
Source: Cancer Discov, 2011 Oct;1(5), p. 420-9.
EPub date: 2011 Aug 25.
PMID: 22586632
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Initial medical attention on patients with early-stage non-small cell lung cancer.
Authors: Chen X, Gorlov IP, Ying J, Merriman KW, Kimmel M, Lu C, Reyes-Gibby CC, Gorlova OY
Source: PLoS One, 2012;7(3), p. e32644.
EPub date: 2012 Mar 7.
PMID: 22412901
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A case-control study of a sex-specific association between a 15q25 variant and lung cancer risk.
Authors: Wei C, Han Y, Spitz MR, Wu X, Chancoco H, Akiva P, Rechavi G, Brand H, Wun I, Frazier ML, Amos CI
Source: Cancer Epidemiol Biomarkers Prev, 2011 Dec;20(12), p. 2603-9.
EPub date: 2011 Oct 25.
PMID: 22028403
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Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.
Authors: Soler Artigas M, Loth DW, Wain LV, Gharib SA, Obeidat M, Tang W, Zhai G, Zhao JH, Smith AV, Huffman JE, Albrecht E, Jackson CM, Evans DM, Cadby G, Fornage M, Manichaikul A, Lopez LM, Johnson T, Aldrich MC, Aspelund T, Barroso I, Campbell H, Cassano PA, Couper DJ, Eiriksdottir G, Franceschini N, Garcia M, Gieger C, Gislason GK, Grkovic I, Hammond CJ, Hancock DB, Harris TB, Ramasamy A, Heckbert SR, Heliövaara M, Homuth G, Hysi PG, James AL, Jankovic S, Joubert BR, Karrasch S, Klopp N, Koch B, Kritchevsky SB, Launer LJ, Liu Y, Loehr LR, Lohman K, Loos RJ, Lumley T, Al Balushi KA, Ang WQ, Barr RG, Beilby J, Blakey JD, Boban M, Boraska V, Brisman J, Britton JR, Brusselle GG, Cooper C, Curjuric I, Dahgam S, Deary IJ, Ebrahim S, Eijgelsheim M, Francks C, Gaysina D, Granell R, Gu X, Hankinson JL, Hardy R, Harris SE, Henderson J, Henry A, Hingorani AD, Hofman A, Holt PG, Hui J, Hunter ML, Imboden M, Jameson KA, Kerr SM, Kolcic I, Kronenberg F, Liu JZ, Marchini J, McKeever T, Morris AD, Olin AC, Porteous DJ, Postma DS, Rich SS, Ring SM, Rivadeneira F, Rochat T, Sayer AA, Sayers I, Sly PD, Smith GD, Sood A, Starr JM, Uitterlinden AG, Vonk JM, Wannamethee SG, Whincup PH, Wijmenga C, Williams OD, Wong A, Mangino M, Marciante KD, McArdle WL, Meibohm B, Morrison AC, North KE, Omenaas E, Palmer LJ, Pietiläinen KH, Pin I, Pola Sbreve Ek O, Pouta A, Psaty BM, Hartikainen AL, Rantanen T, Ripatti S, Rotter JI, Rudan I, Rudnicka AR, Schulz H, Shin SY, Spector TD, Surakka I, Vitart V, Völzke H, Wareham NJ, Warrington NM, Wichmann HE, Wild SH, Wilk JB, Wjst M, Wright AF, Zgaga L, Zemunik T, Pennell CE, Nyberg F, Kuh D, Holloway JW, Boezen HM, Lawlor DA, Morris RW, Probst-Hensch N, International Lung Cancer Consortium, GIANT consortium, Kaprio J, Wilson JF, Hayward C, Kähönen M, Heinrich J, Musk AW, Jarvis DL, Gläser S, Järvelin MR, Ch Stricker BH, Elliott P, O'Connor GT, Strachan DP, London SJ, Hall IP, Gudnason V, Tobin MD
Source: Nat Genet, 2011 Sep 25;43(11), p. 1082-90.
EPub date: 2011 Sep 25.
PMID: 21946350
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The landscape of recombination in African Americans.
Authors: Hinch AG, Tandon A, Patterson N, Song Y, Rohland N, Palmer CD, Chen GK, Wang K, Buxbaum SG, Akylbekova EL, Aldrich MC, Ambrosone CB, Amos C, Bandera EV, Berndt SI, Bernstein L, Blot WJ, Bock CH, Boerwinkle E, Cai Q, Caporaso N, Casey G, Cupples LA, Deming SL, Diver WR, Divers J, Fornage M, Gillanders EM, Glessner J, Harris CC, Hu JJ, Ingles SA, Isaacs W, John EM, Kao WH, Keating B, Kittles RA, Kolonel LN, Larkin E, Le Marchand L, McNeill LH, Millikan RC, Murphy A, Musani S, Neslund-Dudas C, Nyante S, Papanicolaou GJ, Press MF, Psaty BM, Reiner AP, Rich SS, Rodriguez-Gil JL, Rotter JI, Rybicki BA, Schwartz AG, Signorello LB, Spitz M, Strom SS, Thun MJ, Tucker MA, Wang Z, Wiencke JK, Witte JS, Wrensch M, Wu X, Yamamura Y, Zanetti KA, Zheng W, Ziegler RG, Zhu X, Redline S, Hirschhorn JN, Henderson BE, Taylor HA Jr, Price AL, Hakonarson H, Chanock SJ, Haiman CA, Wilson JG, Reich D, Myers SR
Source: Nature, 2011 Jul 20;476(7359), p. 170-5.
EPub date: 2011 Jul 20.
PMID: 21775986
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Dietary patterns affect lung cancer risk in never smokers.
Authors: Gorlova OY, Weng SF, Hernandez L, Spitz MR, Forman MR
Source: Nutr Cancer, 2011;63(6), p. 842-9.
EPub date: 2011 Jul 20.
PMID: 21774612
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Novel genetic variants in the chromosome 5p15.33 region associate with lung cancer risk.
Authors: Pande M, Spitz MR, Wu X, Gorlov IP, Chen WV, Amos CI
Source: Carcinogenesis, 2011 Oct;32(10), p. 1493-9.
EPub date: 2011 Jul 18.
PMID: 21771723
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Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk.
Authors: Wassenaar CA, Dong Q, Wei Q, Amos CI, Spitz MR, Tyndale RF
Source: J Natl Cancer Inst, 2011 Sep 7;103(17), p. 1342-6.
EPub date: 2011 Jul 11.
PMID: 21747048
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Association of smoking with tumor size at diagnosis in non-small cell lung cancer.
Authors: Chen X, Gorlov IP, Merriman KW, Weng SF, Foy M, Keener G, Amos CI, Spitz MR, Kimmel M, Gorlova OY
Source: Lung Cancer, 2011 Dec;74(3), p. 378-83.
EPub date: 2011 Jun 8.
PMID: 21645942
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