|Grant Number:||5R01CA111703-05 Interpret this number|
|Primary Investigator:||Chen, Chu|
|Organization:||Fred Hutchinson Cancer Research Center|
|Project Title:||Molecular Epidemiology of Lung Cancer|
DESCRIPTION (provided by applicant): Tobacco smoke is the major cause of lung cancer, the most common type of fatal cancer worldwide. A possible means by which tobacco smoke exerts its carcinogenic effect is the DNA damage produced by the generation of reactive oxygen species and the formation of DNA adducts. Since the majority of persons who smoke tobacco do not develop lung cancer, it is possible that those who do develop this disease have a relatively poor capacity to repair the DNA damage that results from smoking. In a nested case-control study, we plan to determine whether polymorphisms of enzymes involved in the repair of smoking-induced DNA damage, namely those from the base excision (BER) and nucleotide excision repair (NER) pathways, are associated with risk of lung cancer. We propose to genotype the functional single nucleotide polymorphisms (SNPs) as well as tagging SNPs of 25 DNA repair genes (a total of 331 polymorphisms), that have been resequenced by the Seattle Variation Discovery Resource for the Environmental Genome Project. The lung cancer cases (n = 900) and controls (n = 1800) for the proposed study will come from the participants in the Carotene and Retinol Efficacy Trial (CARET) of lung cancer prevention. Genotyping of cases and controls will utilize DNA extracted from frozen whole blood samples. Detailed quantitative information on smoking and dietary history (using a food frequency questionnaire), obtained prior to the diagnosis of lung cancer, is available through CARET records. Cases and controls will be compared with respect to the prevalence of putative "high risk" genotypes, alone and in combination with other putative "high risk" genotypes within each pathway and in the two pathways combined. Analyses will also examine whether inferred haplotypes and their combinations are associated with risk. We will assess whether associations differ by histologic subtypes and sex. Results will be interpreted with multiple comparisons taken into account. The proposed study has sufficient statistical power to identify interactions between some of the high-risk genotypes/haplotypes, and to investigate whether the risk associated with a particular genotype/haplotype varies by other risk factors, such as smoking intensity and recency, and dietary factors, such as intake of antioxidant-rich fruits and vegetables (e.g. Rosaceae fruits and Cruciferae vegetables), and food-derived nutrients (e.g. carotenoids, vitamin C, and vitamin E).
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.
DNA repair genotype and lung cancer risk in the beta-carotene and retinol efficacy trial.
Authors: Doherty JA, Sakoda LC, Loomis MM, Barnett MJ, Julianto L, Thornquist MD, Neuhouser ML, Weiss NS, Goodman GE, Chen C
Source: Int J Mol Epidemiol Genet, 2013;4(1), p. 11-34.
EPub date: 2013 Mar 18.
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.
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.
Chromosome 15q24-25.1 variants, diet, and lung cancer susceptibility in cigarette smokers.
Authors: Sakoda LC, Loomis MM, Doherty JA, Neuhouser ML, Barnett MJ, Thornquist MD, Weiss NS, Goodman GE, Chen C
Source: Cancer Causes Control, 2011 Mar;22(3), p. 449-61.
EPub date: 2011 Jan 13.