|Grant Number:||3R01CA080127-09S1 Interpret this number|
|Primary Investigator:||Yang, Ping|
|Organization:||Mayo Clinic Rochester|
|Project Title:||Alpha-1 Ad Carriers and Lung Cancer Risk|
DESCRIPTION (provided by applicant): Lung cancer provides an ideal paradigm for investigating environment-host-gene interactions. We are conducting a case-control study that integrates traditional epidemiologic methods with genetic and molecular tools to evaluate three major factors in lung cancer etiology: a gene (PI1) responsible for alpha1-antitrypsin deficiency (alpha1-ATD), chronic obstructive pulmonary disease (COPD), and tobacco smoke exposure. Our results support our hypothesis that ATD allele carriers are at a higher risk than non-carriers to develop lung cancer among cigarette smokers and never smokers (odds ratio of 1.8-2.3), independent of the effects of COPD. The expected population attributable risk of lung cancer due to alpha1-ATD alleles is estimated to be 9- 12%. To understand the pathway between alpha1-antitrypsin and lung cancer risk, it is critical to investigate the role of the ELA2 gene that encodes neutrophil elastase, the natural counterpart of alpha1-antitrypsin. Using function-related single nucleotide polymorphic (SNP) markers at ELA2, we now can feasibly measure neutrophil elastase levels indirectly through the SNP genotypes. Therefore, we further hypothesize that individuals' genotype indicative of an imbalance between neutrophil elastase and alpha1-antitrypsin modifies lung cancer risk. In this competing renewal application, we plan to accomplish four aims: 1) examine the role of the ELA2 gene and its interaction with the PI1 allele type in lung cancer risk; 2) validate our results from aim 1 and assess the effect of smoking cessation among heavy smokers; 3) estimate host effects of emphysema +/- chronic bronchitis or airway obstruction on the results obtained from aims 1-2; and 4) explore the effects of selected genes representing inflammation and oxidative pathways on the results obtained from aims 1-3. We designed a two-stage case-control study to first test our hypotheses using a newly established resource of over 1,200 lung cancer cases, 1,200 full sibling controls, and 1,200 unrelated controls. We will then validate our results in a high-risk group of 2,400 heavy smokers, all with complete data to characterize COPD subgroups. Genotyping will be based on function-related polymorphic DNA markers and PI1 alleles will be determined by isoelectric focusing assay. Analyses will include multivariable regression models for case-unrelated control comparisons and sibling transmission disequilibrium tests for case-sibling control comparisons. From this study, we may find an explanation of why smokers develop lung cancer. Positive results may identify useful and feasible biologic markers for assisting lung cancer screening and early detection, may suggest directions for further research on pathogenic mechanisms, and may provide opportunities for lung cancer risk reduction among former smokers and people with existing lung diseases.
Conserved recurrent gene mutations correlate with pathway deregulation and clinical outcomes of lung adenocarcinoma in never-smokers.
Authors: Sun Z, Wang L, Eckloff BW, Deng B, Wang Y, Wampfler JA, Jang J, Wieben ED, Jen J, You M, Yang P
Source: BMC Med Genomics, 2014 Jun 4;7, p. 32.
EPub date: 2014 Jun 4.
Increased BCAR1 predicts poor outcomes of non-small cell lung cancer in multiple-center patients.
Authors: Deng B, Sun Z, Jason W, Yang P
Source: Ann Surg Oncol, 2013 Dec;20 Suppl 3, p. S701-8.
EPub date: 2013 Aug 1.
Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers.
Authors: Wu X, Wang L, Ye Y, Aakre JA, Pu X, Chang GC, Yang PC, Roth JA, Marks RS, Lippman SM, Chang JY, Lu C, Deschamps C, Su WC, Wang WC, Huang MS, Chang DW, Li Y, Pankratz VS, Minna JD, Hong WK, Hildebrandt MA, Hsiung CA, Yang P
Source: Cancer Res, 2013 Jul 1;73(13), p. 4028-38.
EPub date: 2013 May 23.
Genetic association with overall survival of taxane-treated lung cancer patients - a genome-wide association study in human lymphoblastoid cell lines followed by a clinical association study.
Authors: Niu N, Schaid DJ, Abo RP, Kalari K, Fridley BL, Feng Q, Jenkins G, Batzler A, Brisbin AG, Cunningham JM, Li L, Sun Z, Yang P, Wang L
Source: BMC Cancer, 2012 Sep 24;12, p. 422.
EPub date: 2012 Sep 24.
SH3GL2 is frequently deleted in non-small cell lung cancer and downregulates tumor growth by modulating EGFR signaling.
Authors: Dasgupta S, Jang JS, Shao C, Mukhopadhyay ND, Sokhi UK, Das SK, Brait M, Talbot C, Yung RC, Begum S, Westra WH, Hoque MO, Yang P, Yi JE, Lam S, Gazdar AF, Fisher PB, Jen J, Sidransky D
Source: J Mol Med (Berl), 2013 Mar;91(3), p. 381-93.
EPub date: 2012 Sep 12.
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.
Increased miR-708 expression in NSCLC and its association with poor survival in lung adenocarcinoma from never smokers.
Authors: Jang JS, Jeon HS, Sun Z, Aubry MC, Tang H, Park CH, Rakhshan F, Schultz DA, Kolbert CP, Lupu R, Park JY, Harris CC, Yang P, Jen J
Source: Clin Cancer Res, 2012 Jul 1;18(13), p. 3658-67.
EPub date: 2012 May 9.
Genetic variations and patient-reported quality of life among patients with lung cancer.
Authors: Sloan JA, de Andrade M, Decker P, Wampfler J, Oswold C, Clark M, Yang P
Source: J Clin Oncol, 2012 May 10;30(14), p. 1699-704.
EPub date: 2012 Mar 26.
Relationship between deficits in overall quality of life and non-small-cell lung cancer survival.
Authors: Sloan JA, Zhao X, Novotny PJ, Wampfler J, Garces Y, Clark MM, Yang P
Source: J Clin Oncol, 2012 May 1;30(13), p. 1498-504.
EPub date: 2012 Mar 26.
Asthma and lung cancer risk: a systematic investigation by the International Lung Cancer Consortium.
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Source: Carcinogenesis, 2012 Mar;33(3), p. 587-97.
EPub date: 2011 Dec 22.
Gemcitabine metabolic pathway genetic polymorphisms and response in patients with non-small cell lung cancer.
Authors: Li L, Schaid DJ, Fridley BL, Kalari KR, Jenkins GD, Abo RP, Batzler A, Moon I, Pelleymounter L, Eckloff BW, Wieben ED, Sun Z, Yang P, Wang L
Source: Pharmacogenet Genomics, 2012 Feb;22(2), p. 105-16.
Meta-analysis of 8q24 for seven cancers reveals a locus between NOV and ENPP2 associated with cancer development.
Authors: Brisbin AG, Asmann YW, Song H, Tsai YY, Aakre JA, Yang P, Jenkins RB, Pharoah P, Schumacher F, Conti DV, Duggan DJ, Jenkins M, Hopper J, Gallinger S, Newcomb P, Casey G, Sellers TA, Fridley BL
Source: BMC Med Genet, 2011 Dec 5;12, p. 156.
EPub date: 2011 Dec 5.
Quality of life and symptom burden among long-term lung cancer survivors.
Authors: Yang P, Cheville AL, Wampfler JA, Garces YI, Jatoi A, Clark MM, Cassivi SD, Midthun DE, Marks RS, Aubry MC, Okuno SH, Williams BA, Nichols FC, Trastek VF, Sugimura H, Sarna L, Allen MS, Deschamps C, Sloan JA
Source: J Thorac Oncol, 2012 Jan;7(1), p. 64-70.
Genetic variants associated with the risk of chronic obstructive pulmonary disease with and without lung cancer.
Authors: de Andrade M, Li Y, Marks RS, Deschamps C, Scanlon PD, Olswold CL, Jiang R, Swensen SJ, Sun Z, Cunningham JM, Wampfler JA, Limper AH, Midthun DE, Yang P
Source: Cancer Prev Res (Phila), 2012 Mar;5(3), p. 365-73.
EPub date: 2011 Nov 1.
Systematic evaluation of genetic variants in three biological pathways on patient survival in low-stage non-small cell lung cancer.
Authors: Pankratz VS, Sun Z, Aakre J, Li Y, Johnson C, Garces YI, Aubry MC, Molina JR, Wigle DA, Yang P
Source: J Thorac Oncol, 2011 Sep;6(9), p. 1488-95.
Genetic variation predicting cisplatin cytotoxicity associated with overall survival in lung cancer patients receiving platinum-based chemotherapy.
Authors: Tan XL, Moyer AM, Fridley BL, Schaid DJ, Niu N, Batzler AJ, Jenkins GD, Abo RP, Li L, Cunningham JM, Sun Z, Yang P, Wang L
Source: Clin Cancer Res, 2011 Sep 1;17(17), p. 5801-11.
EPub date: 2011 Jul 20.
Genetic variations in multiple drug action pathways and survival in advanced stage non-small cell lung cancer treated with chemotherapy.
Authors: Li Y, Sun Z, Cunningham JM, Aubry MC, Wampfler JA, Croghan GA, Johnson C, Wu D, Aakre JA, Molina J, Wang L, Pankratz VS, Yang P
Source: Clin Cancer Res, 2011 Jun 1;17(11), p. 3830-40.
Effect of emphysema on lung cancer risk in smokers: a computed tomography-based assessment.
Authors: Li Y, Swensen SJ, Karabekmez LG, Marks RS, Stoddard SM, Jiang R, Worra JB, Zhang F, Midthun DE, de Andrade M, Song Y, Yang P
Source: Cancer Prev Res (Phila), 2011 Jan;4(1), p. 43-50.
EPub date: 2010 Nov 30.
Perceptions of lung cancer risk and beliefs in screening accuracy of spiral computed tomography among high-risk lung cancer family members.
Authors: Sinicrope PS, Rabe KG, Brockman TA, Patten CA, Petersen WO, Slusser J, Yang P, Swensen SJ, Edell ES, de Andrade M, Petersen GM
Source: Acad Radiol, 2010 Aug;17(8), p. 1012-25.
Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium.
Authors: Truong T, Hung RJ, Amos CI, Wu X, Bickeböller H, Rosenberger A, Sauter W, Illig T, Wichmann HE, Risch A, Dienemann H, Kaaks R, Yang P, Jiang R, Wiencke JK, Wrensch M, Hansen H, Kelsey KT, Matsuo K, Tajima K, Schwartz AG, Wenzlaff A, Seow A, Ying C, Staratschek-Jox A, Nürnberg P, Stoelben E, Wolf J, Lazarus P, Muscat JE, Gallagher CJ, Zienolddiny S, Haugen A, van der Heijden HF, Kiemeney LA, Isla D, Mayordomo JI, Rafnar T, Stefansson K, Zhang ZF, Chang SC, Kim JH, Hong YC, Duell EJ, Andrew AS, Lejbkowicz F, Rennert G, Müller H, Brenner H, Le Marchand L, Benhamou S, Bouchardy C, Teare MD, Xue X, McLaughlin J, Liu G, McKay JD, Brennan P, Spitz MR
Source: J Natl Cancer Inst, 2010 Jul 7;102(13), p. 959-71.
EPub date: 2010 Jun 14.
Genetic variation in glutathione metabolism and DNA repair genes predicts survival of small-cell lung cancer patients.
Authors: Sun Z, Chen J, Aakre J, Marks RS, Garces YY, Jiang R, Idowu O, Cunningham JM, Liu Y, Pankratz VS, Yang P
Source: Ann Oncol, 2010 Oct;21(10), p. 2011-6.
EPub date: 2010 May 3.
Genetic variants and risk of lung cancer in never smokers: a genome-wide association study.
Authors: Li Y, Sheu CC, Ye Y, de Andrade M, Wang L, Chang SC, Aubry MC, Aakre JA, Allen MS, Chen F, Cunningham JM, Deschamps C, Jiang R, Lin J, Marks RS, Pankratz VS, Su L, Li Y, Sun Z, Tang H, Vasmatzis G, Harris CC, Spitz MR, Jen J, Wang R, Zhang ZF, Christiani DC, Wu X, Yang P
Source: Lancet Oncol, 2010 Apr;11(4), p. 321-30.
EPub date: 2010 Mar 19.