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Grant Details

Grant Number: 3R01CA084354-10S1 Interpret this number
Primary Investigator: Yang, Ping
Organization: Mayo Clinic Rochester
Project Title: Genetic Determinants of Lung Cancer Survival
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): Prognosis following a diagnosis of primary lung cancer remains very poor; individualized treatment plans according to predicted responses and subsequent survivorship are needed. As an effort to meet this challenge, we have been investigating genetic variations in the human glutathione metabolic system as one of the promising candidates to predict platinum-based treatment outcomes and survival. Six polymorphic DMA markers were tested as proposed. Our data to-date, based on 803 non-small cell lung cancer patients, support the hypothesis that patient survival after platinum-based therapy may be predicted by the glutathione system genotypes. In this renewal application, we propose to accomplish three aims: 1) In-depth evaluation of the host genetic variations on prognosis among patients with advanced stage lung cancer at three levels of outcome: treatment response, prominent adverse drug reactions, and overall and lung cancer-free survival. Two specific expansions to the original study scope are the addition of other important genetic polymorphisms and three additional drug groups that are used in combination with or independently of platinum-based drugs (taxanes, gemcitabine, and epidermal growth factor inhibitors). 2) Because ionizing radiation (radiotherapy) is also commonly used in treating advanced stage lung cancer and often combined with chemotherapy, we will expand our investigation to radiation therapy in relation to treatment response, prominent dose-limiting adverse reactions, and survival. Host genetic variations in the mechanistic pathways of radiation therapy will be studied in parallel to Aim 1. We aim to identify and assess the roles of genetic variations influencing these mechanisms in developing radiotherapy related lung and esophageal damage. 3) We will examine the effects of multiple prognostic factors that have been previously reported and discovered by our team and in the literature. The main and interactive effects of genetic variations responsible for varied responses to chemotherapy and/or radiation therapy and of these other prognostic factors will be systematically evaluated using multivariate models and analyses. Our ambitious yet feasible goal is accomplishable by capitalizing on our established resource that has been supported through a R03 and three R01 grants (with non-overlapping research theme) awarded to our research team over the past 8 years. We anticipate enrolling at least 1100 stage 11 I/I V non-small cell and 400 small cell lung cancer patients. Results from this pharmacogenetic and molecular epidemiology study may suggest new directions to enhance clinical management and to improve survivorship of lung cancer patients. Our ultimate goal is to build comprehensive and clinically useful models in designing patient-specific treatment plans and in predicting patients' treatment response and survival.

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Publications

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.
PMID: 24894543
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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.
PMID: 23904007
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Network-based approach identified cell cycle genes as predictor of overall survival in lung adenocarcinoma patients.
Authors: Li Y, Tang H, Sun Z, Bungum AO, Edell ES, Lingle WL, Stoddard SM, Zhang M, Jen J, Yang P, Wang L
Source: Lung Cancer, 2013 Apr;80(1), p. 91-8.
EPub date: 2013 Jan 26.
PMID: 23357462
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Physical activity level and quality of life in long term lung cancer survivors.
Authors: Solberg Nes L, Liu H, Patten CA, Rausch SM, Sloan JA, Garces YI, Cheville AL, Yang P, Clark MM
Source: Lung Cancer, 2012 Sep;77(3), p. 611-6.
EPub date: 2012 Jun 6.
PMID: 22681871
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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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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.
PMID: 22573352
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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.
PMID: 22454423
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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.
PMID: 22454418
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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.
PMID: 22142333
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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.
PMID: 22134070
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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.
PMID: 22044695
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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.
PMID: 21792076
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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.
PMID: 21775533
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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.
PMID: 21636554
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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.
PMID: 21119049
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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.
PMID: 20548021
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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.
PMID: 20439344
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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.
PMID: 20304703
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Glutathione pathway genetic polymorphisms and lung cancer survival after platinum-based chemotherapy.
Authors: Moyer AM, Sun Z, Batzler AJ, Li L, Schaid DJ, Yang P, Weinshilboum RM
Source: Cancer Epidemiol Biomarkers Prev, 2010 Mar;19(3), p. 811-21.
EPub date: 2010 Mar 3.
PMID: 20200426
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International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants.
Authors: Truong T, Sauter W, McKay JD, Hosgood HD 3rd, Gallagher C, Amos CI, Spitz M, Muscat J, Lazarus P, Illig T, Wichmann HE, Bickeböller H, Risch A, Dienemann H, Zhang ZF, Naeim BP, Yang P, Zienolddiny S, Haugen A, Le Marchand L, Hong YC, Kim JH, Duell EJ, Andrew AS, Kiyohara C, Shen H, Matsuo K, Suzuki T, Seow A, Ng DP, Lan Q, Zaridze D, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Constantinescu V, Bencko V, Foretova L, Janout V, Caporaso NE, Albanes D, Thun M, Landi MT, Trubicka J, Lener M, Lubinski J, EPIC-lung, Wang Y, Chabrier A, Boffetta P, Brennan P, Hung RJ
Source: Carcinogenesis, 2010 Apr;31(4), p. 625-33.
EPub date: 2010 Jan 27.
PMID: 20106900
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Evaluation of glutathione metabolic genes on outcomes in advanced non-small cell lung cancer patients after initial treatment with platinum-based chemotherapy: an NCCTG-97-24-51 based study.
Authors: Yang P, Mandrekar SJ, Hillman SH, Allen Ziegler KL, Sun Z, Wampfler JA, Cunningham JM, Sloan JA, Adjei AA, Perez E, Jett JR
Source: J Thorac Oncol, 2009 Apr;4(4), p. 479-85.
PMID: 19347979
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Non-overlapping and non-cell-type-specific gene expression signatures predict lung cancer survival.
Authors: Sun Z, Wigle DA, Yang P
Source: J Clin Oncol, 2008 Feb 20;26(6), p. 877-83.
PMID: 18281660
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Does marital status impact survival and quality of life in patients with non-small cell lung cancer? Observations from the mayo clinic lung cancer cohort.
Authors: Jatoi A, Novotny P, Cassivi S, Clark MM, Midthun D, Patten CA, Sloan J, Yang P
Source: Oncologist, 2007 Dec;12(12), p. 1456-63.
PMID: 18165623
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Gene expression profiling on lung cancer outcome prediction: present clinical value and future premise.
Authors: Sun Z, Yang P
Source: Cancer Epidemiol Biomarkers Prev, 2006 Nov;15(11), p. 2063-8.
PMID: 17119029
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Histologic grade is an independent prognostic factor for survival in non-small cell lung cancer: an analysis of 5018 hospital- and 712 population-based cases.
Authors: Sun Z, Aubry MC, Deschamps C, Marks RS, Okuno SH, Williams BA, Sugimura H, Pankratz VS, Yang P
Source: J Thorac Cardiovasc Surg, 2006 May;131(5), p. 1014-20.
PMID: 16678584
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Role of the glutathione metabolic pathway in lung cancer treatment and prognosis: a review.
Authors: Yang P, Ebbert JO, Sun Z, Weinshilboum RM
Source: J Clin Oncol, 2006 Apr 10;24(11), p. 1761-9.
PMID: 16603718
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Predicting postrecurrence survival among completely resected nonsmall-cell lung cancer patients.
Authors: Williams BA, Sugimura H, Endo C, Nichols FC, Cassivi SD, Allen MS, Pairolero PC, Deschamps C, Yang P
Source: Ann Thorac Surg, 2006 Mar;81(3), p. 1021-7.
PMID: 16488713
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Can gene expression profiling predict survival for patients with squamous cell carcinoma of the lung?
Authors: Sun Z, Yang P, Aubry MC, Kosari F, Endo C, Molina J, Vasmatzis G
Source: Mol Cancer, 2004 Dec 3;3(1), p. 35.
EPub date: 2004 Dec 3.
PMID: 15579197
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Study design considerations in clinical outcome research of lung cancer using microarray analysis.
Authors: Yang P, Sun Z, Aubry MC, Kosari F, Bamlet W, Endo C, Molina JR, Vasmatzis G
Source: Lung Cancer, 2004 Nov;46(2), p. 215-26.
PMID: 15474670
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Quality of life in 650 lung cancer survivors 6 months to 4 years after diagnosis.
Authors: Svobodník A, Yang P, Novotny PJ, Bass E, Garces YI, Jett JR, Bonner JA, Sloan JA
Source: Mayo Clin Proc, 2004 Aug;79(8), p. 1024-30.
PMID: 15301330
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Gender differences in non-small-cell lung cancer survival: an analysis of 4,618 patients diagnosed between 1997 and 2002.
Authors: Visbal AL, Williams BA, Nichols FC 3rd, Marks RS, Jett JR, Aubry MC, Edell ES, Wampfler JA, Molina JR, Yang P
Source: Ann Thorac Surg, 2004 Jul;78(1), p. 209-15; discussion 215.
PMID: 15223430
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Lung cancer risk reduction after smoking cessation: observations from a prospective cohort of women.
Authors: Ebbert JO, Yang P, Vachon CM, Vierkant RA, Cerhan JR, Folsom AR, Sellers TA
Source: J Clin Oncol, 2003 Mar 1;21(5), p. 921-6.
PMID: 12610194
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