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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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Evidence that the lung Adenocarcinoma EML4-ALK fusion gene is not caused by exposure to secondhand tobacco smoke during childhood.
Authors: Ryan BM, Wang Y, Jen J, Yi ES, Olivo-Marston S, Yang P, Harris CC
Source: Cancer Epidemiol Biomarkers Prev, 2014 Jul;23(7), p. 1432-4.
EPub date: 2014 Apr 22.
PMID: 24755712
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Clinical outcomes and changes in lung function after segmentectomy versus lobectomy for lung cancer cases.
Authors: Deng B, Cassivi SD, de Andrade M, Nichols FC, Trastek VF, Wang Y, Wampfler JA, Stoddard SM, Wigle DA, Shen RK, Allen MS, Deschamps C, Yang P
Source: J Thorac Cardiovasc Surg, 2014 Oct;148(4), p. 1186-1192.e3.
EPub date: 2014 Mar 20.
PMID: 24746994
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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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