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BMC Cancer
Published in: BMC Cancer 1/2012

Open Access 01-12-2012 | Research article

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: Nifang Niu, Daniel J Schaid, Ryan P Abo, Krishna Kalari, Brooke L Fridley, Qiping Feng, Gregory Jenkins, Anthony Batzler, Abra G Brisbin, Julie M Cunningham, Liang Li, Zhifu Sun, Ping Yang, Liewei Wang

Published in: BMC Cancer | Issue 1/2012

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Abstract

Background

Taxane is one of the first line treatments of lung cancer. In order to identify novel single nucleotide polymorphisms (SNPs) that might contribute to taxane response, we performed a genome-wide association study (GWAS) for two taxanes, paclitaxel and docetaxel, using 276 lymphoblastoid cell lines (LCLs), followed by genotyping of top candidate SNPs in 874 lung cancer patient samples treated with paclitaxel.

Methods

GWAS was performed using 1.3 million SNPs and taxane cytotoxicity IC50 values for 276 LCLs. The association of selected SNPs with overall survival in 76 small or 798 non-small cell lung cancer (SCLC, NSCLC) patients were analyzed by Cox regression model, followed by integrated SNP-microRNA-expression association analysis in LCLs and siRNA screening of candidate genes in SCLC (H196) and NSCLC (A549) cell lines.

Results

147 and 180 SNPs were associated with paclitaxel or docetaxel IC50s with p-values <10-4 in the LCLs, respectively. Genotyping of 153 candidate SNPs in 874 lung cancer patient samples identified 8 SNPs (p-value < 0.05) associated with either SCLC or NSCLC patient overall survival. Knockdown of PIP4K2A, CCT5, CMBL, EXO1, KMO and OPN3, genes within 200 kb up-/downstream of the 3 SNPs that were associated with SCLC overall survival (rs1778335, rs2662411 and rs7519667), significantly desensitized H196 to paclitaxel. SNPs rs2662411 and rs1778335 were associated with mRNA expression of CMBL or PIP4K2A through microRNA (miRNA) hsa-miR-584 or hsa-miR-1468.

Conclusions

GWAS in an LCL model system, joined with clinical translational and functional studies, might help us identify genetic variations associated with overall survival of lung cancer patients treated paclitaxel.
Appendix
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Literature
1.
McGrogan BT, Gilmartin B, Carney DN, McCann A: Taxanes, microtubules and chemoresistant breast cancer. Biochim Biophys Acta. 2008, 1785 (2): 96-132.PubMed
2.
Zhao J, Kim JE, Reed E, Li QQ: Molecular mechanism of antitumor activity of taxanes in lung cancer (Review). Int J Oncol. 2005, 27 (1): 247-256.PubMed
3.
Cancer Facts & Figures 2012: 2012, Atlanta: American Cancer Society
4.
Goffin J, Lacchetti C, Ellis PM, Ung YC, Evans WK: First-line systemic chemotherapy in the treatment of advanced non-small cell lung cancer: a systematic review. J Thorac Oncol. 2010, 5 (2): 260-274. 10.1097/JTO.0b013e3181c6f035.CrossRefPubMed
5.
Rodriguez E, Lilenbaum RC: Small cell lung cancer: past, present, and future. Curr Oncol Rep. 2010, 12 (5): 327-334. 10.1007/s11912-010-0120-5.CrossRefPubMed
6.
Lee JJ, Swain SM: Peripheral neuropathy induced by microtubule-stabilizing agents. J Clin Oncol. 2006, 24 (10): 1633-1642. 10.1200/JCO.2005.04.0543.CrossRefPubMed
7.
Rowinsky EK, Donehower RC: Paclitaxel (taxol). N Engl J Med. 1995, 332 (15): 1004-1014. 10.1056/NEJM199504133321507.CrossRefPubMed
8.
Rigas JR: Taxane-platinum combinations in advanced non-small cell lung cancer: a review. Oncologist. 2004, 9 (Suppl 2): 16-23.CrossRefPubMed
9.
Rosell R, Taron M, Alberola V, Massuti B, Felip E: Genetic testing for chemotherapy in non-small cell lung cancer. Lung Cancer. 2003, 41 (Suppl 1): S97-102.CrossRefPubMed
10.
Isla D, Sarries C, Rosell R, Alonso G, Domine M, Taron M, Lopez-Vivanco G, Camps C, Botia M, Nunez L, et al: Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer. Ann Oncol. 2004, 15 (8): 1194-1203. 10.1093/annonc/mdh319.CrossRefPubMed
11.
Gandara DR, Kawaguchi T, Crowley J, Moon J, Furuse K, Kawahara M, Teramukai S, Ohe Y, Kubota K, Williamson SK, et al: Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics. J Clin Oncol. 2009, 27 (21): 3540-3546. 10.1200/JCO.2008.20.8793.CrossRefPubMedPubMedCentral
12.
Leskela S, Jara C, Leandro-Garcia LJ, Martinez A, Garcia-Donas J, Hernando S, Hurtado A, Vicario JC, Montero-Conde C, Landa I, et al: Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity. Pharmacogenomics J. 2010, [Epub ahead of print]
13.
Sissung TM, Mross K, Steinberg SM, Behringer D, Figg WD, Sparreboom A, Mielke S: Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia. Eur J Cancer. 2006, 42 (17): 2893-2896. 10.1016/j.ejca.2006.06.017.CrossRefPubMedPubMedCentral
14.
Rochat B: Role of cytochrome P450 activity in the fate of anticancer agents and in drug resistance: focus on tamoxifen, paclitaxel and imatinib metabolism. Clin Pharmacokinet. 2005, 44 (4): 349-366. 10.2165/00003088-200544040-00002.CrossRefPubMed
15.
Spratlin J, Sawyer MB: Pharmacogenetics of paclitaxel metabolism. Crit Rev Oncol Hematol. 2007, 61 (3): 222-229. 10.1016/j.critrevonc.2006.09.006.CrossRefPubMed
16.
Watters JW, Kraja A, Meucci MA, Province MA, McLeod HL: Genome-wide discovery of loci influencing chemotherapy cytotoxicity. Proc Natl Acad Sci U S A. 2004, 101 (32): 11809-11814. 10.1073/pnas.0404580101.CrossRefPubMedPubMedCentral
17.
O'Brien C, Cavet G, Pandita A, Hu X, Haydu L, Mohan S, Toy K, Rivers CS, Modrusan Z, Amler LC, et al: Functional genomics identifies ABCC3 as a mediator of taxane resistance in HER2-amplified breast cancer. Cancer Res. 2008, 68 (13): 5380-5389. 10.1158/0008-5472.CAN-08-0234.CrossRefPubMed
18.
Kroetz DL, Baldwin RM, Owzar K, Jiang C, Zembutsu H, Kubo M, Nakamura Y, Shulman LN, Ratain MJ: Inherited genetic variation in EPHA5, FGD4, and NRDG1 and paclitaxel (P)-induced peripheral neuropathy (PN): results from a genome-wide association study (GWAS) in CALGB 40101. J Clin Oncol. 2010, 28: 15s-
19.
Li L, Fridley B, Kalari K, Jenkins G, Batzler A, Safgren S, Hildebrandt M, Ames M, Schaid D, Wang L: Gemcitabine and cytosine arabinoside cytotoxicity: association with lymphoblastoid cell expression. Cancer Res. 2008, 68 (17): 7050-7058. 10.1158/0008-5472.CAN-08-0405.CrossRefPubMedPubMedCentral
20.
Li L, Fridley BL, Kalari K, Jenkins G, Batzler A, Weinshilboum RM, Wang L: Gemcitabine and arabinosylcytosin pharmacogenomics: genome-wide association and drug response biomarkers. PLoS One. 2009, 4 (11): e7765-10.1371/journal.pone.0007765.CrossRefPubMedPubMedCentral
21.
Niu N, Qin Y, Fridley BL, Hou J, Kalari KR, Zhu M, Wu TY, Jenkins GD, Batzler A, Wang L: Radiation pharmacogenomics: a genome-wide association approach to identify radiation response biomarkers using human lymphoblastoid cell lines. Genome Res. 2010, 20 (11): 1482-1492. 10.1101/gr.107672.110.CrossRefPubMedPubMedCentral
22.
Yang P, Sun Z, Krowka MJ, Aubry MC, Bamlet WR, Wampfler JA, Thibodeau SN, Katzmann JA, Allen MS, Midthun DE, et al: Alpha1-antitrypsin deficiency carriers, tobacco smoke, chronic obstructive pulmonary disease, and lung cancer risk. Arch Intern Med. 2008, 168 (10): 1097-1103. 10.1001/archinte.168.10.1097.CrossRefPubMedPubMedCentral
23.
Moyer AM, Sun Z, Batzler AJ, Li L, Schaid DJ, Yang P, Weinshilboum RM: Glutathione pathway genetic polymorphisms and lung cancer survival after platinum-based chemotherapy. Cancer Epidemiol Biomarkers Prev. 2010, 19 (3): 811-821. 10.1158/1055-9965.EPI-09-0871.CrossRefPubMedPubMedCentral
24.
25.
Schaid DJ, Batzler AJ, Jenkins GD, Hildebrandt MA: Exact tests of Hardy-Weinberg equilibrium and homogeneity of disequilibrium across strata. Am J Hum Genet. 2006, 79 (6): 1071-1080. 10.1086/510257.CrossRefPubMedPubMedCentral
26.
Cunningham JM, Oberg AL, Borralho PM, Kren BT, French AJ, Wang L, Bot BM, Morlan BW, Silverstein KA, Staggs R, et al: Evaluation of a new high-dimensional miRNA profiling platform. BMC Med Genomics. 2009, 2: 57-10.1186/1755-8794-2-57.CrossRefPubMedPubMedCentral
27.
Brain P, Cousens R: An equation to describe dose responses where there is stimulation of growth at low doses. Weed Res. 1989, 29 (2): 93-96. 10.1111/j.1365-3180.1989.tb00845.x.CrossRef
28.
Van Ewijk PH, Hoekstra JA: Calculation of the EC50 and its confidence interval when subtoxic stimulus is present. Ecotoxicol Environ Saf. 1993, 25 (1): 25-32. 10.1006/eesa.1993.1003.CrossRefPubMed
29.
Wu ZJ, Irizarry RA, Gentleman R, Martinez-Murillo F, Spencer F: A model-based background adjustment for oligonucleotide expression arrays. J Am Stat Assoc. 2004, 99 (468): 909-917. 10.1198/016214504000000683.CrossRef
30.
Li YAG: Mach 1.0: Rapid Haplotype Reconstruction and Missing Genotype Inference. Am J Hum Genet. 2006, S79: 2290-
31.
Bandiera S, Hatem E, Lyonnet S, Henrion-Caude A: microRNAs in diseases: from candidate to modifier genes. Clin Genet. 2010, 77 (4): 306-313. 10.1111/j.1399-0004.2010.01370.x.CrossRefPubMed
32.
Gligorov J, Lotz JP: Preclinical pharmacology of the taxanes: implications of the differences. Oncologist. 2004, 9 (Suppl 2): 3-8.CrossRefPubMed
33.
Mielke S, Sparreboom A, Mross K: Peripheral neuropathy: a persisting challenge in paclitaxel-based regimes. Eur J Cancer. 2006, 42 (1): 24-30. 10.1016/j.ejca.2005.06.030.CrossRefPubMed
34.
Stewart DJ: Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer. Crit Rev Oncol Hematol. 2010, 75 (3): 173-234. 10.1016/j.critrevonc.2009.11.006.CrossRefPubMedPubMedCentral
35.
Sie L, Loong S, Tan EK: Utility of lymphoblastoid cell lines. J Neurosci Res. 2009, 87 (9): 1953-1959. 10.1002/jnr.22000.CrossRefPubMed
36.
Choy E, Yelensky R, Bonakdar S, Plenge RM, Saxena R, De Jager PL, Shaw SY, Wolfish CS, Slavik JM, Cotsapas C, et al: Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines. PLoS Genet. 2008, 4 (11): e1000287-10.1371/journal.pgen.1000287.CrossRefPubMedPubMedCentral
37.
Stark AL, Zhang W, Zhou T, O'Donnell PH, Beiswanger CM, Huang RS, Cox NJ, Dolan ME: Population differences in the rate of proliferation of international HapMap cell lines. Am J Hum Genet. 2010, 87 (6): 829-833. 10.1016/j.ajhg.2010.10.018.CrossRefPubMedPubMedCentral
38.
Cai Y, Yu X, Hu S, Yu J: A brief review on the mechanisms of miRNA regulation. Genomics Proteomics Bioinformatics. 2009, 7 (4): 147-154. 10.1016/S1672-0229(08)60044-3.CrossRefPubMed
39.
Mishra PJ, Mishra PJ, Banerjee D, Bertino JR: MiRSNPs or MiR-polymorphisms, new players in microRNA mediated regulation of the cell: introducing microRNA pharmacogenomics. Cell Cycle. 2008, 7 (7): 853-858. 10.4161/cc.7.7.5666.CrossRefPubMed
40.
Mishra PJ, Humeniuk R, Mishra PJ, Longo-Sorbello GS, Banerjee D, Bertino JR: A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc Natl Acad Sci U S A. 2007, 104 (33): 13513-13518. 10.1073/pnas.0706217104.CrossRefPubMedPubMedCentral
41.
Ishizuka T, Fujimori I, Kato M, Noji-Sakikawa C, Saito M, Yoshigae Y, Kubota K, Kurihara A, Izumi T, Ikeda T, et al: Human carboxymethylenebutenolidase as a bioactivating hydrolase of olmesartan medoxomil in liver and intestine. J Biol Chem. 2010, 285 (16): 11892-11902. 10.1074/jbc.M109.072629.CrossRefPubMedPubMedCentral
42.
Yang X, Zou P, Yao J, Yun D, Bao H, Du R, Long J, Chen X: Proteomic dissection of cell type-specific H2AX-interacting protein complex associated with hepatocellular carcinoma. J Proteome Res. 2010, 9 (3): 1402-1415. 10.1021/pr900932y.CrossRefPubMedPubMedCentral
43.
Clarke JH, Irvine RF: The activity, evolution and association of phosphatidylinositol 5-phosphate 4-kinases. Adv Enzyme Regul. 2011, Epub ahead of print
44.
van den Bout I, Divecha N: PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions. J Cell Sci. 2009, 122 (Pt 21): 3837-3850.CrossRefPubMed
45.
Clarke JH, Wang M, Irvine RF: Localization, regulation and function of type II phosphatidylinositol 5-phosphate 4-kinases. Adv Enzyme Regul. 2010, 50 (1): 12-18. 10.1016/j.advenzreg.2009.10.006.CrossRefPubMedPubMedCentral
46.
Clarke JH, Richardson JP, Hinchliffe KA, Irvine RF: Type II PtdInsP kinases: location, regulation and function. Biochem Soc Symp. 2007, 74: 149-159. 10.1042/BSS0740149.CrossRefPubMed
47.
Bultsma Y, Keune WJ, Divecha N: PIP4Kbeta interacts with and modulates nuclear localization of the high-activity PtdIns5P-4-kinase isoform PIP4Kalpha. Biochem J. 2010, 430 (2): 223-235. 10.1042/BJ20100341.CrossRefPubMed
48.
Wilcox A, Hinchliffe KA: Regulation of extranuclear PtdIns5P production by phosphatidylinositol phosphate 4-kinase 2alpha. FEBS Lett. 2008, 582 (9): 1391-1394. 10.1016/j.febslet.2008.03.022.CrossRefPubMed
49.
Carricaburu V, Lamia KA, Lo E, Favereaux L, Payrastre B, Cantley LC, Rameh LE: The phosphatidylinositol (PI)-5-phosphate 4-kinase type II enzyme controls insulin signaling by regulating PI-3,4,5-trisphosphate degradation. Proc Natl Acad Sci U S A. 2003, 100 (17): 9867-9872. 10.1073/pnas.1734038100.CrossRefPubMedPubMedCentral
50.
Ramel D, Lagarrigue F, Dupuis-Coronas S, Chicanne G, Leslie N, Gaits-Iacovoni F, Payrastre B, Tronchere H: PtdIns5P protects Akt from dephosphorylation through PP2A inhibition. Biochem Biophys Res Commun. 2009, 387 (1): 127-131. 10.1016/j.bbrc.2009.06.139.CrossRefPubMed
51.
Jones DR, Bultsma Y, Keune WJ, Halstead JR, Elouarrat D, Mohammed S, Heck AJ, D'Santos CS, Divecha N: Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kbeta. Mol Cell. 2006, 23 (5): 685-695. 10.1016/j.molcel.2006.07.014.CrossRefPubMed
Metadata
Title
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
Nifang Niu
Daniel J Schaid
Ryan P Abo
Krishna Kalari
Brooke L Fridley
Qiping Feng
Gregory Jenkins
Anthony Batzler
Abra G Brisbin
Julie M Cunningham
Liang Li
Zhifu Sun
Ping Yang
Liewei Wang
Publication date
01-12-2012
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2012
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-12-422

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