Tumor Biology

, Volume 36, Issue 11, pp 8993–9003 | Cite as

RNA-seq analysis of lung adenocarcinomas reveals different gene expression profiles between smoking and nonsmoking patients

  • Yafang Li
  • Xiangjun Xiao
  • Xuemei Ji
  • Bin Liu
  • Christopher I. Amos
Research Article

Abstract

Lung adenocarcinoma is caused by the combination of genetic and environmental effects, and smoking plays an important role in the disease development. Exploring the gene expression profile and identifying genes that are shared or vary between smokers and nonsmokers with lung adenocarcinoma will provide insights into the etiology of this complex cancer. We obtained RNA-seq data from paired normal and tumor tissues from 34 nonsmoking and 34 smoking patients with lung adenocarcinoma (GEO: GSE40419). R Bioconductor, edgeR, was adopted to conduct differential gene expression analysis between paired normal and tumor tissues. A generalized linear model was applied to identify genes that were differentially expressed in nonsmoker and smoker patients as well as genes that varied between these two groups. We identified 2273 genes that showed differential expression with FDR < 0.05 and |logFC| >1 in nonsmoker tumor versus normal tissues; 3030 genes in the smoking group; and 1967 genes were common to both groups. Sixty-eight and 70 % of the identified genes were downregulated in nonsmoking and smoking groups, respectively. The 20 genes such as SPP1, SPINK1, and FAM83A with largest fold changes in smokers also showed similar large and highly significant fold changes in nonsmokers and vice versa, showing commonalities in expression changes for adenocarcinomas in both smokers and nonsmokers for these genes. We also identified 175 genes that were significantly differently expressed between tumor samples from nonsmoker and smoker patients. Gene expression profile varied substantially between smoker and nonsmoker patients with lung adenocarcinoma. Smoking patients overall showed far more complicated disease mechanism and have more dysregulation in their gene expression profiles. Our study reveals pathogenetic differences in smoking and nonsmoking patients with lung adenocarcinoma from transcriptome analysis. We provided a list of candidate genes for further study for disease detection and treatment in both smoking and nonsmoking patients with lung adenocarcinoma.

Keywords

RNA-seq Expression analysis Smoking Lung cancer Lung adenocarcinoma 

Notes

Acknowledgments

This research was partially supported by NIH research grant U19CA148127.

Conflict of interest

None

Supplementary material

13277_2015_3576_MOESM1_ESM.docx (25 kb)
Supplementary 1 (DOCX 24 kb)
13277_2015_3576_MOESM2_ESM.xlsx (646 kb)
Supplementary 2 (XLSX 646 kb)

References

  1. 1.
    Navada S, Lai P, Schwartz AG, Kalemkerian GP. Temporal trends in small cell lung cancer: analysis of the national Surveillance Epidemiology and End-Results (SEER) database [abstract 7082]. J Clin Oncol. 2006;24(18S):384S.Google Scholar
  2. 2.
    Sher T, Dy GK, Adjei AA. Small cell lung cancer. Mayo Clin Proc. 2008;83(3):355–67.CrossRefPubMedGoogle Scholar
  3. 3.
  4. 4.
    Powell HA, Iyen-Omofoman B, Hubbard RB, Baldwin DR, Tata LJ. The association between smoking quality and lung cancer in men and women. Chest. 2013;143(1):123–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Massion PP, Zou Y, Chen H, Jian A, Coulson P, et al. Smoking-related genomic signatures in non-small cell lung cancer. Am J Respir Crit Care Med. 2008;178:1164–72.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers—a different disease. Nature. 2007;7:778–90.Google Scholar
  7. 7.
    Zhao S, Fung-Leung W, Bittner A, Ngo K, Liu X. Comparison of RNA-seq and microarray in transcriptome profiling of activated T cells. PLoS One. 2014. doi: 10.1371/journal.pone.0078644.Google Scholar
  8. 8.
    Cheng P, Chen Y, Li Y, Zhao Z, Gao H, Li D, et al. Comparison of the gene expression profiles between smokers with and without lung cancer using RNA-seq. Asian Pac J Cancer Prev. 2012;13(8):3605–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Beane J, Vick J, Schembri F, Anderlind C, Gower A, Campbell J, et al. Characterizing the impact of smoking and lung cancer on the air way transcriptome using RNA-seq. Cancer Prev Res (Phila). 2011;4(6):803–17.CrossRefGoogle Scholar
  10. 10.
    Han S, Kim W, Hong Y, Hong S, Lee S, Ryu D, et al. RNA sequencing identifies novel markers of non-small cell lung cancer. Lung Cancer. 2014;84(3):229–35.CrossRefPubMedGoogle Scholar
  11. 11.
    Seo J, Ju Y, Lee W, et al. The transcriptional landscape and mutational profile of lung adenocarcinoma. Genome Res. 2012;22:2109–19.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kim SC, Jung Y, Park J, Cho S, et al. A high-dimensional, deep-sequencing study of lung adenocarcinoma in female never-smokers. PLoS One. 2013;8(2):e55596.Google Scholar
  13. 13.
    McCarthy DJ, Chen Y, Smyth GK. Differential expression analysis of multifactor RNA-seq experiments with respect to biological variation. Nucleic Acids Res. 2012;1–10.Google Scholar
  14. 14.
    Lazar V, Suo C, Orear C, Oord VJ, et al. Integrated molecular portrait of non-small cell lung cancers. BMC Medical Genomics. 2013;6:53.Google Scholar
  15. 15.
    Larzabal L, Nguewa PA, Pio R, Blanco D, Scanchez B, et al. Overexpression of TMPRSS4 in on-small cell lung cancer is associated with poor prognosis in patients with squamous histology. Br J Cancer. 2011;105(10):1608–1614.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Hu Z, Lin D, Yuan J, Xiao T, Zhang H, et al. Overexpression of osteopontin is associated with more aggressive phenotypes in human non-small cell lung cancer. Clin Cancer Res 2005; 11(13):4646–4652.CrossRefPubMedGoogle Scholar
  17. 17.
    Sauter W, Rosenberger A, Beckmann L, Kropp S, Mittelstrass K, et al. Matrix metalloproteinase 1 (MMP1) is associated with early-onset lung cancer. Cancer Epidemiol Biomarkers Prev. 2008;17(5):1127–1135.CrossRefPubMedGoogle Scholar
  18. 18.
    Knight SD, Presto J, Linse S, Johansson J. The BRICHOS domain. Amyloid fibril formation and their relationship. Biochemistry. 2013;52(43):7523–7531.Google Scholar
  19. 19.
    Ono S, Tanaka T, Ishida M, Kinoshita A, Fukuoka J, Takaki M, etc. Surfactant protein C G100S mutation causes familial pulmonary fibrosis in Japanese kindred. Eur Respir J. 2011;38(4):861–869.CrossRefPubMedGoogle Scholar
  20. 20.
    Kim SH, Chen G, Jeon C K, Zhao L, Colacino J, et al. Abstract 3124: Smoking effects on CYP24A1 in lung adenocarcinoma: epigenetic changes by smoking. Proceedings: AACR 103rd Annual meeting 2012.Google Scholar
  21. 21.
    Jiang F, Yin Z, Caraway NP, Li R, Katz RL. Genomic profiles in stage I primary non-small cell lung cancer using comparative genomic hybridization analysis of cDNA microarrays. Neoplasia. 2004;6:623–35.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Li R, Wang H, Bekele BN, Jiang F. Identification of putative oncogenes in lung adenocarcinoma by a comprehensive functional genomic approach. Oncogene. 2005;18:2628–35.Google Scholar
  23. 23.
    Choi CGC, Li J, Wang Y, Li L, Zhong L, Ma B, et al. The metalloprotease ADAMTS8 displays antirumor properties through antagonizing EGFR-MEK-ERK signaling and is silenced in cancinomas by CpG methylation. Mol Cancer Res. 2014;12: 228–238.Google Scholar
  24. 24.
    Doree M, Galas S. The cyclin-dependent protein kinases and the control of cell division. FASEB J. 1994;8:1114–21.PubMedGoogle Scholar
  25. 25.
    Yasuda M, Takesue F, Inutsuka S, et al. Overexpression of cyclin B1 in gastric cancer and its clinicopathological significance: an immunohistological study. J Cancer Res Clin Oncol. 2002;128:412–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Korenaga D, Takesue F, Yasuda M et al. The relationship between cyclin B1 overexpression and lymph node metastasis in human colorectal cancer. Surgery. 2001;131:114–120.CrossRefGoogle Scholar
  27. 27.
    Takeno S, Noguchi T, Kikuchi R et al. Prognostic value of cyclin B1 in patients with esophageal squamous cell carcinoma. Cancer. 2002;94:2874–2881.CrossRefPubMedGoogle Scholar
  28. 28.
    Hassan KA, El-Naggar AK, Soria JC et al. Clinical significance of cyclin B1 protein expression in squamous cell carcinoma of the tongue. Clin Cancer Res. 2001;7:2458–2462.PubMedGoogle Scholar
  29. 29.
    Soria JC, Jang SJ, Khuri FR et al. Overexpression of cyclin B1 in early-stage non-small cell lung cancer and its clinical implication. Cancer Res. 2000;60:4000–4004.PubMedGoogle Scholar
  30. 30.
    Yoshida T, Tanaka S, Mogi A, Shitara Y, Kuwano H. The clinical significant of Cyclin B1 and Wee1 expression in non-small-cell lung cancer. Ann Oncol. 2004;15(2):252–256.CrossRefPubMedGoogle Scholar
  31. 31.
    Watson AP, Evans RL, Egland KA. Multiple functions of Sushi Domain Containing 2 (SUSD2) in breast tumorigenesis. Mol Cancer Res. 2012;11(1):74–85.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Pio R, Blanco D, Pajares MJ, Aibar E, Olga D, et al. Development of a novel splice array platform and its application in the identification of alternative splice variants in lung cancer. BMC Genomics. 2010;11:352.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Schroeder EB,Welch VL, Couper D, Nieto FJ, Liao D, Rosamond WD, et al. Lung function and incident coronary heart disease: the atherosclerosis risk in communities study. Am J Epidemiol. 2003:158(12):1171–1181.Google Scholar
  34. 34.
    Taneda K, Namekata T, Hughes D, Suzuki K, Knopp R, Ozasa K. Association of lung function with atherosclerotic risk factors among Japanese Americans: Seattle Nikkei health study. Clin Exp Pharmacol Physiol. 2004;31 Suppl 2:S31–4.CrossRefPubMedGoogle Scholar
  35. 35.
    Dreyer L, Prescott E, Gyntelberg F. Association between atherosclerosis and female lung cancer—a Danish cohort study. Lung Cancer. 2003;42(3):247–254.CrossRefPubMedGoogle Scholar
  36. 36.
    Lu TP, Tsai MH, Lee JM, Hsu CP, Chen PC, et al. Identification of a novel biomarker, SEMA5A, for non-small cell lung carcinoma in nonsmoking women. Cancer Epidemiol Biomarkers Prev. 2010;19(10):2590–2597.CrossRefPubMedGoogle Scholar
  37. 37.
    Lu Y, Yi Y, Liu P, Wen W, James M, Wang D, et al. Common Human Cancer Genes Discovered by Integrated Gene-Expression Analysis. PLoS ONE. 2007;2(11):e1149.Google Scholar
  38. 38.
    Rohrbeck A, Borlak J. Cancer Genomics Identifies Regulatory Gene Networks. Associated with the Transition from Dysplasia to Advanced Lung Adenocarcinomas Induced by c-Raf-1. PLoS One. 2009. doi: 10.1371/journal.pone.0007315.
  39. 39.
    Campioni M, Ambrogi V, Pompeo E, Citro G, Castelli M, Spugnini EP, et al. Identification of genes down-regulated during lung cancer progression: A cDNA array study. J Exp Clin Cancer Res. 2008;27(1):38.Google Scholar
  40. 40.
    Knudson AG. Antioncogenes and human cancer. Proc Natl Acad Sci USA. 1993;90:10914–10921.Google Scholar
  41. 41.
    Zhang T, Zhang DM, Zhao D, Hou XM, Liu XJ, Ling XL, et al. The prognostic value of osteopontin expression in non-small cell lung cancer: a meta-analysis. J Mol Histol. 2014;45(5):533–540.CrossRefPubMedGoogle Scholar
  42. 42.
    Jin Y, Tong D, Tang L, Chen J, Zhou J, Feng Z, et al. Expressions of osteopontin (OPN), ανβ3 and Pim-1 associated with poor prognosis in non-small cell lung cancer (NSCLC). Chin J Cancer Res. 2012;24(2):103–108.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Chen Y, Liu H, Wu W, Li Y, Li J. Osteopontin genetic variants are associated with overall survival in advanced non-small-cell lung cancer patients and bone metastasis. J Exp Clin Cancer Res. 2013;32(45). doi: 10.1186/1756-9966-32-45.
  44. 44.
    Hao Y, Liu J, Wang P, Wang F, Yu Z, Li M, et al. OPN polymorphism is related to the chemotherapy response and prognosis in advanced NSCLC. Int J Genomics. 2014. doi: 10.1155/2014/846142.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Okabe N, Ezaki J, Yamaura T, Muto S, Osugi J, et al. FAM83B is a novel biomarker for diagnosis and prognosis of lung squamous cell carcinoma. Int J Oncol. 2015;46(3):999–1006.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Lu L, Liao GQ, He P, Zhu H, Liu PH, et al. Detection of circulating cancer cells in lung cancer patients with a panel of marker genes. Biochem Biophys Res Commun. 2008;372(4):756–760.CrossRefGoogle Scholar
  47. 47.
    Li Y, Dong X, Yin Y, Su Y, Xu Q, et al. BJ-TSA-9, a novel human tumor-specific gene, has potential as a biomarker as a biomarker of lung cancer. Beoplasia. 2005;7(12):1073–1080.Google Scholar
  48. 48.
    GDS1348 / 002003020005 / FAM83A / Homo sapiens. Analysis of cultured normal bronchial epithelial cells 4 and 24 hours after exposure to 15 minutes of cigarette smoke in order to better understand molecular impact of tobacco exposure. http://www.ncbi.nlm.nih.gov/geo/gds/profileGraph.cgi?&dataset=A5KYKBJEB4MVOzwuoi&dataset=awhtm-la8vptmyyyxx$&gmin=0.511550&gmax=8.553317&absc=&uid=12856830&gds=1348&idref=002003020005&annot=FAM83A

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Yafang Li
    • 1
  • Xiangjun Xiao
    • 1
  • Xuemei Ji
    • 1
  • Bin Liu
    • 2
  • Christopher I. Amos
    • 1
  1. 1.Department of Biomedical Data ScienceDartmouth CollegeHanoverUSA
  2. 2.Department of Genetics, Center for Genetics and GenomicsUniversity of Texas MD Anderson Cancer CenterHoustonUSA

Personalised recommendations