Cancer Causes & Control

, Volume 25, Issue 1, pp 11–23 | Cite as

Tobacco smoking, NBS1 polymorphisms, and survival in lung and upper aerodigestive tract cancers with semi-Bayes adjustment for hazard ratio variation

  • Tingting Yang
  • Po-Yin Chang
  • Sungshim Lani Park
  • Delara Bastani
  • Shen-Chih Chang
  • Hal Morgenstern
  • Donald P. Tashkin
  • Jenny T. Mao
  • Jeanette C. Papp
  • Jian-Yu Rao
  • Wendy Cozen
  • Thomas M. Mack
  • Sander Greenland
  • Zuo-Feng Zhang
Original paper



Although single nucleotide polymorphisms (SNPs) of NBS1 have been associated with susceptibility to lung and upper aerodigestive tract (UADT) cancers, their relations to cancer survival and measures of effect are largely unknown.


Using follow-up data from 611 lung cancer cases and 601 UADT cancer cases from a population-based case–control study in Los Angeles, we prospectively evaluated associations of tobacco smoking and 5 NBS1 SNPs with all-cause mortality. Mortality data were obtained from the Social Security Death Index. We used Cox regression to estimate adjusted hazard ratios (HR) for main effects and ratios of hazard ratios (RHR) derived from product terms to assess hazard ratio variations by each SNP. Bayesian methods were used to account for multiple comparisons.


We observed 406 (66 %) deaths in lung cancer cases and 247 (41 %) deaths in UADT cancer cases with median survival of 1.43 and 1.72 years, respectively. Ever tobacco smoking was positively associated with mortality for both cancers. We observed an upward dose–response association between smoking pack-years and mortality in UADT squamous cell carcinoma. The adjusted HR relating smoking to mortality in non-small cell lung cancer (NSCLC) was greater for cases with the GG genotype of NBS1 rs1061302 than for cases with AA/AG genotypes (semi-Bayes adjusted RHR = 1.97; 95 % limits = 1.14, 3.41).


A history of tobacco smoking at cancer diagnosis was associated with mortality among patients with lung cancer or UADT squamous cell carcinoma. The HR relating smoking to mortality appeared to vary with the NBS1 rs1061302 genotype among NSCLC cases.


Survival NBS1 Lung cancer Upper aerodigestive tract (UADT) cancers Tobacco Bayesian methods 



The authors thank all of the Los Angeles Study participants for their time and effort in supporting this study. This research was supported by the National Institutes of Health [Grant Numbers ES06718, ES01167, CA90833, CA077954, CA09142, CA96134, DA11386] and the Alper Research Center for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center.

Conflict of interest

The authors declare that they have no potential conflicts of interest.

Supplementary material

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Supplementary material 1 (DOCX 38 kb)
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Supplementary material 4 (DOCX 30 kb)


  1. 1.
    Ferlay J, Shin HR, Bray F et al (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917PubMedCrossRefGoogle Scholar
  2. 2.
    Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62:10–29PubMedCrossRefGoogle Scholar
  3. 3.
    Hoyert DL, Xu J (2012) National vital statistics reports. Deaths: preliminary data for 2011. Division of Vital Statistics. CDC/National Center for Health Statistics. vol 61, p 6Google Scholar
  4. 4.
    Gupta S, Kong W, Peng Y, Miao Q, Mackillop WJ (2009) Temporal trends in the incidence and survival of cancers of the upper aerodigestive tract in Ontario and the United States. Int J Cancer 125:2159–2165PubMedCrossRefGoogle Scholar
  5. 5.
    Pulte D, Brenner H (2005) Changes in survival in head and neck cancers in the late 20th and early 21st century: a period analysis. Oncologist 15:994–1001CrossRefGoogle Scholar
  6. 6.
    Sasco AJ, Secretan MB, Straif K (2004) Tobacco smoking and cancer: a brief review of recent epidemiological evidence. Lung Cancer 45(Suppl 2):S3–S9PubMedCrossRefGoogle Scholar
  7. 7.
    Tammemagi CM, Neslund-Dudas C, Simoff M, Kvale P (2004) Smoking and lung cancer survival: the role of comorbidity and treatment. Chest 125:27–37PubMedCrossRefGoogle Scholar
  8. 8.
    Nordquist LT, Simon GR, Cantor A, Alberts WM, Bepler G (2004) Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung. Chest 126:347–351PubMedCrossRefGoogle Scholar
  9. 9.
    Ryk C, Kumar R, Thirumaran RK, Hou SM (2006) Polymorphisms in the DNA repair genes XRCC1, APEX1, XRCC3 and NBS1, and the risk for lung cancer in never- and ever-smokers. Lung Cancer 54:285–292PubMedCrossRefGoogle Scholar
  10. 10.
    Park SL, Bastani D, Goldstein BY et al (2010) Associations between NBS1 polymorphisms, haplotypes and smoking-related cancers. Carcinogenesis 31:1264–1271PubMedCrossRefGoogle Scholar
  11. 11.
    Yang L, Li Y, Cheng M et al (2012) A functional polymorphism at microRNA-629-binding site in the 3′-untranslated region of NBS1 gene confers an increased risk of lung cancer in southern and eastern Chinese population. Carcinogenesis 33:338–347PubMedCrossRefGoogle Scholar
  12. 12.
    Zheng J, Zhang C, Jiang L et al (2011) Functional NBS1 polymorphism is associated with occurrence and advanced disease status of nasopharyngeal carcinoma. Mol Carcinog 50:689–696PubMedCrossRefGoogle Scholar
  13. 13.
    Yang MH, Chang SY, Chiou SH et al (2007) Overexpression of NBS1 induces epithelial-mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer. Oncogene 26:1459–1467PubMedCrossRefGoogle Scholar
  14. 14.
    Yang MH, Chiang WC, Chou TY et al (2006) Increased NBS1 expression is a marker of aggressive head and neck cancer and overexpression of NBS1 contributes to transformation. Clin Cancer Res 12:507–515PubMedCrossRefGoogle Scholar
  15. 15.
    Ricceri F, Matullo G, Vineis P (2012) Is there evidence of involvement of DNA repair polymorphisms in human cancer? Mutat Res 736:117–121PubMedCrossRefGoogle Scholar
  16. 16.
    Lu M, Lu J, Yang X et al (2009) Association between the NBS1 E185Q polymorphism and cancer risk: a meta-analysis. BMC Cancer 9:124PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Cui Y, Morgenstern H, Greenland S et al (2006) Polymorphism of Xeroderma Pigmentosum group G and the risk of lung cancer and squamous cell carcinomas of the oropharynx, larynx and esophagus. Int J Cancer 118:714–720PubMedCrossRefGoogle Scholar
  18. 18.
    Hashibe M, Morgenstern H, Cui Y et al (2006) Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case–control study. Cancer Epidemiol Biomarkers Prev 15:1829–1834PubMedCrossRefGoogle Scholar
  19. 19.
    Sherry ST, Ward MH, Kholodov M et al (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29:308–311PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    De la Vega FM, Lazaruk KD, Rhodes MD, Wenz MH (2005) Assessment of two flexible and compatible SNP genotyping platforms: TaqMan SNP genotyping assays and the SNPlex genotyping system. Mutat Res 573:111–135PubMedCrossRefGoogle Scholar
  21. 21.
    Greene FL, Page DL, Fleming ID et al (eds) (2002) AJCC cancer staging manual, 6th edn. Springer, New YorkGoogle Scholar
  22. 22.
    Vaughan TL, Davis S, Kristal A, Thomas DB (1995) Obesity, alcohol, and tobacco as risk factors for cancers of the esophagus and gastric cardia: adenocarcinoma versus squamous cell carcinoma. Cancer Epidemiol Biomark Prev 4:85–92Google Scholar
  23. 23.
    Ye W, Held M, Lagergren J et al (2004) Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. J Natl Cancer Inst 96:388–396PubMedCrossRefGoogle Scholar
  24. 24.
    Lagergren J, Bergstrom R, Lindgren A, Nyren O (1999) Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 340:825–831PubMedCrossRefGoogle Scholar
  25. 25.
    Wakefield J (2007) A Bayesian measure of the probability of false discovery in genetic epidemiology studies. Am J Hum Genet 81:208–227PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Greenland S (2007) Bayesian perspectives for epidemiological research. II. Regression analysis. Int J Epidemiol 36:195–202PubMedCrossRefGoogle Scholar
  27. 27.
    Greenland S, Poole C (1994) Empirical-Bayes and semi-Bayes approaches to occupational and environmental hazard surveillance. Arch Environ Health 49:9–16PubMedCrossRefGoogle Scholar
  28. 28.
    Greenland S (1992) A semi-Bayes approach to the analysis of correlated multiple associations, with an application to an occupational cancer-mortality study. Stat Med 11:219–230PubMedCrossRefGoogle Scholar
  29. 29.
    Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N (2004) Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 96:434–442PubMedCrossRefGoogle Scholar
  30. 30.
    Oh SS, Chang SC, Cai L et al (2010) Single nucleotide polymorphisms of 8 inflammation-related genes and their associations with smoking-related cancers. Int J Cancer 127:2169–2182PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Liu Y, Shete S, Etzel CJ et al (2010) Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 genes involved in the double-strand break repair pathway predict glioblastoma survival. J Clin Oncol 28:2467–2474PubMedCrossRefGoogle Scholar
  32. 32.
    Landvik NE, Hart K, Skaug V et al (2009) A specific interleukin-1B haplotype correlates with high levels of IL1B mRNA in the lung and increased risk of non-small cell lung cancer. Carcinogenesis 30:1186–1192PubMedCrossRefGoogle Scholar
  33. 33.
    Greenland S (2008) Introduction to regression models. In: Rothman KJ, Greenland S, Lash TL (eds) Modern epidemiology, 3rd edn. Lippincott-Williams-Wilkins, Philadelphia, p 405Google Scholar
  34. 34.
    Greenland S, Christensen R (2001) Data augmentation priors for Bayesian and semi-Bayes analyses of conditional-logistic and proportional-hazards regression. Stat Med 20:2421–2428PubMedCrossRefGoogle Scholar
  35. 35.
    Arnson Y, Shoenfeld Y, Amital H (2010) Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun 34:J258–J265PubMedCrossRefGoogle Scholar
  36. 36.
    Feldman C, Anderson R (2013) Cigarette smoking and mechanisms of susceptibility to infections of the respiratory tract and other organ systems. J Infect 67:169–184PubMedCrossRefGoogle Scholar
  37. 37.
    Nichols L, Saunders R, Knollmann FD (2012) Causes of death of patients with lung cancer. Arch Pathol Lab Med 136:1552–1557PubMedCrossRefGoogle Scholar
  38. 38.
    Johnston-Early A, Cohen MH, Minna JD et al (1980) Smoking abstinence and small cell lung cancer survival. An association. JAMA 244:2175–2179PubMedCrossRefGoogle Scholar
  39. 39.
    Browman GP, Wong G, Hodson I et al (1993) Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 328:159–163PubMedCrossRefGoogle Scholar
  40. 40.
    Browman GP, Mohide EA, Willan A et al (2002) Association between smoking during radiotherapy and prognosis in head and neck cancer: a follow-up study. Head Neck 24:1031–1037PubMedCrossRefGoogle Scholar
  41. 41.
    Pytynia KB, Grant JR, Etzel CJ et al (2004) Matched-pair analysis of survival of never smokers and ever smokers with squamous cell carcinoma of the head and neck. J Clin Oncol 22:3981–3988PubMedCrossRefGoogle Scholar
  42. 42.
    Oliveira LR, Ribeiro-Silva A, Costa JP et al (2008) Prognostic factors and survival analysis in a sample of oral squamous cell carcinoma patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 106:685–695PubMedCrossRefGoogle Scholar
  43. 43.
    Kobayashi J, Antoccia A, Tauchi H, Matsuura S, Komatsu K (2004) NBS1 and its functional role in the DNA damage response. DNA Repair (Amst) 3:855–861CrossRefGoogle Scholar
  44. 44.
    Williams RS, Williams JS, Tainer JA (2007) Mre11-Rad50-Nbs1 is a keystone complex connecting DNA repair machinery, double-strand break signaling, and the chromatin template. Biochem Cell Biol 85:509–520PubMedCrossRefGoogle Scholar
  45. 45.
    Lee JH, Paull TT (2007) Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene 26:7741–7748PubMedCrossRefGoogle Scholar
  46. 46.
    Lavin MF (2007) ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks. Oncogene 26:7749–7758PubMedCrossRefGoogle Scholar
  47. 47.
    Hebbring SJ, Fredriksson H, White KA et al (2006) Role of the Nijmegen breakage syndrome 1 gene in familial and sporadic prostate cancer. Cancer Epidemiol Biomarkers Prev 15:935–938PubMedCrossRefGoogle Scholar
  48. 48.
    Millikan RC, Player JS, Decotret AR, Tse CK, Keku T (2005) Polymorphisms in DNA repair genes, medical exposure to ionizing radiation, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 14:2326–2334PubMedCrossRefGoogle Scholar
  49. 49.
    Kuschel B, Auranen A, McBride S et al (2002) Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol Genet 11:1399–1407PubMedCrossRefGoogle Scholar
  50. 50.
    Hsu HM, Wang HC, Chen ST et al (2007) Breast cancer risk is associated with the genes encoding the DNA double-strand break repair Mre11/Rad50/Nbs1 complex. Cancer Epidemiol Biomarkers Prev 16:2024–2032PubMedCrossRefGoogle Scholar
  51. 51.
    Sanyal S, Festa F, Sakano S et al (2004) Polymorphisms in DNA repair and metabolic genes in bladder cancer. Carcinogenesis 25:729–734PubMedCrossRefGoogle Scholar
  52. 52.
    Figueroa JD, Malats N, Rothman N et al (2007) Evaluation of genetic variation in the double-strand break repair pathway and bladder cancer risk. Carcinogenesis 28:1788–1793PubMedCrossRefGoogle Scholar
  53. 53.
    Jiang L, Liang J, Jiang M et al (2011) Functional polymorphisms in the NBS1 gene and acute lymphoblastic leukemia susceptibility in a Chinese population. Eur J Haematol 86:199–205PubMedCrossRefGoogle Scholar
  54. 54.
    Huang MD, Chen XF, Xu G et al (2012) Genetic variation in the NBS1 gene is associated with hepatic cancer risk in a Chinese population. DNA Cell Biol 31:678–682PubMedCrossRefGoogle Scholar
  55. 55.
    Xu JL, Hu LM, Huang MD et al (2012) Genetic variants of NBS1 predict clinical outcome of platinum-based chemotherapy in advanced non-small cell lung cancer in Chinese. Asian Pac J Cancer Prev 13:851–856PubMedCrossRefGoogle Scholar
  56. 56.
    Hsu DS, Chang SY, Liu CJ et al (2010) Identification of increased NBS1 expression as a prognostic marker of squamous cell carcinoma of the oral cavity. Cancer Sci 101:1029–1037PubMedCrossRefGoogle Scholar
  57. 57.
    Greenland S (2006) Bayesian perspectives for epidemiological research: I. Foundations and basic methods. Int J Epidemiol 35:765–775PubMedCrossRefGoogle Scholar
  58. 58.
    Tsao AS, Liu D, Lee JJ, Spitz M, Hong WK (2006) Smoking affects treatment outcome in patients with advanced nonsmall cell lung cancer. Cancer 106:2428–2436PubMedCrossRefGoogle Scholar
  59. 59.
    Sun Z, Aubry MC, Deschamps C et al (2006) 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. J Thorac Cardiovasc Surg 131:1014–1020PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Tingting Yang
    • 1
    • 2
  • Po-Yin Chang
    • 2
  • Sungshim Lani Park
    • 3
  • Delara Bastani
    • 2
  • Shen-Chih Chang
    • 2
  • Hal Morgenstern
    • 4
  • Donald P. Tashkin
    • 5
  • Jenny T. Mao
    • 6
  • Jeanette C. Papp
    • 7
  • Jian-Yu Rao
    • 8
  • Wendy Cozen
    • 9
  • Thomas M. Mack
    • 9
  • Sander Greenland
    • 2
    • 10
  • Zuo-Feng Zhang
    • 2
    • 11
  1. 1.Zhejiang Provincial CDCHangzhouPeople’s Republic of China
  2. 2.Department of Epidemiology, Fielding School of Public HealthUniversity of California, Los Angeles (UCLA)Los AngelesUSA
  3. 3.Epidemiology ProgramUniversity of Hawaii Cancer CenterHonoluluUSA
  4. 4.Departments of Epidemiology, Environmental Health Sciences, and Urology, Schools of Public Health and Medicine, and Comprehensive Cancer CenterUniversity of MichiganAnn ArborUSA
  5. 5.Division of Pulmonary and Critical Care MedicineUCLA David Geffen School of MedicineLos AngelesUSA
  6. 6.Pulmonary and Critical Care SectionNew Mexico VA Healthcare SystemAlbuquerqueUSA
  7. 7.Department of Human GeneticsUCLALos AngelesUSA
  8. 8.Department of PathologyUCLA David Geffen School of MedicineLos AngelesUSA
  9. 9.Departments of Preventive Medicine and PathologyKeck School of Medicine at University of Southern CaliforniaLos AngelesUSA
  10. 10.Department of StatisticsUCLALos AngelesUSA
  11. 11.Jonsson Comprehensive Cancer CenterUCLALos AngelesUSA

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