Skip to main content

Advertisement

SpringerLink
Log in

Polymorphisms in Apoptosis-Related Genes and Survival of Patients with Early-Stage Non-Small-Cell Lung Cancer

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Purpose

This study was conducted to determine the association between single-nucleotide polymorphisms (SNPs) in apoptosis-related genes and survival outcomes of patients with early-stage non-small-cell lung cancer (NSCLC).

Methods

Three hundred ten consecutive patients with surgically resected NSCLC were enrolled. Twenty-five SNPs in 17 apoptosis-related genes were genotyped by a sequenome mass spectrometry-based genotyping assay. The genotype associations with overall survival (OS) and disease-free survival (DFS) were analyzed.

Results

Three SNPs (TNFRSF10B rs1047266, TNFRSF1A rs4149570, and PPP1R13L rs1005165) were significantly associated with survival outcomes on multivariate analysis. When the three SNPs were combined, OS and DFS were decreased as the number of bad genotypes increased (P trend for OS and DFS = 7 × 10−5 and 1 × 10−4, respectively). Patients with one bad genotype, and patients with two or three bad genotypes had significantly worse OS and DFS compared with those with no bad genotypes [adjusted hazard ratio (aHR) for OS = 2.27, 95% confidence interval (CI) = 1.22–4.21, P = 0.01, aHR for DFS = 1.74, 95% CI = 1.08–2.81, P = 0.02; aHR for OS = 4.11, 95% CI = 2.03–8.29, P = 8 × 10−5; and aHR for DFS = 2.89, 95% CI = 1.64–5.11, P = 3 × 10−4, respectively].

Conclusion

Three SNPs in apoptosis-related genes were identified as possible prognostic markers of survival in patients with early-stage NSCLC. The SNPs, and particularly their combined genotypes, can be used to identify patients at high risk for poor disease outcome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

    Article  PubMed  Google Scholar 

  2. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350:351–60.

    Article  PubMed  Google Scholar 

  3. Coate LE, John T, Tsao MS, Shepherd FA. Molecular predictive and prognostic markers in non-small cell lung cancer. Lancet Oncol. 2009;10:1001–10.

    Article  CAS  PubMed  Google Scholar 

  4. Raff M. Cell suicide for beginners. Nature. 1998;396:119–22.

    Article  CAS  PubMed  Google Scholar 

  5. Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis. 2000;21:485–95.

    Article  CAS  PubMed  Google Scholar 

  6. Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature. 2001;411:342–8.

    Article  CAS  PubMed  Google Scholar 

  7. Shivapurkar N, Reddy J, Chaudhary PM, Gazdar AF. Apoptosis and lung cancer: a review. J Cell Biochem. 2003;88:885–98.

    Article  CAS  PubMed  Google Scholar 

  8. Schmitz A, Bayer J, Dechamps N, Thomas G. Intrinsci susceptibility to radiation-induced apoptosis of human lymphocyte subpopulations. Int J Radat Oncol Biol Phys. 2003;57:769–78.

    Article  Google Scholar 

  9. Camplejohn RS, Hodgson S, Carter N, Kato BS, Spector TD. Heretability of DNA-damage-induced apoptosis and its relationship with age in lymphocytes from female twins. Br J Cancer. 2006;95:520–4.

    Article  CAS  PubMed  Google Scholar 

  10. Chen B, Liu S, Wang XL, Xu W, Li Y, Zhao WH, et al. TRAIL-R1 polymorphisms and cancer susceptibility: an evidence-based meta-analysis. Eur J Cancer. 2009;45:2598–2605.

    Article  CAS  PubMed  Google Scholar 

  11. Jang JS, Kim KM, Kang KH et al. Polymorphisms in the survivin gene and the risk of lung cancer. Lung Cancer. 2008;60:31–9.

    Article  PubMed  Google Scholar 

  12. Li Y, Qiu LX, Shen XK, Lv XJ, Qian XP, Song Y. A meta-analysis of TP53 codon 72 polymorphism and lung cancer risk: evidence from 15,857 subjects. Lung Cancer. 2009;66:15–21.

    Article  PubMed  Google Scholar 

  13. Gupta R, Sharma SC, Das SN. Association of TNF-alpha and TNFR1 promoters and 3’ UTR region of TNFR2 gene polymorphisms with genetic susceptibility to tobacco-related oral carcinoma in Asian Indians. Oral Oncol. 2008;44:455–63.

    Article  CAS  PubMed  Google Scholar 

  14. Yuan HY, Chiou JJ, Tseng WH et al. FASTSNP: an always up-to-date and extended service for SNP function analysis and prioritization. Nucleic Acids Res. 2006;34:W635–41.

    Article  CAS  PubMed  Google Scholar 

  15. Stephens M, Donnelly P. A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003;73:1162–9.

    Article  CAS  PubMed  Google Scholar 

  16. Gabriel SB, Schaffner SF, Nguyen H et al. The structure of haplotype blocks in the human genome. Science. 2002;296:2225–9.

    Article  CAS  PubMed  Google Scholar 

  17. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001;104:487–501.

    Article  CAS  PubMed  Google Scholar 

  18. Aggarwal BB. Signaling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 2003;3:745–56.

    Article  CAS  PubMed  Google Scholar 

  19. Han JY, Hong EK, Choi BG, et al. Death receptor 5 and Bcl-2 protein expression as predictors of tumor response to gemcitabine and cisplatin in patients with advanced non-small cell lung cancer. Med Oncol. 2003;20:355–62.

    Article  CAS  PubMed  Google Scholar 

  20. Jin H, Yang R, Fong S, et al. Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand cooperates with chemotherapy to inhibit orthotopic lung growth and improve survival. Cancer Res. 2004;64:4900–5.

    Article  CAS  PubMed  Google Scholar 

  21. Leithner K, Stacher E, Wurm R, et al. Nuclear and cytoplasmic death receptor 5 as prognostic factors in patients with non-small cell lung cancer treated with chemotherapy. Lung Cancer. 2009;65:98–104.

    Article  PubMed  Google Scholar 

  22. Zhuang L, Lee CS, Scolyer RA, et al. Progression of melanoma is associated with decreased expression of death receptors for tumor necrosis factor-related apoptosis-inducing ligand. Hum Pathol. 2006;37:1286–94.

    Article  CAS  PubMed  Google Scholar 

  23. Camidge DR. The potential of death receptor 4- and 5-directed therapies in the treatment of lung cancer. Clin Lung Cancer. 2007;8:413–9.

    Article  CAS  PubMed  Google Scholar 

  24. Jin H, Yang R, Ross J, et al. Cooperation of the agonistic DR5 antibody apomab with chemotherapy to inhibit orthotopic lung tumor growth and improve survival. Clin Cancer Res. 2008;14:7733–40.

    Article  CAS  PubMed  Google Scholar 

  25. Ashkenazi A, Holland P, Eckhardt SG. Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). J Clin Oncol. 2008;26:3621–30.

    Article  CAS  PubMed  Google Scholar 

  26. Hymowitz SG, Christinger HW, Fuh G, et al. Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol Cell. 1999;4:563–71.

    Article  CAS  PubMed  Google Scholar 

  27. Balkwill F. Tumor necrosis factor or tumor promoting factor? Cytokine Growth Factor Rev. 2002;13:135–41.

    Article  CAS  PubMed  Google Scholar 

  28. Mocellin S, Rossi CR, Pilati P, Nitti D. Tumor necrosis factor, cancer and anticancer therapy. Cytokine Growth Factor Rev. 2005;16:35–53.

    Article  CAS  PubMed  Google Scholar 

  29. Kim S, Moon SM, Kim YS, et al. TNFR1 promoter -329G/T polymorphism results in allele specific repression in TNFR1 expression. Biochem Biophys Res Commun. 2008;368–401.

  30. Yang JP, Hori M, Sande T, Okamoto T. Identification of a novel inhibitor of nuclear factor-кB, RelA-associated inhibitor. J Biol Chem. 1999;18:6938–47.

    Google Scholar 

  31. Bergamaschi D, Samuels Y, O’Neil NJ, et al. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat Genet. 2003;33:162–7.

    Article  CAS  PubMed  Google Scholar 

  32. Grabe N. Alibaba2: context specific identification of transcription factor binding sites. In Silico Biol. 2002;2:S1–S15.

    PubMed  Google Scholar 

  33. Vogel U, Laros I, Jacobsen NR et al. Two regions in chromosome 19q13.2-3 are associated with risk of lung cancer. Mut Res. 2004;546:65–74.

    CAS  Google Scholar 

  34. Neumann AS, Sturgis EM, Wei Q. Nucleotide excision repair as a marker for susceptibility to tobacco-related cancers: a review of molecular epidemiological studies. Mol Carcinog. 2005;42:65–92.

    Article  CAS  PubMed  Google Scholar 

  35. Takenaka T, Yano T, Kiyohara C, et al. Effects of excision repair cross-complementation group 1 (ERCC1) single nucleotide polymorphisms on the prognosis of non-small cell lung cancer patients. Lung Cancer. 2009 (in press).

  36. Chanock SJ, Manolio T, Boehnke M, et al. Replicating genotype-phenotype associations. Nature. 2007;447:655–60.

    Article  CAS  PubMed  Google Scholar 

  37. Taylor JMG, Ankerst DP, Andridge RR. Validation of biomark-based prediction models. Clin Cancer Res. 2008;14:5977–83.

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

This study was supported by the National R&D Program for Cancer Control Ministry of Health & Welfare (0720550-2) and the Regional Technology Innovation Program of the Ministry of Commerce, Industry and Energy (RTI04-01-01) of Republic of Korea.

Disclosures

The authors indicated no commercial interest.

Author information

Authors and Affiliations

  1. Department of Thoracic Surgery, Kyungpook National University Hospital, Daegu, Korea

    Eung Bae Lee MD & Sukki Cho MD

  2. Cancer Research Center, Kyungpook National University Hospital, Daegu, Korea

    Hyo-Sung Jeon PhD & Jae Yong Park MD

  3. Department of Internal Medicine, Kyungpook National University Hospital, Daegu, 700-412, Korea

    Seung Soo Yoo MD, Sung-Ick Cha MD, Young Mo Kang MD, Chang Ho Kim MD, Tae Hoon Jung MD & Jae Yong Park MD

  4. Department of Biochemistry and Cell Biology, Kyungpook National University Hospital, Daegu, Korea

    Yi Young Choi MS, Hyo-Gyoung Kang MS, Jin Eun Choi PhD, Byung-Heon Lee MD, Rang-Woon Park MD, In-San Kim MD & Jae Yong Park MD

  5. Department of Pathology, Kyungpook National University Hospital, Daegu, Korea

    Tae-In Park MD

  6. Department of Thoracic and Cardiovascular Surgery, Seoul National University School of Medicine, Seoul, Korea

    Sanghoon Jheon MD

Authors
  1. Eung Bae Lee MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyo-Sung Jeon PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seung Soo Yoo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi Young Choi MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hyo-Gyoung Kang MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sukki Cho MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sung-Ick Cha MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jin Eun Choi PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tae-In Park MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Byung-Heon Lee MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Rang-Woon Park MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. In-San Kim MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Young Mo Kang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Chang Ho Kim MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Sanghoon Jheon MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Tae Hoon Jung MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jae Yong Park MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jae Yong Park MD.

Additional information

Eung Bae Lee, Hyo-Sung Jeon have contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, E.B., Jeon, HS., Yoo, S.S. et al. Polymorphisms in Apoptosis-Related Genes and Survival of Patients with Early-Stage Non-Small-Cell Lung Cancer. Ann Surg Oncol 17, 2608–2618 (2010). https://doi.org/10.1245/s10434-010-1082-4

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-010-1082-4

Keywords

Search

Navigation