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Polymorphisms of p16, p27, p73, and MDM2 Modulate Response and Survival of Pancreatic Cancer Patients Treated with Preoperative Chemoradiation

  • Gastrointestinal Oncology
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Abstract

Genetic polymorphisms play an important role in clinical response to cytotoxic therapies. We hypothesized that polymorphisms in cell cycle genes may modulate response to preoperative chemoradiation and survival of pancreatic cancer patients. We evaluated 12 single-nucleotide polymorphisms (SNPs) of ten cell cycle genes in 88 patients with resectable adenocarcinoma of the pancreatic head who were treated with neoadjuvant concurrent gemcitabine and radiotherapy. Response was assessed by computerized tomography obtained before and 4–6 weeks after preoperative treatment. Time to tumor progression and survival after treatment were measured. Patients underwent pancreaticoduodenectomy (PD) if no disease progression was found at restaging after preoperative therapy. MDM2 T309G and p16 C580T genotype distributions were significantly different in the patients who underwent PD and those who did not (P = 0.025 for MDM2; P = 0.016 for p16). The MDM2 and p27 genotypes had a significant effect on survival times after treatment (log-rank test, P = 0.010 and P = 0.050, respectively). A strong joint effect of these two genes was observed (log-rank test, P = 0.010). The p73 and p16 polymorphic genotypes were significantly associated with shorter time to tumor progression (log-rank test, P = 0.021 and P = 0.039, respectively). A gene-dosage effect on time to tumor progression was observed for polymorphisms in the p73, p16, and MDM2 genes. The hazard ratios for patients with one, two, or three adverse genotypes were 2.13 (1.04–4.36), 3.18 (1.37–7.39), and 10.09 (3.17–32.05), respectively. These findings suggest these polymorphisms in the cell cycle genes are promising prognostic markers for patients with pancreatic cancer.

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References

  1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43–66.

    Article  PubMed  Google Scholar 

  2. Bardeesy N, DePinho RA. Pancreatic cancer biology and genetics. Nat Rev Cancer. 2002;2:897–909.

    Article  PubMed  CAS  Google Scholar 

  3. Galmarini CM, Mackey JR, Dumontet C. Nucleoside analogues: mechanisms of drug resistance and reversal strategies. Leukemia. 2001;15:875–90.

    Article  PubMed  CAS  Google Scholar 

  4. Ueno H, Kiyosawa K, Kaniwa N. Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy? Br J Cancer. 2007;97:145–51.

    Article  PubMed  CAS  Google Scholar 

  5. Li D, Li Y, Jiao L, et al. Effects of base excision repair gene polymorphisms on pancreatic cancer survival. Int J Cancer. 2007;120:1748–54.

    Article  PubMed  CAS  Google Scholar 

  6. Li D, Liu H, Jiao L, et al. Significant effect of homologous recombination DNA repair gene polymorphisms on pancreatic cancer survival. Cancer Res. 2006;66:3323–30.

    Article  PubMed  CAS  Google Scholar 

  7. Li D, Frazier M, Evans DB, Hess KR, Crane CH, Jiao L, et al. Single nucleotide polymorphisms of RecQ1, RAD54L, and ATM genes are associated with reduced survival of pancreatic cancer. J Clin Oncol. 2006;24:1720–8.

    Article  PubMed  CAS  Google Scholar 

  8. de las Penas R, Sanchez-Ronco M, Alberola V, et al. Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients. Ann Oncol. 2006;17:668–75.

    Article  Google Scholar 

  9. Bosken CH, Wei Q, Amos CI, Spitz MR. An analysis of DNA repair as a determinant of survival in patients with non-small-cell lung cancer. J Natl Cancer Inst. 2002;94:1091–9.

    PubMed  Google Scholar 

  10. Elledge SJ. Cell cycle checkpoints: preventing an identity crisis. Science. 1996;274:1664–72.

    Article  PubMed  CAS  Google Scholar 

  11. Momand J, Wu HH, Dasgupta G. MDM2–master regulator of the p53 tumor suppressor protein. Gene. 2000;242:15–29.

    Article  PubMed  CAS  Google Scholar 

  12. Chen J, Wu X, Lin J, Levine AJ. mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein. Mol Cell Biol. 1996;16:2445–52.

    PubMed  CAS  Google Scholar 

  13. Haupt Y, Barak Y, Oren M. Cell type-specific inhibition of p53-mediated apoptosis by mdm2. EMBO J. 1996;15:1596–606.

    PubMed  CAS  Google Scholar 

  14. Dong M, Ma G, Tu W, Guo KJ, Tian YL, Dong YT. Clinicopathological significance of p53 and mdm2 protein expression in human pancreatic cancer. World J Gastroenterol. 2005;11:2162–5.

    PubMed  CAS  Google Scholar 

  15. Bond GL, Hu W, Bond EE, et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119:591–602.

    Article  PubMed  CAS  Google Scholar 

  16. Li M, Zhang Z, Hill DL, Wang H, Zhang R. Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3 K/mTOR/ETS2 pathway. Cancer Res. 2007;67:1988–96.

    Article  PubMed  CAS  Google Scholar 

  17. Macaluso M, Montanari M, Cinti C, Giordano A. Modulation of cell cycle components by epigenetic and genetic events. Semin Oncol. 2005;32:452–7.

    Article  PubMed  CAS  Google Scholar 

  18. Zhang HS, Postigo AA, Dean DC. Active transcriptional repression by the Rb-E2F complex mediates G1 arrest triggered by p16INK4a, TGFbeta, and contact inhibition. Cell. 1999;97:53–61.

    Article  PubMed  CAS  Google Scholar 

  19. Whelan AJ, Bartsch D, Goodfellow PJ. Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med. 1995;333:975–7.

    Article  PubMed  CAS  Google Scholar 

  20. Sauroja I, Smeds J, Vlaykova T, et al. Analysis of G(1)/S checkpoint regulators in metastatic melanoma. Genes Chromosomes Cancer. 2000;28:404–14.

    Article  PubMed  CAS  Google Scholar 

  21. Ostruszka LJ, Shewach DS. The role of cell cycle progression in radiosensitization by 2′,2′-difluoro-2′-deoxycytidine. Cancer Res. 2000;60:6080–8.

    PubMed  CAS  Google Scholar 

  22. Kranz D, Dobbelstein M. Nongenotoxic p53 activation protects cells against S-phase-specific chemotherapy. Cancer Res. 2006;66:10274–80.

    Article  PubMed  CAS  Google Scholar 

  23. Kaghad M, Bonnet H, Yang A, et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell. 1997;90:809–19.

    Article  PubMed  CAS  Google Scholar 

  24. Stiewe T, Putzer BM. Role of p73 in malignancy: tumor suppressor or oncogene? Cell Death Differ. 2002;9:237–45.

    Article  PubMed  CAS  Google Scholar 

  25. Jost CA, Marin MC, Kaelin WG, Jr. p73 is a simian [correction of human] p53-related protein that can induce apoptosis. Nature. 1997;389:191–4.

    Article  PubMed  CAS  Google Scholar 

  26. Wang XQ, Ongkeko WM, Lau AW, Leung KM, Poon RY. A possible role of p73 on the modulation of p53 level through MDM2. Cancer Res. 2001;61:1598–603.

    PubMed  CAS  Google Scholar 

  27. Pfeifer D, Arbman G, Sun XF. Polymorphism of the p73 gene in relation to colorectal cancer risk and survival. Carcinogenesis. 2005;26:103–7.

    Article  PubMed  CAS  Google Scholar 

  28. Niwa Y, Hirose K, Matsuo K, et al. Association of p73 G4C14-to-A4T14 polymorphism at exon 2 and p53 Arg72Pro polymorphism with the risk of endometrial cancer in Japanese subjects. Cancer Lett. 2005;219:183–90.

    Article  PubMed  CAS  Google Scholar 

  29. Hu Z, Miao X, Ma H, et al. Dinucleotide polymorphism of p73 gene is associated with a reduced risk of lung cancer in a Chinese population. Int J Cancer. 2005;114:455–60.

    Article  PubMed  CAS  Google Scholar 

  30. Li G, Sturgis EM, Wang LE, et al. Association of a p73 exon 2 G4C14-to-A4T14 polymorphism with risk of squamous cell carcinoma of the head and neck. Carcinogenesis. 2004;25:1911–6.

    Article  PubMed  CAS  Google Scholar 

  31. Li G, Wang LE, Chamberlain RM, Amos CI, Spitz MR, Wei Q. p73 G4C14-to-A4T14 polymorphism and risk of lung cancer. Cancer Res. 2004;64:6863–6.

    Article  PubMed  CAS  Google Scholar 

  32. Niwa Y, Hamajima N, Atsuta Y, et al. Genetic polymorphisms of p73 G4C14-to-A4T14 at exon 2 and p53 Arg72Pro and the risk of cervical cancer in Japanese. Cancer Lett. 2004;205:55–60.

    Article  PubMed  CAS  Google Scholar 

  33. Hishida A, Matsuo K, Tajima K, et al. Polymorphisms of p53 Arg72Pro, p73 G4C14-to-A4T14 at exon 2 and p21 Ser31Arg and the risk of non-Hodgkin’s lymphoma in Japanese. Leuk Lymphoma. 2004;45:957–64.

    Article  PubMed  CAS  Google Scholar 

  34. Ryan BM, McManus R, Daly JS, Carton E, Keeling PW, Reynolds JV, et al. A common p73 polymorphism is associated with a reduced incidence of oesophageal carcinoma. Br J Cancer. 2001;85:1499–503.

    Article  PubMed  CAS  Google Scholar 

  35. Li H, Yao L, Ouyang T, et al. Association of p73 G4C14-to-A4T14 (GC/AT) polymorphism with breast cancer survival. Carcinogenesis. 2007;28:372–7.

    Article  PubMed  Google Scholar 

  36. Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ. The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature. 1998;396:177–80.

    Article  PubMed  CAS  Google Scholar 

  37. Coqueret O. New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol. 2003;13:65–70.

    Article  PubMed  CAS  Google Scholar 

  38. Tsihlias J, Kapusta L, Slingerland J. The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu Rev Med. 1999;50:401–23.

    Article  PubMed  CAS  Google Scholar 

  39. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501–12.

    Article  PubMed  CAS  Google Scholar 

  40. Li G, Sturgis EM, Wang LE, et al. Association between the V109G polymorphism of the p27 gene and the risk and progression of oral squamous cell carcinoma. Clin Cancer Res. 2004;10:3996–4002.

    Article  PubMed  CAS  Google Scholar 

  41. Kibel AS, Suarez BK, Belani J, et al. CDKN1A and CDKN1B polymorphisms and risk of advanced prostate carcinoma. Cancer Res. 2003;63:2033–6.

    PubMed  CAS  Google Scholar 

  42. Chang BL, Zheng SL, Isaacs SD, et al. A polymorphism in the CDKN1B gene is associated with increased risk of hereditary prostate cancer. Cancer Res. 2004;64:1997–9.

    Article  PubMed  CAS  Google Scholar 

  43. Figueiredo JC, Knight JA, Cho S, et al. Polymorphisms cMyc-N11S and p27-V109G and breast cancer risk and prognosis. BMC Cancer. 2007;7:99.

    Google Scholar 

  44. Ma H, Jin G, Hu Z, et al. Variant genotypes of CDKN1A and CDKN1B are associated with an increased risk of breast cancer in Chinese women. Int J Cancer. 2006;119:2173–8.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Haidee Chancoco for DNA extraction and Dr. Henry F. Gomez for data collection. This research was supported in part by National Cancer Institute grants P20 CA101936 and U01 CA111302; National Institutes of Health Cancer Center Support grant CA16672 (Frazier, ML); and the Janis Davis Gordon Memorial Postdoctoral Fellowship, Division of Cancer Prevention, U.T. M.D. Anderson Cancer Center (Chen, J).

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Authors and Affiliations

  1. Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, Unit 1365, 1155 Pressler Boulevard, Houston, TX, 77030, USA

    Jinyun Chen MD, Christopher I. Amos PhD & Marsha L. Frazier PhD

  2. Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Donghui Li PhD & James L. Abbruzzese MD

  3. Department of Cancer Genetics, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Ann M. Killary PhD

  4. Program in Human and Molecular Genetics, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA

    Ann M. Killary PhD, Subrata Sen PhD, Christopher I. Amos PhD & Marsha L. Frazier PhD

  5. Department of Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Subrata Sen PhD

  6. Departments of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Douglas B. Evans MD

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  1. Jinyun Chen MD
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Correspondence to Marsha L. Frazier PhD.

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Chen, J., Li, D., Killary, A.M. et al. Polymorphisms of p16, p27, p73, and MDM2 Modulate Response and Survival of Pancreatic Cancer Patients Treated with Preoperative Chemoradiation. Ann Surg Oncol 16, 431–439 (2009). https://doi.org/10.1245/s10434-008-0220-8

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