Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Nov 22;83(11):1443–1447. doi: 10.1054/bjoc.2000.1479

A polymorphism of the interleukin-1 β gene influences survival in pancreatic cancer

M D Barber 1, J J Powell 1, S F Lynch 1, K C H Fearon 1, J A Ross 1
PMCID: PMC2363418  PMID: 11076651

Abstract

Pro-inflammatory cytokines contribute to the cachexia associated with pancreatic cancer and stimulate the acute phase response which has been associated with shortened survival in such patients. Polymorphisms of cytokine genes may influence their production. The present study examined the effect of a polymorphism of the interleukin (IL)-1b gene upon the inflammatory state and survival in pancreatic cancer. Genomic DNA was obtained from 64 patients with pancreatic cancer and 101 healthy controls. Using the polymerase chain reaction and subsequent TaqI restriction enzyme digestion the subject's genotype for a diallelic polymorphism of the interleukin-1b gene was established. IL-1b production by peripheral blood mononuclear cells and serum C-reactive protein (CRP) levels from patients were also examined and survival noted. Patients homozygous for allele 2 of the IL-1b gene had significantly shorter survival than other groups (P = 0.0001). These patients also exhibited higher IL-1b production (P = 0.022). Possession of allele 2 was also associated with significantly shorter survival (median 144 vs 256 days, P = 0.034) and significantly higher CRP level (P = 0.0003). The possession of a genotype resulting in increased IL-1b production was associated with shortened survival and increased serum CRP level. This may reflect the role of IL-1b in inducing an acute phase protein response and cachexia in cancer or may be related to changes in tumour phenotye. © 2000 Cancer Research Campaign http://www.bjcancer.com

Keywords: pancreatic cancer, interleukin-1β, genetic polymorphisms, prognostic factors, C-reactive protein

Full Text

The Full Text of this article is available as a PDF (238.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahlgren J. D. Epidemiology and risk factors in pancreatic cancer. Semin Oncol. 1996 Apr;23(2):241–250. [PubMed] [Google Scholar]
  2. Barber M. D., Powell J. J., Lynch S. F., Gough N. J., Fearon K. C., Ross J. A. Two polymorphisms of the tumour necrosis factor gene do not influence survival in pancreatic cancer. Clin Exp Immunol. 1999 Sep;117(3):425–429. doi: 10.1046/j.1365-2249.1999.01005.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bioque G., Crusius J. B., Koutroubakis I., Bouma G., Kostense P. J., Meuwissen S. G., Peña A. S. Allelic polymorphism in IL-1 beta and IL-1 receptor antagonist (IL-1Ra) genes in inflammatory bowel disease. Clin Exp Immunol. 1995 Nov;102(2):379–383. doi: 10.1111/j.1365-2249.1995.tb03793.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Castell J. V., Gómez-Lechón M. J., David M., Fabra R., Trullenque R., Heinrich P. C. Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6. Hepatology. 1990 Nov;12(5):1179–1186. doi: 10.1002/hep.1840120517. [DOI] [PubMed] [Google Scholar]
  5. Clark B. D., Collins K. L., Gandy M. S., Webb A. C., Auron P. E. Genomic sequence for human prointerleukin 1 beta: possible evolution from a reverse transcribed prointerleukin 1 alpha gene. Nucleic Acids Res. 1986 Oct 24;14(20):7897–7914. doi: 10.1093/nar/14.20.7897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Falconer J. S., Fearon K. C., Plester C. E., Ross J. A., Carter D. C. Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer. Ann Surg. 1994 Apr;219(4):325–331. doi: 10.1097/00000658-199404000-00001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Falconer J. S., Fearon K. C., Ross J. A., Elton R., Wigmore S. J., Garden O. J., Carter D. C. Acute-phase protein response and survival duration of patients with pancreatic cancer. Cancer. 1995 Apr 15;75(8):2077–2082. doi: 10.1002/1097-0142(19950415)75:8<2077::aid-cncr2820750808>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  8. Gelin J., Moldawer L. L., Lönnroth C., Sherry B., Chizzonite R., Lundholm K. Role of endogenous tumor necrosis factor alpha and interleukin 1 for experimental tumor growth and the development of cancer cachexia. Cancer Res. 1991 Jan 1;51(1):415–421. [PubMed] [Google Scholar]
  9. Gershenwald J. E., Fong Y. M., Fahey T. J., 3rd, Calvano S. E., Chizzonite R., Kilian P. L., Lowry S. F., Moldawer L. L. Interleukin 1 receptor blockade attenuates the host inflammatory response. Proc Natl Acad Sci U S A. 1990 Jul;87(13):4966–4970. doi: 10.1073/pnas.87.13.4966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hellerstein M. K., Meydani S. N., Meydani M., Wu K., Dinarello C. A. Interleukin-1-induced anorexia in the rat. Influence of prostaglandins. J Clin Invest. 1989 Jul;84(1):228–235. doi: 10.1172/JCI114145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Heresbach D., Alizadeh M., Dabadie A., Le Berre N., Colombel J. F., Yaouanq J., Bretagne J. F., Semana G. Significance of interleukin-1beta and interleukin-1 receptor antagonist genetic polymorphism in inflammatory bowel diseases. Am J Gastroenterol. 1997 Jul;92(7):1164–1169. [PubMed] [Google Scholar]
  12. Mahony S. M., Tisdale M. J. Induction of weight loss and metabolic alterations by human recombinant tumour necrosis factor. Br J Cancer. 1988 Sep;58(3):345–349. doi: 10.1038/bjc.1988.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Matthys P., Dijkmans R., Proost P., Van Damme J., Heremans H., Sobis H., Billiau A. Severe cachexia in mice inoculated with interferon-gamma-producing tumor cells. Int J Cancer. 1991 Aug 19;49(1):77–82. doi: 10.1002/ijc.2910490115. [DOI] [PubMed] [Google Scholar]
  14. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Moldawer L. L., Andersson C., Gelin J., Lundholm K. G. Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. Am J Physiol. 1988 Mar;254(3 Pt 1):G450–G456. doi: 10.1152/ajpgi.1988.254.3.G450. [DOI] [PubMed] [Google Scholar]
  16. Moldawer L. L., Copeland E. M., 3rd Proinflammatory cytokines, nutritional support, and the cachexia syndrome: interactions and therapeutic options. Cancer. 1997 May 1;79(9):1828–1839. [PubMed] [Google Scholar]
  17. Pociot F., Mølvig J., Wogensen L., Worsaae H., Nerup J. A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest. 1992 Jun;22(6):396–402. doi: 10.1111/j.1365-2362.1992.tb01480.x. [DOI] [PubMed] [Google Scholar]
  18. Reeds P. J., Fjeld C. R., Jahoor F. Do the differences between the amino acid compositions of acute-phase and muscle proteins have a bearing on nitrogen loss in traumatic states? J Nutr. 1994 Jun;124(6):906–910. doi: 10.1093/jn/124.6.906. [DOI] [PubMed] [Google Scholar]
  19. Rosewicz S., Wiedenmann B. Pancreatic carcinoma. Lancet. 1997 Feb 15;349(9050):485–489. doi: 10.1016/s0140-6736(96)05523-7. [DOI] [PubMed] [Google Scholar]
  20. Strassmann G., Fong M., Kenney J. S., Jacob C. O. Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest. 1992 May;89(5):1681–1684. doi: 10.1172/JCI115767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Stüber F., Petersen M., Bokelmann F., Schade U. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med. 1996 Mar;24(3):381–384. doi: 10.1097/00003246-199603000-00004. [DOI] [PubMed] [Google Scholar]
  22. Vidal-Vanaclocha F., Alvarez A., Asumendi A., Urcelay B., Tonino P., Dinarello C. A. Interleukin 1 (IL-1)-dependent melanoma hepatic metastasis in vivo; increased endothelial adherence by IL-1-induced mannose receptors and growth factor production in vitro. J Natl Cancer Inst. 1996 Feb 21;88(3-4):198–205. doi: 10.1093/jnci/88.3-4.198. [DOI] [PubMed] [Google Scholar]
  23. Vidal-Vanaclocha F., Amézaga C., Asumendi A., Kaplanski G., Dinarello C. A. Interleukin-1 receptor blockade reduces the number and size of murine B16 melanoma hepatic metastases. Cancer Res. 1994 May 15;54(10):2667–2672. [PubMed] [Google Scholar]
  24. Wigmore S. J., Plester C. E., Ross J. A., Fearon K. C. Contribution of anorexia and hypermetabolism to weight loss in anicteric patients with pancreatic cancer. Br J Surg. 1997 Feb;84(2):196–197. [PubMed] [Google Scholar]
  25. Yasumoto K., Mukaida N., Harada A., Kuno K., Akiyama M., Nakashima E., Fujioka N., Mai M., Kasahara T., Fujimoto-Ouchi K. Molecular analysis of the cytokine network involved in cachexia in colon 26 adenocarcinoma-bearing mice. Cancer Res. 1995 Feb 15;55(4):921–927. [PubMed] [Google Scholar]
  26. van den Bosch R. P., van der Schelling G. P., Klinkenbijl J. H., Mulder P. G., van Blankenstein M., Jeekel J. Guidelines for the application of surgery and endoprostheses in the palliation of obstructive jaundice in advanced cancer of the pancreas. Ann Surg. 1994 Jan;219(1):18–24. doi: 10.1097/00000658-199401000-00004. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES