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Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 2/2010

Open Access 01-02-2010 | Original Article

Polymorphisms in the CD28/CTLA4/ICOS genes: role in malignant melanoma susceptibility and prognosis?

Authors: Marna G. Bouwhuis, Andreas Gast, Adina Figl, Alexander M. M. Eggermont, Kari Hemminki, Dirk Schadendorf, Rajiv Kumar

Published in: Cancer Immunology, Immunotherapy | Issue 2/2010

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Abstract

The appearance of vitiligo and spontaneous regression of the primary lesion in melanoma patients illustrate a relationship between tumor immunity and autoimmunity. T lymphocytes play a major role both in tumor immunity and autoimmunity. CD28, Cytotoxic T lymphocyte antigen 4 (CTLA4) and inducible costimulator (ICOS) molecules are important secondary signal molecules in the T lymphocyte activation. Single nucleotide polymorphisms (SNPs) in the CD28/CTLA4/ICOS gene region were reported to be associated with several autoimmune diseases including, type-1 diabetes, SLE, autoimmune thyroid diseases and celiac disease. In this study, we investigated the association of SNPs in the CD28, CTLA4 and ICOS genes with the risk of melanoma. We also assessed the prognostic effect of the different polymorphisms in melanoma patients. Twenty-four tagging SNPs across the three genes and four additional SNPs were genotyped in a cohort of 763 German melanoma patients and 734 healthy German controls. Influence on prognosis was determined in 587 melanoma cases belonging to stage I or II of the disease. In general, no differences in genotype or allele frequencies were detected between melanoma patients and controls. However, the variant alleles for two polymorphisms in the CD28 gene were differentially distributed in cases and controls. Similarly no association of any polymorphism with prognosis, except for the rs3181098 polymorphism in the CD28 gene, was observed. In addition, individuals with AA genotype for rs11571323 polymorphism in the ICOS gene showed reduced overall survival. However, keeping in view the correction for multiple hypothesis testing our results suggest that the polymorphisms in the CD28, CTLA4 and ICOS genes at least do not modulate risk of melanoma and nor do those influence the disease prognosis in the investigated population.

Literature
  1. Uchi H, Stan R, Turk MJ, Engelhorn ME, Rizzuto GA, Goldberg SM, Wolchok JD, Houghton AN (2006) Unraveling the complex relationship between cancer immunity and autoimmunity: lessons from melanoma and vitiligo. Adv Immunol 90:215–241View ArticlePubMed
  2. Atkins MB, Mier JW, Parkinson DR, Gould JA, Berkman EM, Kaplan MM (1988) Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. N Engl J Med 318:1557–1563PubMed
  3. Phan GQ, Attia P, Steinberg SM, White DE, Rosenberg SA (2001) Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 19:3477–3482PubMed
  4. Gogas H, Ioannovich J, Dafni U, Stavropoulou-Giokas C, Frangia K, Tsoutsos D, Panagiotou P, Polyzos A, Papadopoulos O, Stratigos A et al (2006) Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354:709–718View ArticlePubMed
  5. Bouwhuis MG, Suciu S, Collette S, Aamdal S, Kruit WH, Bastholt L, Stierner U, Sales F, Patel P, Punt CJ et al (2009) Autoimmune antibodies and recurrence-free interval in melanoma patients treated with adjuvant interferon. J Natl Cancer Inst 101:869–877View ArticlePubMed
  6. Teft WA, Kirchhof MG, Madrenas J (2006) A molecular perspective of CTLA-4 function. Annu Rev Immunol 24:65–97View ArticlePubMed
  7. Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family revisited. Annu Rev Immunol 23:515–548View ArticlePubMed
  8. Appleman LJ, Berezovskaya A, Grass I, Boussiotis VA (2000) CD28 costimulation mediates T cell expansion via IL-2-independent and IL-2-dependent regulation of cell cycle progression. J Immunol 164:144–151PubMed
  9. Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KM, Smith AN, Di Genova G et al (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511View ArticlePubMed
  10. Amundsen SS, Naluai AT, Ascher H, Ek J, Gudjonsdottir AH, Wahlstrom J, Lie BA, Sollid LM (2004) Genetic analysis of the CD28/CTLA4/ICOS (CELIAC3) region in coeliac disease. Tissue Antigens 64:593–599View ArticlePubMed
  11. Cozar JM, Romero JM, Aptsiauri N, Vazquez F, Vilchez JR, Tallada M, Garrido F, Ruiz-Cabello F (2007) High incidence of CTLA-4 AA (CT60) polymorphism in renal cell cancer. Hum Immunol 68:698–704View ArticlePubMed
  12. Erfani N, Razmkhah M, Talei AR, Pezeshki AM, Doroudchi M, Monabati A, Ghaderi A (2006) Cytotoxic T lymphocyte antigen-4 promoter variants in breast cancer. Cancer Genet Cytogenet 165:114–120View ArticlePubMed
  13. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr, Kirkwood JM et al (2001) Final version of the American Joint Committee on cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635–3648PubMed
  14. Ramirez-Montagut T, Turk MJ, Wolchok JD, Guevara-Patino JA, Houghton AN (2003) Immunity to melanoma: unraveling the relation of tumor immunity and autoimmunity. Oncogene 22:3180–3187View ArticlePubMed
  15. Gogas H, Metaxas Y, Dafni U, Polyzos A, Fountzilas G, Pectasides E, Skarlos D, Tsoutsos D, Panagiotou P, Spyropoulou-Vlachou M et al (2008) Evaluation of CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon. J Clin Oncol 26: Suppl; abstr 9054
  16. Sun T, Zhou Y, Yang M, Hu Z, Tan W, Han X, Shi Y, Yao J, Guo Y, Yu D et al (2008) Functional genetic variations in cytotoxic T-lymphocyte antigen 4 and susceptibility to multiple types of cancer. Cancer Res 68:7025–7034View ArticlePubMed
  17. Magistrelli G, Jeannin P, Herbault N, Benoit De Coignac A, Gauchat JF, Bonnefoy JY, Delneste Y (1999) A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells. Eur J Immunol 29:3596–3602View ArticlePubMed
  18. Anjos S, Nguyen A, Ounissi-Benkalha H, Tessier MC, Polychronakos C (2002) A common autoimmunity predisposing signal peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele. J Biol Chem 277:46478–46486View ArticlePubMed
  19. Piras G, Monne M, Uras A, Palmas A, Murineddu M, Arru L, Bianchi A, Calvisi A, Curreli L, Gaviano E et al (2005) Genetic analysis of the 2q33 region containing CD28-CTLA4-ICOS genes: association with non-Hodgkin’s lymphoma. Br J Haematol 129:784–790View ArticlePubMed
  20. Cheng TY, Lin JT, Chen LT, Shun CT, Wang HP, Lin MT, Wang TE, Cheng AL, Wu MS (2006) Association of T-cell regulatory gene polymorphisms with susceptibility to gastric mucosa-associated lymphoid tissue lymphoma. J Clin Oncol 24:3483–3489View ArticlePubMed
  21. Wang XB, Zhao X, Giscombe R, Lefvert AK (2002) A CTLA-4 gene polymorphism at position −318 in the promoter region affects the expression of protein. Genes Immun 3:233–234View ArticlePubMed
  22. Suwalska K, Pawlak E, Karabon L, Tomkiewicz A, Dobosz T, Urbaniak-Kujda D, Kuliczkowski K, Wolowiec D, Jedynak A, Frydecka I (2008) Association studies of CTLA-4, CD28, and ICOS gene polymorphisms with B-cell chronic lymphocytic leukemia in the Polish population. Hum Immunol 69:193–201View ArticlePubMed
  23. Dilmec F, Ozgonul A, Uzunkoy A, Akkafa F (2008) Investigation of CTLA-4 and CD28 gene polymorphisms in a group of Turkish patients with colorectal cancer. Int J Immunogenet 35:317–321View ArticlePubMed
  24. Heinzmann A, Plesnar C, Kuehr J, Forster J, Deichmann KA (2000) Common polymorphisms in the CTLA-4 and CD28 genes at 2q33 are not associated with asthma or atopy. Eur J Immunogenet 27:57–61View ArticlePubMed
  25. Breunis WB, Tarazona-Santos E, Chen R, Kiley M, Rosenberg SA, Chanock SJ (2008) Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade. J Immunother 31:586–590View ArticlePubMed
Metadata
Title
Polymorphisms in the CD28/CTLA4/ICOS genes: role in malignant melanoma susceptibility and prognosis?
Authors
Marna G. Bouwhuis
Andreas Gast
Adina Figl
Alexander M. M. Eggermont
Kari Hemminki
Dirk Schadendorf
Rajiv Kumar
Publication date
01-02-2010
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 2/2010
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-009-0751-2

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