Skip to main content

Advertisement

SpringerLink
Log in

Variations of the melanocortin-1 receptor and the glutathione-S transferase T1 and M1 genes in cutaneous malignant melanoma

  • Original Paper
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

Variations in the melanocortin-1 receptor (MC1R) and in the glutathione-S transferase genes mu1 (GSTM1) and theta 1 (GSTT1) have been reported to influence UV sensitivity and melanoma risk. MC1R is one of the major genes that determine skin pigmentation because the melanocortin-1 receptor regulates eumelanin synthesis. GSTT1 and GSTM1 are enzymes expressed in the skin that detoxify products of oxidative stress reactions caused by UV irradiation. In this study variations in the MC1R, GSTM1 and T1 genes were analyzed in 347 healthy subjects and 322 patients with cutaneous malignant melanoma by direct cycle sequencing, RFLP and multiplex PCR. Important phenotypic characteristics of the study participants were obtained to assess whether genetic associations occurred independently of phenotypic risk factors for melanoma. We found an association of the MC1R D84E and R151C polymorphisms with melanoma (odds ratios for carriage of the rare allele 4.96, 95% CI [1.06–23.13], P = 0.032, and 1.69, 95% CI [1.12–2.55], P = 0.013, respectively). Melanoma risk increased with the number of variant MC1R alleles carried by an individual (P = 0.003). In a multivariate model, however, only the D84E polymorphism influenced melanoma risk independently of the risk factors fair skin type, high nevus count and high age (P = 0.047). There was no effect of homozygous GST M1 or T1 deletions on melanoma risk. In contrast to previous data, there was no evidence that GSTM1 deficiency influences melanoma risk in the subgroup of individuals with red or blond hair.

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

Similar content being viewed by others

References

  1. Bataille V (2000) Genetics of familial and sporadic melanoma. Clin Exp Dermatol 25:464–470

    Article  PubMed  CAS  Google Scholar 

  2. Bataille V (2003) Genetic epidemiology of melanoma. Eur J Cancer 39:1341–1347

    Article  PubMed  CAS  Google Scholar 

  3. Bell DA, Thompson CL, Taylor J, Miller CR, Perera F, Hsieh LL, Lucier GW (1992) Genetic monitoring of human polymorphic cancer susceptibility genes by polymerase chain reaction: application to glutathione transferase mu. Environ Health Perspect 98:113–117

    PubMed  CAS  Google Scholar 

  4. Bertram CG, Gaut RM, Barrett JH, Randerson-Moor J, Whitaker L, Turner F, Bataille V, dos SS I, Swerdlow AJ, Bishop DT, Newton Bishop JA (2004) An assessment of a variant of the DNA repair gene XRCC3 as a possible nevus or melanoma susceptibility genotype. J Invest Dermatol 122:429–432

    Article  PubMed  CAS  Google Scholar 

  5. Blankenburg S, König IR, Mössner R, Laspe P, Thoms KM, Krüger U, Khan SG, Westphal G, Berking C, Volkenandt M, Reich K, Neumann C, Ziegler A, Kraemer KH, Emmert S (2005) Assessment of 3 xeroderma pigmentosum group C gene polymorphisms and risk of cutaneous melanoma: a case-control study. Carcinogenesis 26:1085–1090

    Article  PubMed  CAS  Google Scholar 

  6. Burchill SA, Ito S, Thody AJ (1993) Effects of melanocyte-stimulating hormone on tyrosinase expression and melanin synthesis in hair follicular melanocytes of the mouse. J Endocrinol 137:189–195

    Article  PubMed  CAS  Google Scholar 

  7. Cejas P, Casado E, Belda-Iniesta C, De Castro J, Espinosa E, Redondo A, Sereno M, Garcia-Cabezas MA, Vara JA, Dominguez-Caceres A, Perona R, Gonzalez-Baron M (2004) Implications of oxidative stress and cell membrane lipid peroxidation in human cancer (Spain). Cancer Causes Control 15:707–719

    Article  PubMed  Google Scholar 

  8. Garbe C, Buttner P, Weiss J, Soyer HP, Stocker U, Kruger S, Roser M, Weckbecker J, Panizzon R, Bahmer F (1994) Risk factors for developing cutaneous melanoma and criteria for identifying persons at risk: multicenter case-control study of the Central Malignant Melanoma Registry of the German Dermatological Society. J Invest Dermatol 102:695–699

    Article  PubMed  CAS  Google Scholar 

  9. Hill HZ, Hill GJ (2000) UVA, pheomelanin and the carcinogenesis of melanoma. Pigment Cell Res 13:140–144

    Article  PubMed  Google Scholar 

  10. Holland EA, Schmid H, Kefford RF, Mann GJ (1999) CDKN2A (P16(INK4a)) and CDK4 mutation analysis in 131 Australian melanoma probands: effect of family history and multiple primary melanomas. Genes Chromosomes Cancer 25:339–348

    Article  PubMed  CAS  Google Scholar 

  11. Ichii-Jones F, Lear JT, Heagerty AH, Smith AG, Hutchinson PE, Osborne J, Bowers B, Jones PW, Davies E, Ollier WE, Thomson W, Yengi L, Bath J, Fryer AA, Strange RC (1998) Susceptibility to melanoma: influence of skin type and polymorphism in the melanocyte stimulating hormone receptor gene. J Invest Dermatol 111:218–221

    Article  PubMed  CAS  Google Scholar 

  12. Jackson S, Harland M, Turner F, Taylor C, Chambers PA, Randerson-Moor J, Swerdlow AJ, I Dos SS, Beswick S, Bishop DT, Newton Bishop JA (2005) No Evidence for BRAF as a melanoma/nevus susceptibility gene. Cancer Epidemiol Biomarkers Prev 14:913–918

    Article  PubMed  CAS  Google Scholar 

  13. Kanetsky PA, Holmes R, Walker A, Najarian D, Swoyer J, Guerry D, Halpern A, Rebbeck TR (2001) Interaction of glutathione S-transferase M1 and T1 genotypes and malignant melanoma. Cancer Epidemiol Biomarkers Prev 10:509–513

    PubMed  CAS  Google Scholar 

  14. Kennedy C, ter Huurne J, Berkhout M, Gruis N, Bastiaens M, Bergman W, Willemze R, Bavinck JN (2001) Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color. J Invest Dermatol 117:294–300

    Article  PubMed  CAS  Google Scholar 

  15. Kerb R, Brockmoller J, Reum T, Roots I (1997) Deficiency of glutathione S-transferases T1 and M1 as heritable factors of increased cutaneous UV sensitivity. J Invest Dermatol 108:229–232

    Article  PubMed  CAS  Google Scholar 

  16. Kerb R, Brockmoller J, Schlagenhaufer R, Sprenger R, Roots I, Brinkmann U (2002) Influence of GSTT1 and GSTM1 genotypes on sunburn sensitivity. Am J Pharmacogenomics 2:147–154

    Article  PubMed  CAS  Google Scholar 

  17. La Torre G, Boccia S, Ricciardi G (2005) Glutathione S-transferase M1 status and gastric cancer risk: a meta-analysis. Cancer Lett 217:53–60

    Article  PubMed  CAS  Google Scholar 

  18. Lear JT, Smith AG, Strange RC, Fryer AA (2000) Detoxifying enzyme genotypes and susceptibility to cutaneous malignancy. Br J Dermatol 142:8–15

    Article  PubMed  CAS  Google Scholar 

  19. Lee EY, Williamson R, Watt P, Hughes MC, Green AC, Whiteman DC (2006) Sun exposure and host phenotype as predictors of cutaneous melanoma associated with neval remnants or dermal elastosis. Int J Cancer (in press)

  20. Luger TA, Brzoska T, Scholzen TE, Kalden DH, Sunderkötter C, Armstrong C, Ansel J (2000) The role of alpha-MSH as a modulator of cutaneous inflammation. Ann N Y Acad Sci 917:232–238

    Article  PubMed  CAS  Google Scholar 

  21. Matichard E, Verpillat P, Meziani R, Gerard B, Descamps V, Legroux E, Burnouf M, Bertrand G, Bouscarat F, Archimbaud A, Picard C, Ollivaud L, Basset-Seguin N, Kerob D, Lanternier G, Lebbe C, Crickx B, Grandchamp B, Soufir N (2004) Melanocortin 1 receptor (MC1R) gene variants may increase the risk of melanoma in France independently of clinical risk factors and UV exposure. J Med Genet 41:e13

    Article  PubMed  CAS  Google Scholar 

  22. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    PubMed  CAS  Google Scholar 

  23. Moral A, Palou J, Lafuente A, Molina R, Piulachs J, Castel T, Trias M (1997) Immunohistochemical study of alpha, mu and pi class glutathione S transferase expression in malignant melanoma. MMM Group. Multidisciplinary Malignant Melanoma Group. Br J Dermatol 136:345–50

    Article  PubMed  CAS  Google Scholar 

  24. Naldi L, Altieri A, Imberti GL, Gallus S, Bosetti C, La Vecchia C (2005) Sun exposure, phenotypic characteristics, and cutaneous malignant melanoma. An analysis according to different clinico-pathological variants and anatomic locations (Italy). Cancer Causes Control 16:893–899

    Article  PubMed  Google Scholar 

  25. Naysmith L, Waterston K, Ha T, Flanagan N, Bisset Y, Ray A, Wakamatsu K, Ito S, Rees JL (2004) Quantitative measures of the effect of the melanocortin 1 receptor on human pigmentary status. J Invest Dermatol 122:423–428

    Article  PubMed  CAS  Google Scholar 

  26. Neumann AG, Nagaeva O, Mandrika I, Petrovska R, Muceniece R, Mincheva-Nilsson L, Wikberg JE (2001) MC(1) receptors are constitutively expressed on leucocyte subpopulations with antigen presenting and cytotoxic functions. Clin Exp Immunol 126:441–446

    Article  Google Scholar 

  27. Palmer JS, Duffy DL, Box NF, Aitken JF, O’Gorman LE, Green AC, Hayward NK, Martin NG, Sturm RA (2000) Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype? Am J Hum Genet 66:176–186

    Article  PubMed  CAS  Google Scholar 

  28. Panizzon RG, Guggisberg D (1999) [Clinical aspects and pathology of melanoma]. Ther Umsch 56:302–308

    Article  PubMed  CAS  Google Scholar 

  29. Pemble S, Schroeder KR, Spencer SR, Meyer DJ, Hallier E, Bolt HM, Ketterer B, Taylor JB (1994) Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem J 300:271–276

    PubMed  CAS  Google Scholar 

  30. Rees JL (2004) The genetics of sun sensitivity in humans. Am J Hum Genet 75:739–751

    Article  PubMed  CAS  Google Scholar 

  31. Reich K, Westphal G, Schulz T, Muller M, Zipprich S, Fuchs T, Hallier E, Neumann C (1999) Combined analysis of polymorphisms of the tumor necrosis factor-alpha and interleukin-10 promoter regions and polymorphic xenobiotic metabolizing enzymes in psoriasis. J Invest Dermatol 113:214–220

    Article  PubMed  CAS  Google Scholar 

  32. Robinson SJ, Healy E (2002) Human melanocortin 1 receptor (MC1R) gene variants alter melanoma cell growth and adhesion to extracellular matrix. Oncogene 21:8037–8046

    Article  PubMed  CAS  Google Scholar 

  33. Royston P, Altman DG (1994) Regression using fractional polynomials of continuous covariats: Parsimonious parametric modelling. Appl Stat 43:429–467

    Article  Google Scholar 

  34. Sanchez-Laorden BL, Sanchez-Mas J, Martinez-Alonso E, Martinez-Menarguez JA, Garcia-Borron JC, Jimenez-Cervantes C (2006) Dimerization of the human melanocortin 1 receptor: functional consequences and dominant-negative effects. J Invest Dermatol 126:172–181

    Article  PubMed  CAS  Google Scholar 

  35. Shanley SM, Chenevix-Trench G, Palmer J, Hayward N (1995) Glutathione S-transferase GSTM1 null genotype is not overrepresented in Australian patients with nevoid basal cell carcinoma syndrome or sporadic melanoma. Carcinogenesis 16:2003–2004

    PubMed  CAS  Google Scholar 

  36. Sturm RA, Duffy DL, Box NF, Chen W, Smit DJ, Brown DL, Stow JL, Leonard JH, Martin NG (2003) The role of melanocortin-1 receptor polymorphism in skin cancer risk phenotypes. Pigment Cell Res 16:266–272

    Article  PubMed  CAS  Google Scholar 

  37. Sturm RA, Teasdale RD, Box NF (2001) Human pigmentation genes: identification, structure and consequences of polymorphic variation. Gene 277:49–62

    Article  PubMed  CAS  Google Scholar 

  38. Tomescu D, Kavanagh G, Ha T, Campbell H, Melton DW (2001) Nucleotide excision repair gene XPD polymorphisms and genetic predisposition to melanoma. Carcinogenesis 22:403–408

    Article  PubMed  CAS  Google Scholar 

  39. Ziegler AK, König IR (2006) A statistical approach to genetic epidemiology. Concepts and applications. Wiley-VCH, Weinheim

    Google Scholar 

Download references

Acknowledgments

We thank Melanie Walter and Karoline Jobst for excellent technical assistance. This work was supported by the Frauenförderungsprogramm of the Georg-August-University, Göttingen to RM.

Author information

Authors and Affiliations

  1. Department of Dermatology, Georg-August-University, Von-Siebold-Strasse 3, 37075, Göttingen, Germany

    Rotraut Mössner, Nils Anders, Ullrich Krüger, Diane Schmidt & Kristian Reich

  2. Department of Clinical Pharmacology, Georg-August-University, Robert-Koch-Strasse 40, 37075, Göttingen, Germany

    Nils Anders, Jürgen Brockmöller & Rolf Kaiser

  3. Department of Dermatology, Ludwig-Maximilians-University, Frauenlobstr. 9-11, 80337, München, Germany

    Carola Berking & Matthias Volkenandt

  4. Institute of Medical Biometry and Statistics, University at Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany

    Inke R. König & Andreas Ziegler

  5. Department of Occupational Health, Georg-August-University, Waldweg 37, 37073, Göttingen, Germany

    Götz A. Westphal

  6. Dermatologikum Hamburg, Stephansplatz 5, 20354, Hamburg, Germany

    Kristian Reich

Authors
  1. Rotraut Mössner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nils Anders
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Inke R. König
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ullrich Krüger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Diane Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carola Berking
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andreas Ziegler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jürgen Brockmöller
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rolf Kaiser
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Matthias Volkenandt
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Götz A. Westphal
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kristian Reich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kristian Reich.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mössner, R., Anders, N., König, I.R. et al. Variations of the melanocortin-1 receptor and the glutathione-S transferase T1 and M1 genes in cutaneous malignant melanoma. Arch Dermatol Res 298, 371–379 (2007). https://doi.org/10.1007/s00403-006-0708-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-006-0708-7

Keywords

Search

Navigation