Association of Inherited Variation in Toll-Like Receptor Genes with Malignant Melanoma Susceptibility and Survival

The family of Toll-like receptors (TLRs) is critical in linking innate and acquired immunity. Polymorphisms in the genes encoding TLRs have been associated with autoimmune diseases and cancer. We investigated the genetic variation of TLR genes and its potential impact on melanoma susceptibility and patient survival. The study included 763 cutaneous melanoma cases recruited in Germany and 736 matched controls that were genotyped for 47 single nucleotide polymorphisms (SNPs) in 8 TLR genes. The relationship between genotype, disease status and survival was investigated taking into account patient and tumor characteristics, and melanoma treatment. Analysis of 7 SNPs in TLR2, 7 SNPs in TLR3 and 8 SNPs in TLR4 showed statistically significant differences in distribution of inferred haplotypes between cases and controls. No individual polymorphism was associated with disease susceptibility except for the observed tendency for TLR2-rs3804099 (odds ratio OR  = 1.15, 95% CI 0.99–1.34, p = 0.07) and TLR4-rs2149356 (OR = 0.85, 95% CI 0.73–1.00, p = 0.06). Both polymorphisms were part of the haplotypes associated with risk modulation. An improved overall survival (Hazard ratio HR 0.53, 95% CI 0.32–0.88) and survival following metastasis (HR 0.55, 95% CI 0.34–0.91) were observed in carriers of the variant allele (D299G) of TLR4-rs4986790. In addition various TLR2, TLR4 and TLR5 haplotypes were associated with increased overall survival. Our results point to a novel association between TLR gene variants and haplotypes with melanoma survival. Our data suggest a role for the D299G polymorphism in the TLR4 gene in overall survival and a potential link with systemic treatment at stage IV of the disease. The polymorphic amino acid residue, located in the ectodomain of TLR4, can have functional consequences.

[1]  J. Kirkwood,et al.  Prognostic significance of autoimmunity during treatment of melanoma with interferon , 2006, Seminars in Immunopathology.

[2]  E. Bell,et al.  Role of Polymorphic Variants as Genetic Modulators of Infection in Neonatal Sepsis , 2010, Pediatric Research.

[3]  J. Pignon,et al.  Immunogenic death of colon cancer cells treated with oxaliplatin , 2010, Oncogene.

[4]  H. Inoko,et al.  Association of toll-like receptor 2 gene polymorphisms with normal tension glaucoma , 2009, Molecular vision.

[5]  K. Drzewiecki,et al.  Spontaneous regression of metastases from melanoma: review of the literature , 2009, Melanoma research.

[6]  Peter Kraft,et al.  Toll-like Receptor Signaling Pathway Variants and Prostate Cancer Mortality , 2009, Cancer Epidemiology Biomarkers & Prevention.

[7]  W. Isaacs,et al.  Association of IL10 and Other immune response‐ and obesity‐related genes with prostate cancer in CLUE II , 2009, The Prostate.

[8]  S. Agarwala.  Current systemic therapy for metastatic melanoma , 2009, Expert review of anticancer therapy.

[9]  Hayyoung Lee,et al.  The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex , 2009, Nature.

[10]  S. Weiland,et al.  Toll-like receptor heterodimer variants protect from childhood asthma. , 2008, The Journal of allergy and clinical immunology.

[11]  T. Hawn,et al.  Toll-like receptor polymorphisms and susceptibility to human disease. , 2008, Clinical science.

[12]  L. Zhao,et al.  Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy. , 2008, The Journal of infectious diseases.

[13]  Helen Y Wang,et al.  Toll-like receptors and immune regulation: implications for cancer therapy , 2008, Oncogene.

[14]  E. El-Omar,et al.  Polymorphisms in Toll-like receptor genes and risk of cancer , 2008, Oncogene.

[15]  L. Zitvogel,et al.  The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy , 2007, Immunological reviews.

[16]  A. Krieg,et al.  Toll‐like receptors 7, 8, and 9: linking innate immunity to autoimmunity , 2007, Immunological reviews.

[17]  A. Aderem,et al.  A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis , 2007, Genes and Immunity.

[18]  J. Witte,et al.  Toll-Like Receptor 4 Genetic Variation and Advanced Prostate Cancer Risk , 2007, Cancer Epidemiology Biomarkers & Prevention.

[19]  A. Marshak‐Rothstein.  Toll-like receptors in systemic autoimmune disease , 2006, Nature Reviews Immunology.

[20]  I. Santin,et al.  No Association of TLR2 and TLR4 Polymorphisms with Type I Diabetes Mellitus in the Basque Population , 2006, Annals of the New York Academy of Sciences.

[21]  S. Akira,et al.  Toll-like receptors and innate immunity , 2006, Journal of Molecular Medicine.

[22]  M. Boukhvalova,et al.  Analysis of TLR4 Polymorphic Variants: New Insights into TLR4/MD-2/CD14 Stoichiometry, Structure, and Signaling1 , 2006, The Journal of Immunology.

[23]  D. Hunter,et al.  Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. , 2005, Cancer research.

[24]  D. Schwartz,et al.  Polymorphisms of the Toll-like receptors and human disease. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[25]  R. Medzhitov,et al.  Toll-like receptors: linking innate and adaptive immunity. , 2004, Microbes and infection.

[26]  D. Malhotra,et al.  TLR2 Arg677Trp polymorphism in leprosy: revisited , 2005, Human Genetics.

[27]  D. Nowak,et al.  Toll-like receptor 2 as a major gene for asthma in children of European farmers. , 2004, The Journal of allergy and clinical immunology.

[28]  C. Garbe,et al.  Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomised clinical trials. , 2003, The Lancet. Oncology.

[29]  S. Steinberg,et al.  Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  S. Akira,et al.  Toll-like receptors: critical proteins linking innate and acquired immunity , 2001, Nature Immunology.

[31]  M. Atkins,et al.  Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. , 1988, The New England journal of medicine.