title: Genetic associations of the interleukin locus at 1q32.1 with clinical outcomes of cutaneous melanoma.
abstract: BACKGROUND
  Due to high melanoma immunogenicity, germline genetic variants in immune pathways have been studied for association with melanoma prognosis. However, limited candidate selection, inadequate power, or lack of independent validation have hampered the reproducibility of these prior findings, preventing personalised clinical applicability in melanoma prognostication. Our objective was to assess the prognostic utility of genetic variants in immunomodulatory pathways for prediction of melanoma clinical outcomes.
  
  
  METHODS
  We genotyped 72 tag single nucleotide polymorphisms (SNPs) in 44 immunomodulatory genes in a population sample of 1022 melanoma patients and performed Cox regression analysis to test the association between SNPs and melanoma recurrence-free (RFS) and overall survival (OS). We have further investigated the most significant associations using a fine mapping strategy and followed with functional analyses in CD4+ T cells in a subset of 75 melanoma patients.
  
  
  RESULTS
  The most significant associations were found with melanoma OS for rs3024493 in IL10 at chromosome 1q32.1 (heterozygous HR 0.58, 95% CI 0.39 to 0.86; p=0.0006), a variant previously shown to be linked with autoimmune conditions. Multiple additional SNPs at 1q32.1 were also nominally associated with OS confirming at least two independent association signals in this locus. In addition, we found rs3024493 associated with the downregulation of interleukin 10 (IL10) secretion in CD4+ T cells.
  
  
  CONCLUSIONS
  We discovered novel associations of IL10 with melanoma survival at 1q32.1, suggesting this locus should be considered as a novel melanoma prognostic biomarker with potential for aiding melanoma patient management. Our findings also provide further support for an alternative role of IL10 in stimulation of anti-tumour immune response.
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, USA Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Rendleman
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, USA Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA.
authors.forename: Matjaz
authors.initials: M
authors.lastname: Vogelsang
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, USA The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA Department of Pathology, New York University School of Medicine, New York, USA.
authors.forename: Anuj
authors.initials: A
authors.lastname: Bapodra
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, USA Department of Medicine, New York University School of Medicine, New York, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Adaniel
authors.affiliation: The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA Department of Medicine, New York University School of Medicine, New York, USA Ronald O. Perelman Department of Dermatology, New York University, New York, USA.
authors.forename: Ines
authors.initials: I
authors.lastname: Silva
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, USA The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA Department of Pathology, New York University School of Medicine, New York, USA.
authors.forename: Duane
authors.initials: D
authors.lastname: Moogk
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, USA Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA.
authors.forename: Carlos N
authors.initials: CN
authors.lastname: Martinez
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, USA The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Fleming
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, USA Department of Medicine, New York University School of Medicine, New York, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Shields
authors.affiliation: The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA Department of Surgery, New York University School of Medicine, New York, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Shapiro
authors.affiliation: The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA Department of Surgery, New York University School of Medicine, New York, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Berman
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, USA The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA Department of Medicine, New York University School of Medicine, New York, USA Ronald O. Perelman Department of Dermatology, New York University, New York, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlick
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, USA The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA Ronald O. Perelman Department of Dermatology, New York University, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Polsky
authors.affiliation: Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA.
authors.forename: Yongzhao
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, USA The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA Department of Medicine, New York University School of Medicine, New York, USA Ronald O. Perelman Department of Dermatology, New York University, New York, USA.
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, USA The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA Department of Pathology, New York University School of Medicine, New York, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Krogsgaard
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, USA Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhoff
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002878:Chromosomes, Human, Pair 1; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D056747:Immunomodulation / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics* / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012878:Skin Neoplasms / Q000235:genetics* / Q000276:immunology; D055815:Young Adult; D000096142:Cutaneous Malignant Melanoma
chemical_list: C508609:IL10 protein, human; D007378:Interleukins; D016753:Interleukin-10
keywords: SNP; immune response; melanoma; survival