Justin Rendleman1, Matjaz Vogelsang1, Anuj Bapodra2, Christina Adaniel3, Ines Silva4, Duane Moogk2, Carlos N Martinez1, Nathaniel Fleming5, Jerry Shields3, Richard Shapiro6, Russell Berman6, Anna Pavlick7, David Polsky8, Yongzhao Shao9, Iman Osman7, Michelle Krogsgaard2, Tomas Kirchhoff1. 1. 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. 2. 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. 3. Perlmutter Cancer Center, New York University School of Medicine, New York, USA Department of Medicine, New York University School of Medicine, New York, USA. 4. 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. 5. 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. 6. 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. 7. 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. 8. 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. 9. 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.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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 melanomapatients 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 melanomapatients. 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 melanomapatient management. Our findings also provide further support for an alternative role of IL10 in stimulation of anti-tumour immune response. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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