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Genetic associations of the interleukin locus at 1q32.1 with clinical outcomes of cutaneous melanoma
  1. Justin Rendleman1,2,3,
  2. Matjaz Vogelsang1,2,3,
  3. Anuj Bapodra1,3,4,
  4. Christina Adaniel1,5,
  5. Ines Silva3,5,6,
  6. Duane Moogk1,3,4,
  7. Carlos N Martinez1,2,3,
  8. Nathaniel Fleming1,3,
  9. Jerry Shields1,5,
  10. Richard Shapiro3,7,
  11. Russell Berman3,7,
  12. Anna Pavlick1,3,5,6,
  13. David Polsky1,3,6,
  14. Yongzhao Shao2,3,
  15. Iman Osman1,3,5,6,
  16. Michelle Krogsgaard1,3,4,
  17. Tomas Kirchhoff1,2,3
  1. 1Perlmutter Cancer Center, New York University School of Medicine, New York, USA
  2. 2Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA
  3. 3The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA
  4. 4Department of Pathology, New York University School of Medicine, New York, USA
  5. 5Department of Medicine, New York University School of Medicine, New York, USA
  6. 6Ronald O. Perelman Department of Dermatology, New York University, New York, USA
  7. 7Department of Surgery, New York University School of Medicine, New York, USA
  1. Correspondence to Dr Tomas Kirchhoff, Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, New York, NY 10016, USA; Tomas.Kirchhoff{at}nyumc.org

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.

  • melanoma
  • immune response
  • SNP
  • survival

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