title: The Expression Quantitative Trait Loci in Immune Pathways and their Effect on Cutaneous Melanoma Prognosis.
abstract: The identification of personalized germline markers with biologic relevance for the prediction of cutaneous melanoma prognosis is highly demanded but to date, it has been largely unsuccessful. As melanoma progression is controlled by host immunity, here we present a novel approach interrogating immunoregulatory pathways using the genome-wide maps of expression quantitative trait loci (eQTL) to reveal biologically relevant germline variants modulating cutaneous melanoma outcomes.
  
  
  
  Using whole genome eQTL data from a healthy population, we identified 385 variants significantly impacting the expression of 268 immune-relevant genes. The 40 most significant eQTLs were tested in a prospective cohort of 1,221 patients with cutaneous melanoma for their association with overall (OS) and recurrence-free survival using Cox regression models.
  
  
  
  We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (HR, 0.56; 95% CI, 0.41-0.77; P = 0.0002) and rs6695772, controlling the expression of BATF3 (HR, 1.64; 95% CI, 1.19-2.24; P = 0.0019). Both associations map in the previously suspected melanoma prognostic locus at 1q32. Furthermore, we show that their combined effect on melanoma OS is substantially enhanced reaching the level of clinical applicability (HR, 1.92; 95% CI, 1.43-2.60; P = 2.38e-5).
  
  
  
  Our unique approach of interrogating lymphocyte-specific eQTLs reveals novel and biologically relevant immunomodulatory eQTL predictors of cutaneous melanoma prognosis that are independent of current histopathologic markers. The significantly enhanced combined effect of identified eQTLs suggests the personalized utilization of both SNPs in a clinical setting, strongly indicating the promise of the proposed design for the discovery of prognostic or risk germline markers in other cancers. Clin Cancer Res; 22(13); 3268-80. ©2016 AACR.
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York.
authors.forename: Matjaz
authors.initials: M
authors.lastname: Vogelsang
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York.
authors.forename: Carlos N
authors.initials: CN
authors.lastname: Martinez
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York.
authors.forename: Justin
authors.initials: J
authors.lastname: Rendleman
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. Department of Pathology, New York University School of Medicine, New York, New York.
authors.forename: Anuj
authors.initials: A
authors.lastname: Bapodra
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. Department of Pathology, New York University School of Medicine, New York, New York.
authors.forename: Karolina
authors.initials: K
authors.lastname: Malecek
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York.
authors.forename: Artur
authors.initials: A
authors.lastname: Romanchuk
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York.
authors.forename: Esther
authors.initials: E
authors.lastname: Kazlow
authors.affiliation: The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Shapiro
authors.affiliation: The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. Department of Surgery, New York University School of Medicine, New York, New York.
authors.forename: Russell S
authors.initials: RS
authors.lastname: Berman
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. Department of Pathology, New York University School of Medicine, New York, New York.
authors.forename: Michelle
authors.initials: M
authors.lastname: Krogsgaard
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. Department of Medicine, New York University School of Medicine, New York, New York. Ronald O. Perelman, Department of Dermatology, New York University, New York, New York.
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.affiliation: Perlmutter Cancer Center, New York University School of Medicine, New York, New York. Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, New York. The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, New York. tomas.kirchhoff@nyumc.org.
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhoff
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis* / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D040641:Quantitative Trait Loci / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D000096142:Cutaneous Malignant Melanoma
chemical_list: C099359:BATF protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D014408:Biomarkers, Tumor; C421250:IL19 protein, human; D007378:Interleukins