title: Association of Common Genetic Polymorphisms with Melanoma Patient IL-12p40 Blood Levels, Risk, and Outcomes.
abstract: Recent investigation has identified association of IL-12p40 blood levels with melanoma recurrence and patient survival. No studies have investigated associations of single-nucleotide polymorphisms (SNPs) with melanoma patient IL-12p40 blood levels or their potential contributions to melanoma susceptibility or patient outcome. In the current study, 818,237 SNPs were available for 1,804 melanoma cases and 1,026 controls. IL-12p40 blood levels were assessed among 573 cases (discovery), 249 cases (case validation), and 299 controls (control validation). SNPs were evaluated for association with log[IL-12p40] levels in the discovery data set and replicated in two validation data sets, and significant SNPs were assessed for association with melanoma susceptibility and patient outcomes. The most significant SNP associated with log[IL-12p40] was in the IL-12B gene region (rs6897260, combined P=9.26 × 10(-38)); this single variant explained 13.1% of variability in log[IL-12p40]. The most significant SNP in EBF1 was rs6895454 (combined P=2.24 × 10(-9)). A marker in IL12B was associated with melanoma susceptibility (rs3213119, multivariate P=0.0499; OR=1.50, 95% CI 1.00-2.24), whereas a marker in EBF1 was associated with melanoma-specific survival in advanced-stage patients (rs10515789, multivariate P=0.02; HR=1.93, 95% CI 1.11-3.35). Both EBF1 and IL12B strongly regulate IL-12p40 blood levels, and IL-12p40 polymorphisms may contribute to melanoma susceptibility and influence patient outcome.
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; These authors contributed equally to this work. Electronic address: sfang@mdanderson.org.
authors.forename: Shenying
authors.initials: S
authors.lastname: Fang
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Surgery, Virginia Piper Cancer Institute, Minneapolis, Minnesota, USA.
authors.forename: Yun S
authors.initials: YS
authors.lastname: Chun
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Huey
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Merrick I
authors.initials: MI
authors.lastname: Ross
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Electronic address: jelee@mdanderson.org.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gershenwald
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Janice N
authors.initials: JN
authors.lastname: Cormier
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Royal
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Lucci
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Schacherer
authors.affiliation: Division of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Dawen
authors.initials: D
authors.lastname: Sui
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Roland L
authors.initials: RL
authors.lastname: Bassett
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Li-E
authors.initials: LE
authors.lastname: Wang
authors.affiliation: Duke Cancer Institute, Duke University Medical Center and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Geisel College of Medicine, Community and Family Medicine, Dartmouth College, Lebanon, New Hampshire, USA; These authors contributed equally to this work.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; These authors contributed equally to this work.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lee
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D016001:Confidence Intervals; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000097:blood* / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000097:blood / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D015203:Reproducibility of Results; D018570:Risk Assessment; D012878:Skin Neoplasms / Q000097:blood / Q000235:genetics* / Q000401:mortality; D016019:Survival Analysis
chemical_list: C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40
references.citation: Swiss Med Wkly. 2001 Aug 11;131(31-32):445-54
references.pmid: 11641967
references.citation: Immunol Lett. 2002 Feb 1;80(2):75-9
references.pmid: 11750037
references.citation: Nat Rev Immunol. 2003 Feb;3(2):133-46
references.pmid: 12563297
references.citation: Am J Hum Genet. 2004 Oct;75(4):709-15
references.pmid: 15322986
references.citation: J Immunol. 1996 Feb 1;156(3):1095-100
references.pmid: 8557984
references.citation: Curr Opin Immunol. 1998 Aug;10(4):413-7
references.pmid: 9722917
references.citation: Immunol Rev. 2004 Dec;202:96-105
references.pmid: 15546388
references.citation: Nature. 2006 Jul 27;442(7101):461-5
references.pmid: 16688182
references.citation: Trends Immunol. 2007 Jan;28(1):33-8
references.pmid: 17126601
references.citation: Am J Hum Genet. 2007 Feb;80(2):273-90
references.pmid: 17236132
references.citation: Science. 2008 Nov 7;322(5903):881-8
references.pmid: 18988837
references.citation: Annu Rev Genomics Hum Genet. 2009;10:387-406
references.pmid: 19715440
references.citation: Genes Chromosomes Cancer. 2010 May;49(5):425-38
references.pmid: 20140953
references.citation: BMC Bioinformatics. 2010;11:134
references.pmid: 20233392
references.citation: Am J Hum Genet. 2010 Jul 9;87(1):139-45
references.pmid: 20598278
references.citation: Immunotherapy. 2010 Sep;2(5):697-709
references.pmid: 20874653
references.citation: Nat Genet. 2010 Nov;42(11):985-90
references.pmid: 20953190
references.citation: Hum Mol Genet. 2011 Dec 15;20(24):5012-23
references.pmid: 21926416
references.citation: N Engl J Med. 2013 Jul 11;369(2):134-44
references.pmid: 23724846
references.citation: N Engl J Med. 2013 Jul 11;369(2):187-9
references.pmid: 23724866
references.citation: N Engl J Med. 2013 Jul 11;369(2):122-33
references.pmid: 23724867
references.citation: J Clin Invest. 2013 Aug;123(8):3383-94
references.pmid: 23867552
references.citation: PLoS One. 2013;8(12):e85642
references.pmid: 24392023
references.citation: J Immunol. 2014 Jun 15;192(12):6028-36
references.pmid: 24821971
references.citation: Int J Cancer. 2015 Apr 15;136(8):1874-80
references.pmid: 25196740