title: Pleiotropic and sex-specific effects of cancer GWAS SNPs on melanoma risk in the population architecture using genomics and epidemiology (PAGE) study.
abstract: BACKGROUND
  Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk.
  
  
  METHODS
  We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies.
  
  
  RESULTS
  We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e-4).
  
  
  CONCLUSIONS
  We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Jonathan M
authors: JM
authors: Kocarnik
authors: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: S Lani
authors: SL
authors: Park
authors: Department of Epidemiology, Richard M. Fairbanks School of Public Health, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, Indiana, United States of America.
authors: Jiali
authors: J
authors: Han
authors: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America.
authors: Logan
authors: L
authors: Dumitrescu
authors: Cancer Prevention Institute of California, Fremont, California, United States of America.
authors: Iona
authors: I
authors: Cheng
authors: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
authors: Lynne R
authors: LR
authors: Wilkens
authors: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Fredrick R
authors: FR
authors: Schumacher
authors: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
authors: Laurence
authors: L
authors: Kolonel
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Chris S
authors: CS
authors: Carlson
authors: Department of Epidemiology, Case Western Reserve University, Cleveland, Ohio, United States of America; Biostatistics Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors: Dana C
authors: DC
authors: Crawford
authors: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors: Robert J
authors: RJ
authors: Goodloe
authors: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors: Holli H
authors: HH
authors: Dilks
authors: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors: Paxton
authors: P
authors: Baker
authors: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America.
authors: Danielle
authors: D
authors: Richardson
authors: Department of Genetics, Rutgers University, Piscataway, New Jersey, United States of America.
authors: Tara C
authors: TC
authors: Matise
authors: Information Sciences Institute, University of Southern California, Marina del Rey, California, United States of America.
authors: José Luis
authors: JL
authors: Ambite
authors: Department of Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Fengju
authors: F
authors: Song
authors: Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors: Abrar A
authors: AA
authors: Qureshi
authors: Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors: Mingfeng
authors: M
authors: Zhang
authors: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors: David
authors: D
authors: Duggan
authors: Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, NCI, NIH, Bethesda, Maryland, United States of America.
authors: Carolyn
authors: C
authors: Hutter
authors: Division of Genomic Medicine, NHGRI, NIH, Bethesda, Maryland, Untied States of America.
authors: Lucia
authors: L
authors: Hindorff
authors: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee, United States of America.
authors: William S
authors: WS
authors: Bush
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Charles
authors: C
authors: Kooperberg
authors: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
authors: Loic
authors: L
authors: Le Marchand
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Ulrike
authors: U
authors: Peters
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D058685:Genetic Pleiotropy; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D056186:Metagenomics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D012306:Risk; D012737:Sex Factors; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D019098:Telomerase / Q000235:genetics
chemical_list: C422445:CLPTM1L protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C509186:TERT protein, human; D019098:Telomerase