title: Inherited genetic variants associated with occurrence of multiple primary melanoma.
abstract: Recent studies, including genome-wide association studies, have identified several putative low-penetrance susceptibility loci for melanoma. We sought to determine their generalizability to genetic predisposition for multiple primary melanoma in the international population-based Genes, Environment, and Melanoma (GEM) Study. GEM is a case-control study of 1,206 incident cases of multiple primary melanoma and 2,469 incident first primary melanoma participants as the control group. We investigated the odds of developing multiple primary melanoma for 47 SNPs from 21 distinct genetic regions previously reported to be associated with melanoma. ORs and 95% confidence intervals were determined using logistic regression models adjusted for baseline features (age, sex, age by sex interaction, and study center). We investigated univariable models and built multivariable models to assess independent effects of SNPs. Eleven SNPs in 6 gene neighborhoods (TERT/CLPTM1L, TYRP1, MTAP, TYR, NCOA6, and MX2) and a PARP1 haplotype were associated with multiple primary melanoma. In a multivariable model that included only the most statistically significant findings from univariable modeling and adjusted for pigmentary phenotype, back nevi, and baseline features, we found TERT/CLPTM1L rs401681 (P = 0.004), TYRP1 rs2733832 (P = 0.006), MTAP rs1335510 (P = 0.0005), TYR rs10830253 (P = 0.003), and MX2 rs45430 (P = 0.008) to be significantly associated with multiple primary melanoma, while NCOA6 rs4911442 approached significance (P = 0.06). The GEM Study provides additional evidence for the relevance of these genetic regions to melanoma risk and estimates the magnitude of the observed genetic effect on development of subsequent primary melanoma.
authors.affiliation: Departments of Dermatology and Surgery, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: David C
authors.initials: DC
authors.lastname: Gibbs
authors.affiliation: Departments of Epidemiology and Biostatistics and Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Irene
authors.initials: I
authors.lastname: Orlow
authors.affiliation: Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kanetsky
authors.affiliation: Department of Internal Medicine, University of New Mexico Cancer Center, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Li
authors.initials: L
authors.lastname: Luo
authors.affiliation: Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Kricker
authors.affiliation: Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Armstrong
authors.affiliation: Department of Epidemiology, University of California, Irvine, California.
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
authors.affiliation: USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.affiliation: Cancer Care Ontario, Toronto, Ontario, Canada.
authors.forename: Loraine D
authors.initials: LD
authors.lastname: Marrett
authors.affiliation: British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Gallagher
authors.affiliation: Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Zanetti
authors.affiliation: Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rosso
authors.affiliation: The George Institute for Global Health, Oxford Martin School & Nuffield Department of Population Health, Oxford University, United Kingdom.
authors.forename: Terence
authors.initials: T
authors.lastname: Dwyer
authors.affiliation: Departments of Epidemiology and Biostatistics and Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ajay
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Departments of Epidemiology and Biostatistics and Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Emily
authors.initials: E
authors.lastname: La Pilla
authors.affiliation: Women's College Hospital, Toronto, Ontario, Canada.
authors.forename: Lynn
authors.initials: L
authors.lastname: From
authors.affiliation: Departments of Epidemiology and Biostatistics and Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Busam
authors.affiliation: Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Cust
authors.affiliation: Departments of Dermatology and Surgery, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: David W
authors.initials: DW
authors.lastname: Ollila
authors.affiliation: Departments of Epidemiology and Biostatistics and Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Colin B
authors.initials: CB
authors.lastname: Begg
authors.affiliation: Department of Internal Medicine, University of New Mexico Cancer Center, University of New Mexico, Albuquerque, New Mexico.
authors.forename: Marianne
authors.initials: M
authors.lastname: Berwick
authors.affiliation: Departments of Dermatology and Surgery, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. nancy_thomas@med.unc.edu.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Thomas
mesh_terms: D001315:Australia / Q000453:epidemiology; D014408:Biomarkers, Tumor / Q000235:genetics*; D002170:Canada / Q000453:epidemiology; D016022:Case-Control Studies; D005060:Europe / Q000453:epidemiology; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007390:International Agencies; D008545:Melanoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012878:Skin Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D014481:United States / Q000453:epidemiology
chemical_list: D014408:Biomarkers, Tumor
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