title: Genome-Wide Association Studies of Multiple Keratinocyte Cancers.
abstract: There is strong evidence for a role of environmental risk factors involved in susceptibility to develop multiple keratinocyte cancers (mKCs), but whether genes are also involved in mKCs susceptibility has not been thoroughly investigated. We investigated whether single nucleotide polymorphisms (SNPs) are associated with susceptibility for mKCs. A genome-wide association study (GWAS) of 1,666 cases with mKCs and 1,950 cases with single KC (sKCs; controls) from Harvard cohorts (the Nurses' Health Study [NHS], NHS II, and the Health Professionals Follow-Up Study) and the Framingham Heart Study was carried-out using over 8 million SNPs (stage-1). We sought to replicate the most significant statistical associations (p-value≤ 5.5x10-6) in an independent cohort of 574 mKCs and 872 sKCs from the Rotterdam Study. In the discovery stage, 40 SNPs with suggestive associations (p-value ≤5.5x10-6) were identified, with eight independent SNPs tagging all 40 SNPs. The most significant SNP was located at chromosome 9 (rs7468390; p-value = 3.92x10-7). In stage-2, none of these SNPs replicated and only two of them were associated with mKCs in the same direction in the combined meta-analysis. We tested the associations for 19 previously reported basal cell carcinoma-related SNPs (candidate gene association analysis), and found that rs1805007 (MC1R locus) was significantly associated with risk of mKCs (p-value = 2.80x10-4). Although the suggestive SNPs with susceptibility for mKCs were not replicated, we found that previously identified BCC variants may also be associated with mKC, which the most significant association (rs1805007) located at the MC1R gene.
authors.affiliation: Department of Dermatology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Luba M
authors.initials: LM
authors.lastname: Pardo
authors.affiliation: Department of Dermatology, Warren Alpert Medical School, Brown University, Providence Rhode Island, United State of America.|Department of Epidemiology, School of Public Health, Brown University, Rhode Island, United State of America.
authors.forename: Wen-Qing
authors.initials: WQ
authors.lastname: Li
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United State of America.|Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda Maryland MD United State of America.
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: Department of Dermatology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Joris A C
authors.initials: JA
authors.lastname: Verkouteren
authors.affiliation: Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United State of America.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA, United State of America.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United State of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.affiliation: Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA, United State of America.
authors.forename: Constance
authors.initials: C
authors.lastname: Turman
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United State of America.|Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, United State of America.|Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, United State of America.
authors.forename: Jiali
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Dermatology, Warren Alpert Medical School, Brown University, Providence Rhode Island, United State of America.|Department of Epidemiology, School of Public Health, Brown University, Rhode Island, United State of America.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United State of America.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Cho
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United State of America.|Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United State of America.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Murabito
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United State of America.|Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda Maryland MD United State of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: Department of Dermatology, Warren Alpert Medical School, Brown University, Providence Rhode Island, United State of America.|Department of Epidemiology, School of Public Health, Brown University, Rhode Island, United State of America.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United State of America.
authors.forename: Abrar A
authors.initials: AA
authors.lastname: Qureshi
authors.affiliation: Department of Dermatology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Tamar
authors.initials: T
authors.lastname: Nijsten
mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015603:Keratinocytes; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide