title: Association of genetic variants in CDK6 and XRCC1 with the risk of dysplastic nevi in melanoma-prone families.
abstract: Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each single-nucleotide polymorphism (SNP) separately, adjusted for age, sex, CMM, and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific P-values. Two genes, CDK6 (cyclin-dependent kinase 6) and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation-positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and -negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent data sets (random-effect meta-analysis: P<0.0001). Our findings suggest that some genetic variants may contribute to DN risk independently of their association with CMM in melanoma-prone families.
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, Maryland, USA; Office of In Vitro Diagnostics and Radiological Health, CDRH/FDA, Silver Spring, Maryland, USA.
authors.forename: Xueying
authors.initials: X
authors.lastname: Liang
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, Maryland, USA.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Pfeiffer
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, Maryland, USA.
authors.forename: Wen-Qing
authors.initials: WQ
authors.lastname: Li
authors.affiliation: INSERM, UMR-946, Genetic Variation and Human Diseases Unit, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France; Université Paris Sud, Le Kremlin Bicêtre, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Brossard
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, Maryland, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Burke
authors.affiliation: Information Management Services, Inc., Rockville, Maryland, USA.
authors.forename: William
authors.initials: W
authors.lastname: Wheeler
authors.affiliation: Department of Dermatology, M Bufalini Hospital, Cesena, Italy.
authors.forename: Donato
authors.initials: D
authors.lastname: Calista
authors.affiliation: Department of Dermatology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Maria Concetta
authors.initials: MC
authors.lastname: Fargnoli
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy; Laboratory of Genetics of Rare Hereditary Cancers, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ghiorzo
authors.affiliation: Department of Dermatology, University of L'Aquila, L'Aquila, Italy.
authors.forename: Ketty
authors.initials: K
authors.lastname: Peris
authors.affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy; Laboratory of Genetics of Rare Hereditary Cancers, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Bianchi-Scarra
authors.affiliation: INSERM, UMR-946, Genetic Variation and Human Diseases Unit, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France; Université d'Evry-Val d'Essonne, Evry, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Chaudru
authors.affiliation: Commissariat à l'Energie Atomique (CEA), Institut de Génomique, Centre National de Génotypage, Evry, France.
authors.forename: Diana
authors.initials: D
authors.lastname: Zelenika
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, Maryland, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Maeder
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, Maryland, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdette
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, Maryland, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, Maryland, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, Maryland, USA.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
authors.affiliation: INSERM, UMR-946, Genetic Variation and Human Diseases Unit, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Demenais
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, Maryland, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tucker
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, Maryland, USA.
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, Maryland, USA. Electronic address: Royang@mail.nih.gov.
authors.forename: Xiaohong R
authors.initials: XR
authors.lastname: Yang
mesh_terms: D000328:Adult; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004416:Dysplastic Nevus Syndrome / Q000453:epidemiology / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008545:Melanoma / Q000453:epidemiology / Q000235:genetics*; D008875:Middle Aged; D012307:Risk Factors; D012878:Skin Neoplasms / Q000453:epidemiology / Q000235:genetics*; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6
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