title: Genetic variants in DNA repair genes and the risk of cutaneous malignant melanoma in melanoma-prone families with/without CDKN2A mutations.
abstract: Cutaneous malignant melanoma (CMM) is an etiologically heterogeneous disease with genetic, environmental (sun exposure) and host (pigmentation/nevi) factors and their interactions contributing to risk. Genetic variants in DNA repair genes may be particularly important since their altered function in response to sun exposure-related DNA damage maybe related to risk for CMM. However, systematic evaluations of genetic variants in DNA repair genes are limited, particularly in high-risk families. We comprehensively analyzed DNA repair gene polymorphisms and CMM risk in melanoma-prone families with/without CDKN2A mutations. A total of 586 individuals (183 CMM) from 53 families (23 CDKN2A (+), 30 CDKN2A (-)) were genotyped for 2964 tagSNPs in 131 DNA repair genes. Conditional logistic regression, conditioning on families, was used to estimate trend p-values, odds ratios and 95% confidence intervals for the association between CMM and each SNP separately, adjusted for age and sex. p-Values for SNPs in the same gene were combined to yield gene specific p-values. Two genes, POLN and PRKDC, were significantly associated with melanoma after Bonferroni correction for multiple testing (p = 0.0003 and 0.00035, respectively). DCLRE1B showed suggestive association (p = 0.0006). 28 ∼ 56% of genotyped SNPs in these genes had single SNP p < 0.05. The most significant SNPs in POLN and PRKDC had similar effects in CDKN2A (+) and CDKN2A (-) families. Our finding suggests that polymorphisms in DNA repair genes, POLN and PRKDC, were associated with increased melanoma risk in melanoma families with and without CDKN2A mutations.
authors.affiliation: Division of Cancer Epidemiology and Genetics, NCI/NIH, Bethesda, MD, USA.
authors.forename: Xueying Sharon
authors.initials: XS
authors.lastname: Liang
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Pfeiffer
authors.forename: William
authors.initials: W
authors.lastname: Wheeler
authors.forename: Dennis
authors.initials: D
authors.lastname: Maeder
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdette
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tucker
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.forename: Xiaohong R
authors.initials: XR
authors.lastname: Yang
mesh_terms: D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005090:Exodeoxyribonucleases; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D004259:DNA-Directed DNA Polymerase; C546205:POLN protein, human; C493741:DCLRE1B protein, human; D005090:Exodeoxyribonucleases; D045643:DNA Repair Enzymes