title: Rare Germline Copy Number Variations and Disease Susceptibility in Familial Melanoma.
abstract: Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and single nucleotide polymorphism arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g., PARP1, CDKN2A) or cosegregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare cosegregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shi
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Weiyin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hyland
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.
authors.forename: Hunter
authors.initials: H
authors.lastname: Bennett
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.
authors.forename: Yanzi
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Xijun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA; Statistics Collaborative, Inc., Washington, DC, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Burke
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Song
authors.affiliation: Computational Genomics Research Group, Center for Biomedical Informatics & Information Technology, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Chih Hao
authors.initials: CH
authors.lastname: Hsu
authors.affiliation: Computational Genomics Research Group, Center for Biomedical Informatics & Information Technology, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yan
authors.affiliation: Computational Genomics Research Group, Center for Biomedical Informatics & Information Technology, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Qingrong
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Computational Genomics Research Group, Center for Biomedical Informatics & Information Technology, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Daoud
authors.initials: D
authors.lastname: Meerzaman
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Casey L
authors.initials: CL
authors.lastname: Dagnall
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdette
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Belynda
authors.initials: B
authors.lastname: Hicks
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Freedman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tucker
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.
authors.forename: Alisa M
authors.initials: AM
authors.lastname: Goldstein
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA. Electronic address: royang@mail.nih.gov.
authors.forename: Xiaohong R
authors.initials: XR
authors.lastname: Yang
mesh_terms: D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D015994:Incidence; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D018570:Risk Assessment; D017423:Sequence Analysis, RNA; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D000096142:Cutaneous Malignant Melanoma