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Rare variant, gene-...
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Artomov, MykytaHarvard University,Broad Institute
(author)
Rare variant, gene-based association study of hereditary melanoma using whole-exome sequencing
- Article/chapterEnglish2017
Publisher, publication year, extent ...
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2017-06-03
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Oxford University Press (OUP),2017
Numbers
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LIBRIS-ID:oai:lup.lub.lu.se:fe57645c-531e-43e9-8f90-debe0c832ede
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https://lup.lub.lu.se/record/fe57645c-531e-43e9-8f90-debe0c832edeURI
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https://doi.org/10.1093/jnci/djx083DOI
Supplementary language notes
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Language:English
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Summary in:English
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Classification
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Subject category:art swepub-publicationtype
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Subject category:ref swepub-contenttype
Notes
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Background: Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Because the contribution of rare coding variants is not as well characterized, we performed an exome-wide, gene-based association study of familial cutaneous melanoma (CM) and ocular melanoma (OM). Methods: Using 11 990 jointly processed individual DNA samples, whole-exome sequencing was performed, followed by largescale joint variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used for statistical analysis of genetic variation. Fourmodels were used to estimate the association among different types of variants. In vitro functional validation was performed using three humanmelanoma cell lines in 2D and 3D proliferation assays. In vivo tumor growth was assessed using xenografts of humanmelanoma A375melanoma cells in nudemice (eightmice per group). All statistical tests were two-sided. Results: Strong signals were detected for CDKN2A (Pmin = 6.16×10-8) in the CM cohort (n=273) and BAP1 (Pmin = 3.83×10-6) in the OM (n=99) cohort. Eleven genes that exhibited borderline association (P < 10-4) were independently validated using The Cancer Genome Atlas melanoma cohort (379 CM, 47 OM) and a matched set of 3563 European controls with CDKN2A (P = .009), BAP1 (P = .03), and EBF3 (P = 4.75×10-4), a candidate risk locus, all showing evidence of replication. EBF3 was then evaluated using germline data from a set of 132 familial melanoma cases and 4769 controls of UK origin (joint P = 1.37×10-5). Somatically, loss of EBF3 expression correlated with progression, poorer outcome, and high MITF tumors. Functionally, induction of EBF3 in melanoma cells reduced cell growth in vitro, retarded tumor formation in vivo, and reduced MITF levels. Conclusions: The results of this large rare variant germline association study further define the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Stratigos, Alexander J.National and Kapodistrian University of Athens
(author)
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Kim, IvanaMassachusetts Eye and Ear Infirmary
(author)
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Kumar, RajMassachusetts General Hospital
(author)
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Lauss, MartinLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Melanoma Genomics,Forskargrupper vid Lunds universitet,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University Research Groups(Swepub:lu)med-mlu
(author)
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Reddy, Bobby Y.Massachusetts General Hospital
(author)
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Miao, BenchunMassachusetts General Hospital
(author)
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Robles-Espinoza, Carla DanielaWellcome Trust Sanger Institute,National Autonomous University of Mexico
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Sankar, AravindWellcome Trust Sanger Institute
(author)
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Njauw, Ching NiMassachusetts General Hospital
(author)
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Shannon, KristenMassachusetts General Hospital
(author)
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Gragoudas, Evangelos S.Massachusetts Eye and Ear Infirmary
(author)
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Lane, Anne MarieMassachusetts Eye and Ear Infirmary
(author)
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Iyer, VivekWellcome Trust Sanger Institute
(author)
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Newton-Bishop, Julia A.University of Leeds
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Bishop, D. TimothyUniversity of Leeds
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Holland, Elizabeth A.University of Sydney
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Mann, Graham J.University of Sydney
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Singh, TarjinderWellcome Trust
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Barrett, Jeffrey CWellcome Trust Sanger Institute
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Adams, David JWellcome Trust Sanger Institute
(author)
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Jönsson, GöranLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Lunds Melanomstudiegrupp,Forskargrupper vid Lunds universitet,Melanoma Genomics,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund Melanoma Study Group,Lund University Research Groups(Swepub:lu)onk-gjo
(author)
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Daly, Mark J.Broad Institute,Wellcome Trust
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Tsao, HensinMassachusetts General Hospital,Wellcome Trust
(author)
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Harvard UniversityBroad Institute
(creator_code:org_t)
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In:Journal of the National Cancer Institute: Oxford University Press (OUP)109:120027-88741460-2105
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Artomov, Mykyta
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Stratigos, Alexa ...
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Kim, Ivana
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Kumar, Raj
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Lauss, Martin
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Reddy, Bobby Y.
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Miao, Benchun
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Robles-Espinoza, ...
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Sankar, Aravind
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Njauw, Ching Ni
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Shannon, Kristen
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Gragoudas, Evang ...
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Lane, Anne Marie
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Iyer, Vivek
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Newton-Bishop, J ...
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Bishop, D. Timot ...
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Holland, Elizabe ...
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Mann, Graham J.
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Singh, Tarjinder
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Barrett, Jeffrey ...
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Adams, David J
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Jönsson, Göran
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Daly, Mark J.
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Tsao, Hensin
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
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Lund University