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Rare variant, gene-...
Rare variant, gene-based association study of hereditary melanoma using whole-exome sequencing
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- Artomov, Mykyta (författare)
- Harvard University,Broad Institute
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- Stratigos, Alexander J. (författare)
- National and Kapodistrian University of Athens
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- Kim, Ivana (författare)
- Massachusetts Eye and Ear Infirmary
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- Kumar, Raj (författare)
- Massachusetts General Hospital
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- Lauss, Martin (författare)
- Lund 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
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- Reddy, Bobby Y. (författare)
- Massachusetts General Hospital
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- Miao, Benchun (författare)
- Massachusetts General Hospital
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- Robles-Espinoza, Carla Daniela (författare)
- Wellcome Trust Sanger Institute,National Autonomous University of Mexico
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- Sankar, Aravind (författare)
- Wellcome Trust Sanger Institute
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- Njauw, Ching Ni (författare)
- Massachusetts General Hospital
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- Shannon, Kristen (författare)
- Massachusetts General Hospital
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- Gragoudas, Evangelos S. (författare)
- Massachusetts Eye and Ear Infirmary
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- Lane, Anne Marie (författare)
- Massachusetts Eye and Ear Infirmary
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- Iyer, Vivek (författare)
- Wellcome Trust Sanger Institute
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- Newton-Bishop, Julia A. (författare)
- University of Leeds
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- Bishop, D. Timothy (författare)
- University of Leeds
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- Holland, Elizabeth A. (författare)
- University of Sydney
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- Mann, Graham J. (författare)
- University of Sydney
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- Singh, Tarjinder (författare)
- Wellcome Trust
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- Barrett, Jeffrey C (författare)
- Wellcome Trust Sanger Institute
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- Adams, David J (författare)
- Wellcome Trust Sanger Institute
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- Jönsson, Göran (författare)
- Lund 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
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- Daly, Mark J. (författare)
- Broad Institute,Wellcome Trust
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- Tsao, Hensin (författare)
- Massachusetts General Hospital,Wellcome Trust
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(creator_code:org_t)
- 2017-06-03
- 2017
- Engelska.
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 109:12
- Relaterad länk:
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http://dx.doi.org/10...
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https://academic.oup...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
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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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
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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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visa fler...
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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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