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Comparative genomic...
Comparative genomics reveals that loss of lunatic fringe (LFNG) promotes melanoma metastasis
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- Del Castillo Velasco-Herrera, Martin (author)
- Wellcome Trust Sanger Institute
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- van der Weyden, Louise (author)
- Wellcome Trust Sanger Institute
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- Nsengimana, Jeremie (author)
- St James's University Hospital
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- Speak, Anneliese O. (author)
- Wellcome Trust Sanger Institute
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- Sjöberg, Marcela K. (author)
- Pontifical Catholic University of Chile
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- Bishop, David Timothy (author)
- St James's University Hospital
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- Jönsson, Göran (author)
- Lund University,Lunds universitet,Melanoma Genomics,Forskargrupper vid Lunds universitet,Lund University Research Groups,Skåne University Hospital
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- Newton-Bishop, Julia (author)
- St James's University Hospital
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- Adams, David J. (author)
- Wellcome Trust Sanger Institute
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(creator_code:org_t)
- 2018-01-07
- 2018
- English.
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In: Molecular Oncology. - : Wiley. - 1574-7891. ; 12:2, s. 239-255
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Abstract
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- Metastasis is the leading cause of death in patients with advanced melanoma, yet the somatic alterations that aid tumour cell dissemination and colonisation are poorly understood. Here, we deploy comparative genomics to identify and validate clinically relevant drivers of melanoma metastasis. To do this, we identified a set of 976 genes whose expression level was associated with a poor outcome in patients from two large melanoma cohorts. Next, we characterised the genomes and transcriptomes of mouse melanoma cell lines defined as weakly metastatic, and their highly metastatic derivatives. By comparing expression data between species, we identified lunatic fringe (LFNG), among 28 genes whose expression level is predictive of poor prognosis and whose altered expression is associated with a prometastatic phenotype in mouse melanoma cells. CRISPR/Cas9-mediated knockout of Lfng dramatically enhanced the capability of weakly metastatic melanoma cells to metastasise in vivo, a phenotype that could be rescued with the Lfng cDNA. Notably, genomic alterations disrupting LFNG are found exclusively in human metastatic melanomas sequenced as part of The Cancer Genome Atlas. Using comparative genomics, we show that LFNG expression plays a functional role in regulating melanoma metastasis.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- Comparative genomics
- CRISPR
- Melanoma
- RNA-Seq
Publication and Content Type
- art (subject category)
- ref (subject category)
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