Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma

Melanomas originating from mucosal surfaces have low mutation burden, genomic instability, and poor prognosis. To identify potential driver genes, we sequenced hundreds of cancer-related genes in 43 human mucosal melanomas, cataloging point mutations, amplifications, and deletions. The gene, which e...

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Bibliographic Details
Published in:	Science (American Association for the Advancement of Science) 2018-11, Vol.362 (6418), p.1055-1060
Main Authors:	Ablain, Julien, Xu, Mengshu, Rothschild, Harriet, Jordan, Richard C, Mito, Jeffrey K, Daniels, Brianne H, Bell, Caitlin F, Joseph, Nancy M, Wu, Hong, Bastian, Boris C, Zon, Leonard I, Yeh, Iwei
Format:	Article
Language:	eng
Subjects:	Adaptor Proteins, Signal Transducing Animals Cancer Cell activation Cell proliferation CRISPR Danio rerio Deactivation Drug resistance Drug Resistance, Neoplasm - genetics Drugs Fishing Gene Deletion Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Genes Genes, Neoplasm Genomic instability Genomics Genotypes Humans Hunting Inactivation Intracellular Signaling Peptides and Proteins - genetics Kinases Life Sciences MAP kinase Melanoma Melanoma - genetics Melanoma - pathology Melanoma, Experimental - genetics Membrane Proteins - genetics Mitogen-Activated Protein Kinases - genetics Mitogen-Activated Protein Kinases - metabolism Modelling Mucosa Mucous Membrane - enzymology Mucous Membrane - pathology Mutation Narcotics Patients Protein-tyrosine kinase Proteins Proto-Oncogene Proteins c-kit - genetics Signal Transduction Signaling Skin Neoplasms - genetics Skin Neoplasms - pathology Tissues Tumor suppressor genes Tumors Tyrosine Zebrafish
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Summary:	Melanomas originating from mucosal surfaces have low mutation burden, genomic instability, and poor prognosis. To identify potential driver genes, we sequenced hundreds of cancer-related genes in 43 human mucosal melanomas, cataloging point mutations, amplifications, and deletions. The gene, which encodes a negative regulator of mitogen-activated protein kinase (MAPK) signaling, was inactivated in 37% of the tumors. Four distinct genotypes were associated with loss. Using a rapid, tissue-specific CRISPR technique to model these genotypes in zebrafish, we found that functions as a tumor suppressor, particularly in the context of mutations. knockdown caused MAPK activation, increased cell proliferation, and conferred resistance to drugs inhibiting KIT tyrosine kinase activity. These findings provide a rationale for MAPK inhibition in SPRED1-deficient melanomas and introduce a zebrafish modeling approach that can be used more generally to dissect genetic interactions in cancer.
ISSN:	0036-8075 1095-9203