biostudies-literatureAblain JThe Ellison FoundationMelanoma Research FoundationHoward Hughes Medical InstituteNHLBI NIH HHSNational Cancer InstituteMelanoma Research AllianceNCI NIH HHSDermatology FoundationNational Institutes of HealthV Foundation for Cancer ResearchTerry Patters Melanoma Foundation1055-1060https://www.ebi.ac.uk/biostudies/studies/S-EPMC6475924biostudies-literatureUnknown362(6418)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 <i>SPRED1</i> 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 <i>SPRED1</i> loss. Using a rapid, tissue-specific CRISPR technique to model these genotypes in zebrafish, we found that <i>SPRED1</i> functions as a tumor suppressor, particularly in the context of <i>KIT</i> mutations. <i>SPRED1</i> knockdown caused MAPK activation, increased cell proliferation, and conferred resistanScience (New York, N.Y.)Human tumor genomics and zebrafish modeling identify &lt;i&gt;SPRED1&lt;/i&gt; loss as a driver of mucosal melanoma.PMC6475924R35 CA220481K99CA201465T32 HL007627P01 CA163222R01 CA103846U24CA196067K99 CA2014651R35CA220481U24 CA196067R01CA103846Yeh IXu MJordan RCRothschild HBastian BCZon LIAblain JMito JKBell CFJoseph NMDaniels BHWu HfalseHuman tumor genomics and zebrafish modeling identify &lt;i&gt;SPRED1&lt;/i&gt; 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 <i>SPRED1</i> 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 <i>SPRED1</i> loss. Using a rapid, tissue-specific CRISPR technique to model these genotypes in zebrafish, we found that <i>SPRED1</i> functions as a tumor suppressor, particularly in the context of <i>KIT</i> mutations. <i>SPRED1</i> knockdown caused MAPK activation, increased cell proliferation, and conferred resistan2018-01-01T00:00:00Z2018 Nov2026-05-04T21:04:27.035Z2019-06-06T22:47:03ZS-EPMC64759243038546510.1126/science.aau6509