Human tumor genomics and zebrafish modeling identify <i>SPRED1</i> loss as a driver of mucosal melanoma.

ABSTRACT: 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 SPRED1 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 SPRED1 loss. Using a rapid, tissue-specific CRISPR technique to model these genotypes in zebrafish, we found that SPRED1 functions as a tumor suppressor, particularly in the context of KIT mutations. SPRED1 knockdown caused MAPK activation, increased cell proliferation, and conferred resistan

SUBMITTER: Ablain J 

PROVIDER: S-EPMC6475924 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature