Human Tumor Genomics and Zebrafish Modeling Identify Loss As a Driver of Mucosal Melanoma

Overview

Journal Science

Specialty Science

Date 2018 Nov 3

PMID 30385465

Citations 78

Authors

Julien Ablain

Mengshu Xu

Harriet Rothschild

Richard C Jordan

Jeffrey K Mito

Brianne H Daniels

Caitlin F Bell

Nancy M Joseph

Hong Wu

Boris C Bastian

Leonard I Zon

Iwei Yeh

Affiliations

Soon will be listed here.

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 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.

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