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Science. 2018 Nov 30;362(6418):1055-1060. doi: 10.1126/science.aau6509. Epub 2018 Nov 1.

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

Ablain J#1, Xu M#2,3, Rothschild H1, Jordan RC2,4,5, Mito JK1,6, Daniels BH2,4, Bell CF7, Joseph NM4, Wu H8, Bastian BC#2,3, Zon LI#9,10,11, Yeh I#12,3.

Author information

1
Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02115, USA.
2
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
5
Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
6
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
7
Department of Medicine, Stanford University Medical Center, Stanford, CA 94305, USA.
8
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
9
Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02115, USA. iwei.yeh@ucsf.edu leonard.zon@enders.tch.harvard.edu.
10
Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
11
Howard Hughes Medical Institute, Boston Children's Hospital and Harvard University, Boston, MA 02115, USA.
12
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. iwei.yeh@ucsf.edu leonard.zon@enders.tch.harvard.edu.
#
Contributed equally

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 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.

PMID:
30385465
PMCID:
PMC6475924
DOI:
10.1126/science.aau6509
[Indexed for MEDLINE]
Free PMC Article

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