Journal
SCIENCE
Volume 362, Issue 6418, Pages 1055-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aau6509
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Funding
- Melanoma Research Foundation
- Dermatology Foundation
- Melanoma Research Alliance
- Ellison Foundation
- Starr Foundation
- V Foundation
- Terry Patters Melanoma Foundation
- National Cancer Institute [1R35CA220481, R01CA103846, K99CA201465, U24CA196067, T32HL007627]
- NATIONAL CANCER INSTITUTE [U24CA196067, R01CA103846, R35CA220481, K99CA201465] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL007627] Funding Source: NIH RePORTER
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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.
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