Ablain, J., Xu, M., Rothschild, H., Jordan, R.C., Mito, J.K., Daniels, B.H., Bell, C.F., Joseph, N.M., Wu, H., Bastian, B.C., Zon, L.I., Yeh, I. (2018) Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma.. Science (New York, N.Y.). 362(6418):1055-1060.
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, cataloguing point mutations, amplifications and deletions. The SPRED1 gene, which encodes a negative regulator of 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.