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

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Science  30 Nov 2018:
Vol. 362, Issue 6418, pp. 1055-1060
DOI: 10.1126/science.aau6509

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Hunting and fishing for cancer genes

Mucosal melanoma is a rare, but deadly, form of melanoma that occurs in sun-protected tissues. Little is known about the genetic alterations that drive the growth of these tumors. Ablain et al. sequenced mucosal melanomas from 43 patients and found that a substantial fraction showed inactivation or loss of SPRED1, a gene that encodes a negative regulator of RAS–MAPK (mitogen-activated protein kinase) signaling. Using a platform called MAZERATI (Modeling Approach in Zebrafish for Rapid Tumor Initiation), they discovered that SPRED1 loss may help explain the poor response of melanoma patients to drugs that inhibit the KIT tyrosine kinase. The results suggest that a combination of KIT inhibitors and drugs that inhibit MAPK signaling may be more effective.

Science, this issue p. 1055

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.

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