Targeted sequencing identifies biallelic SPRED1 inactivation in 16 of 43 patients with mucosal melanoma.
Major finding: Targeted sequencing identifies biallelic SPRED1 inactivation in 16 of 43 patients with mucosal melanoma.
Concept: In zebrafish SPRED1 loss cooperates with KIT mutations to activate MAPK and accelerate tumor growth.
Impact: SPRED1 mutations in patients with mucosal melanoma may potentially sensitize to MAPK inhibition.
Mucosal melanomas are distinct from UV-induced melanomas in that they harbor fewer point mutations and are instead characterized by genomic instability with amplifications and deletions. Unlike cutaneous melanomas, mucosal melanomas rarely harbor known MAPK-activating alterations, but the genetics of mucosal melanomas remain poorly characterized. Recurrent activating mutations in KIT have been identified in 15% of patients, but KIT inhibitors have not produced durable clinical responses. Patients with mucosal melanoma have a poor prognosis in part due to the lack of targeted therapies. Ablain, Xu, and colleagues performed targeted sequencing of cancer-related genes in tumors from 43 patients with mucosal melanoma to identify oncogenic drivers and potential therapeutic targets. SPRED1, which encodes a negative regulator RAS/MAPK pathway signaling, was subject to inactivation in 37% of the tumors, suggesting that it may act as a tumor suppressor. SPRED1 recruits NF1 to the plasma membrane to catalyze the conversion of active RAS to inactive RAS, and SPRED1 loss was mutually exclusive with NF1 biallelic mutations, which occurred in 12% of patients. SPRED1 mutations did co-occur with KIT alterations, with 30% of tumors with SPRED1 loss also harboring KIT alterations. Based on these findings, spred1 was deleted in zebrafish melanocytes to determine if it acts as a tumor suppressor in vivo. spred1 deletion accelerated melanoma growth in combination with oncogenic drivers, such as KIT mutations, indicating that SPRED1 is a tumor suppressor. SPRED1 loss in KIT-mutant human melanoma cells increased MAPK activity and proliferation. Further, SPRED1 depletion conferred resistance to KIT inhibitors in KIT-mutant melanoma cells. Collectively, these findings indicate that SPRED1 is a tumor suppressor subject to inactivating mutations in mucosal melanoma and suggest the potential for treating SPRED1-deficient melanoma with MAPK inhibitors.
Ablain J, Xu M, Rothschild H, Jordan RC, Mito JK, Daniels BH, et al. Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma. Science 2018 Nov 1 [Epub ahead of print].
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