RRAGC Mutations Activate mTORC1 Signaling in Follicular Lymphoma

Follicular lymphoma is a B-cell neoplasm with characteristic mutations in epigenetic regulators and the t(14;18) translocation. Genome-wide genetic profiling provides the opportunity to discover novel biomarkers. To address this, Okosun, Wolfson, and colleagues performed exome sequencing on successive tumor biopsies from five patients with follicular lymphoma. In the discovery cohort, 4 of 5 patients had somatic mutations in RAS-related GTP binding C (RRAGC) which were observed in the dominant clone and maintained during disease progression. Targeted sequencing of a larger cohort of patients with follicular lymphoma found RRAGC mutations in 17% of patients, which were primarily missense mutations in highly conserved residues in the nucleotide-binding domain. RRAGC mutations were rare in other hematologic malignancies and nonhematologic cancers, suggesting a functional importance of this mutation in follicular lymphoma. RRAGC encodes RagC, which forms heterodimers with other RAG proteins and complexes with the vacuolar ATPase (V-ATPase) to activate mTOR complex 1 (mTORC1). The genes encoding two subunits of the V-ATPase complex, ATP6V1B2 and ATP6AP1, were also frequently and mutually exclusively mutated in follicular lymphoma, and strongly correlated with the presence of RRAGC mutations. RNA sequencing of RRAGC-mutant follicular lymphoma tumors showed upregulation of mTOR targets compared to wild-type. The binding of RAG GTPase heterodimers to mTORC1 is essential for its amino acid–induced activation, and mutant RagC exhibited increased binding to the mTORC1 subunit Raptor. Further, RagC mutants activated mTORC1, even under conditions of amino acid deprivation. Taken together, these findings indicate that mutations in RRAGC activate mTORC1 signaling independent of amino acid availability and suggest that RagC may be an effective therapeutic target in follicular lymphoma.

Okosun J, Wolfson RL, Wang J, Araf S, Wilkins L, Castellano BM, et al. Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma. Nat Genet 2015 Dec 21 [Epub ahead of print].

• ©2016 American Association for Cancer Research.