Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

• Published in: Nature genetics Vol. 48; no. 2; pp. 183 - 188
• Main Authors: Okosun, Jessica, Wolfson, Rachel L, Wang, Jun, Araf, Shamzah, Wilkins, Lucy, Castellano, Brian M, Escudero-Ibarz, Leire, Al Seraihi, Ahad Fahad, Richter, Julia, Bernhart, Stephan H, Efeyan, Alejo, Iqbal, Sameena, Matthews, Janet, Clear, Andrew, Guerra-Assunção, José Afonso, Bödör, Csaba, Quentmeier, Hilmar, Mansbridge, Christopher, Johnson, Peter, Davies, Andrew, Strefford, Jonathan C, Packham, Graham, Barrans, Sharon, Jack, Andrew, Du, Ming-Qing, Calaminici, Maria, Lister, T Andrew, Auer, Rebecca, Montoto, Silvia, Gribben, John G, Siebert, Reiner, Chelala, Claude, Zoncu, Roberto, Sabatini, David M, Fitzgibbon, Jude
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2016; Nature Publishing Group
• Subjects: 45/23; 45/44; 45/91; 631/208/212; 692/699/1541/1990/291; Agriculture; Amino Acid Sequence; Amino acids; Animal Genetics and Genomics; Animals; Biomedicine; Blood diseases; Cancer; Cancer Research; Cloning; Deoxyribonucleic acid; Development and progression; DNA; Gene Function; Gene mutations; Genetic aspects; Genomes; Health aspects; Hematology; Human Genetics; Humans; Hypotheses; Identification and classification; letter; Lymphoma; Lymphoma, Follicular - genetics; Lymphomas; Mechanistic Target of Rapamycin Complex 1; Medical research; Molecular Sequence Data; Monomeric GTP-Binding Proteins - chemistry; Monomeric GTP-Binding Proteins - genetics; Multiprotein Complexes - chemistry; Multiprotein Complexes - genetics; Mutation; Phosphotransferases; Scholarships & fellowships; Sequence Homology, Amino Acid; TOR Serine-Threonine Kinases - chemistry; TOR Serine-Threonine Kinases - genetics; Translocation; Tumors
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3473

Jessica Okosun, David Sabatini and colleagues identify recurrent RRAGC mutations in follicular lymphoma, resulting in activated mTORC1 signaling. The activating nature of the mutations, their existence within the dominant clone and their stability during disease progression support the potential of these mutations as promising candidates for targeted therapy. Follicular lymphoma is an incurable B cell malignancy 1 characterized by the t(14;18) translocation and mutations affecting the epigenome 2 , 3 . Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined 2 , 3 , 4 , 5 , 6 , 7 , the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL) 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . Using a combination of discovery exome and extended targeted sequencing, we identified recurrent somatic mutations in RRAGC uniquely enriched in patients with follicular lymphoma (17%). More than half of the mutations preferentially co-occurred with mutations in ATP6V1B2 and ATP6AP1 , which encode components of the vacuolar H + -ATP ATPase (V-ATPase) known to be necessary for amino acid−induced activation of mTORC1. The RagC variants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation. The activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting.