Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

Nat Genet. 2016 Feb;48(2):183-8. doi: 10.1038/ng.3473. Epub 2015 Dec 21.

Abstract

Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL). 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Humans
  • Lymphoma, Follicular / genetics*
  • Mechanistic Target of Rapamycin Complex 1
  • Molecular Sequence Data
  • Monomeric GTP-Binding Proteins / chemistry
  • Monomeric GTP-Binding Proteins / genetics*
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics*
  • Mutation*
  • Sequence Homology, Amino Acid
  • TOR Serine-Threonine Kinases / chemistry
  • TOR Serine-Threonine Kinases / genetics*

Substances

  • Multiprotein Complexes
  • RRAGC protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • Monomeric GTP-Binding Proteins