Genomics

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Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma


ABSTRACT: Follicular lymphoma (FL) is an incurable B-cell malignancy characterized by the t(14;18) and mutations in one or more components of the epigenome. Whilst frequent gene mutations in signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlap with the closely-related diffuse large B cell lymphoma (DLBCL). A combination of discovery exome and extended targeted sequencing revealed recurrent somatic mutations in RRAGC uniquely enriched in FL patients (17%). More than half of the mutations preferentially co-occurred with ATP6V1B2 and ATP6AP1 mutations, components of the vacuolar H+-adenosine triphosphate ATPase (v-ATPase) known to be necessary for amino acid-dependent mTORC1 activation. RagC mutants increased raptor binding whilst rendering mTORC1 signaling resistant to amino acid deprivation through nucleotide-independent mechanisms. Collectively, the activating nature of the RRAGC mutations, their existence within the dominant clone and stability during disease progression supports their potential as an excellent candidate to be therapeutically exploited.

PROVIDER: EGAS00001001190 | EGA |

REPOSITORIES: EGA

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Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma.

Okosun Jessica J   Wolfson Rachel L RL   Wang Jun J   Araf Shamzah S   Wilkins Lucy L   Castellano Brian M BM   Escudero-Ibarz Leire L   Al Seraihi Ahad Fahad AF   Richter Julia J   Bernhart Stephan H SH   Efeyan Alejo A   Iqbal Sameena S   Matthews Janet J   Clear Andrew A   Guerra-Assunção José Afonso JA   Bödör Csaba C   Quentmeier Hilmar H   Mansbridge Christopher C   Johnson Peter P   Davies Andrew A   Strefford Jonathan C JC   Packham Graham G   Barrans Sharon S   Jack Andrew A   Du Ming-Qing MQ   Calaminici Maria M   Lister T Andrew TA   Auer Rebecca R   Montoto Silvia S   Gribben John G JG   Siebert Reiner R   Chelala Claude C   Zoncu Roberto R   Sabatini David M DM   Fitzgibbon Jude J  

Nature genetics 20151221 2


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 R  ...[more]

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