Recurrent non-coding U1-snRNA mutations drive cryptic splicing in Shh medulloblastoma
Menée à partir d'échantillons tumoraux prélevés sur des patients atteints d'un médulloblastome Shh, cette étude met en évidence le rôle, dans l'altération des processus d'épissage, l'inactivation de gènes suppresseurs de tumeur et l'activation d'oncogènes, de mutations récurrentes non codantes au niveau du gène du petit ARN nucléaire U1
Recurrent somatic single nucleotide variants (SNVs) in cancer are largely confined to protein-coding genes, and are rare in most paediatric cancers1–3. Here we report highly recurrent hotspot mutations of U1 spliceosomal small nuclear RNAs (snRNAs) in ~50% of Sonic hedgehog medulloblastomas (Shh-MB), which were not present across other medulloblastoma subgroups. This U1-snRNA hotspot mutation (r.3a>g), was identified in <0.1% of 2,442 cancers across 36 other tumour types. Largely absent from infant Shh-MB, the mutation occurs in 97% of adults (Shhδ), and 25% of adolescents (Shhα). The U1-snRNA mutation occurs in the 5′ splice site binding region, and snRNA mutant tumours have significantly disrupted RNA splicing with an excess of 5′ cryptic splicing events. Mutant U1-snRNA-mediated alternative splicing inactivates tumour suppressor genes (PTCH1), and activates oncogenes (GLI2, CCND2), represents a novel target for therapy, and constitutes a highly recurrent and tissue-specific mutation of a non-protein coding gene in cancer.