Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

Abstract

Recurrent somatic single nucleotide variants (SNVs) in cancer are largely confined to protein coding genes, and are rare in most pediatric cancers 1-3. 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 tumor 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 tumors have significantly disrupted RNA splicing with an excess of 5′ cryptic splicing events. Mutant U1-snRNA mediated alternative splicing inactivates tumor 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. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Invited Review: DNA methylation‐based classification of paediatric brain tumours

“…Further guidance may be for directed germline testing as germline variants in PTCH1 , SUFU , GPR161 and TP53 are mostly restricted to SHH MBs, whereas APC germline alterations may be specific to WNT tumours and BRCA2 and PALB2 were identified across SHH, Group3 and Group 4 tumours . Recently, highly recurrent hotspot mutations of U1 spliceosomal small nuclear RNAs have been identified in around 50% of SHH MBs . Intriguingly, the mutations are almost exclusively found in the methylation class of adolescent and adult tumours and are virtually absent in infant cases, thus DNA methylation profiling may be used to identify cases to further test for this alteration.…”

“…Intriguingly, the mutations are almost exclusively found in the methylation class of adolescent and adult tumours and are virtually absent in infant cases, thus DNA methylation profiling may be used to identify cases to further test for this alteration. This unusual non‐protein‐coding mutation results in disrupted RNA splicing and may represent a future target for therapy .…”

Transcriptional analysis supports the expression of human snRNA variants and reveals U2 snRNA homeostasis by an abundant U2 variant

“…Lastly, mutations in multiple U2 snRNP components have been associated with various cancers and mutations to other snRNAs have been observed in various diseases and developmental disorders (reviewed in Padgett, 2012). SNPs in the canonical U1 snRNA genes are associated with various cancers Suzuki et al, 2019). Therefore, it is important to consider that disease-associated SNPs in either the canonical U2 snRNA array or expressed snRNA variants may exist but remain undetected.…”

Hnrnpul1 controls transcription, splicing, and modulates skeletal and limb development in vivo

“…Tissue specific phenotypes likely occur through varying composition of components of the spliceosome within different tissues, and through varying target transcript expression in tissues (reviewed in (Baralle and Giudice, 2017)). Improvements in sequencing technology have helped identify many disease-causing AS mutations, consequently our understanding of how global genome mutations in splicing regulatory networks impact tissue-specific development and disease has also expanded (Cieply and Carstens, 2015; Suzuki et al, 2019). We anticipate that each developmental phenotype we observe could be due to changes in multiple tissue-specific hnrnpul1 , making mechanistic analysis complex, but affirming the multi-system role of AS genes.…”