Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Recurrent somatic variants in cancer are typically rare in pediatric cancers and primarily affect protein-coding genes.
• U1 spliceosomal small nuclear RNAs (snRNAs) are crucial components of the spliceosome, involved in RNA splicing.

Purpose of the Study:

• To investigate the role of mutations in non-coding genes, specifically U1 snRNAs, in paediatric cancers.
• To identify recurrent mutations in U1 snRNAs within specific medulloblastoma subgroups.

Main Methods:

• Whole-exome sequencing and variant analysis of medulloblastoma samples.
• RNA sequencing to assess splicing patterns and identify cryptic splicing events.
• Analysis of mutation frequency across different cancer types and patient demographics.

Main Results:

• Discovery of highly recurrent hotspot mutations (r.3A>G) in U1 snRNA in approximately 50% of Sonic hedgehog (SHH) medulloblastomas.
• These U1 snRNA mutations were found in 97% of adult and 25% of adolescent SHH medulloblastomas, but rarely in infant cases or other cancer types (<0.1%).
• Mutations in U1 snRNA lead to disrupted RNA splicing, increased 5' cryptic splicing, inactivation of tumor suppressors (PTCH1), and activation of oncogenes (GLI2, CCND2).

Conclusions:

• U1 snRNA mutations represent a novel class of highly recurrent, tissue-specific mutations in a non-coding gene in cancer.
• These mutations significantly alter gene expression through aberrant splicing, driving SHH medulloblastoma development.
• Targeting the alternative splicing mediated by mutant U1 snRNA presents a potential therapeutic strategy for SHH medulloblastomas.