Hotspot mutations in U1 snRNA are associated with several cancers and cause aberrant splicing.

  • Major Finding: Hotspot mutations in U1 snRNA are associated with several cancers and cause aberrant splicing.

  • Concept: These mutations are common in adult (97%) and adolescent (25%) Sonic Hedgehog medulloblastoma.

  • Impact: These studies establish a link between U1-hotspot mutations and cancer, especially medulloblastoma.

Mutations that cause genome-wide missplicing have recently been established to drive pathogenesis in some cancer types, but most spliceosomal mutations that have been characterized are in protein subunits of the spliceosome, whereas the spliceosome's RNA components have been understudied in comparison. In several cancer types, Shuai, Suzuki, Navarro, and colleagues found evidence of recurrent A-to-C and A-to-G mutations at the third nucleotide of U1 snRNA, a spliceosome component. U1 uses base pairing to recognize the 5′ splice site; thus, this mutation causes normal 5′ splice sites to be missed and creates aberrant splice junctions, including in recognized cancer drivers. These results provide evidence for a previously unknown mechanism by which splicing defects may promote cancer development. Notably, the group discovered that U1-hotspot mutations occurred with high frequency in medulloblastoma, a finding that was further investigated by Suzuki, Kumar, and colleagues. Their study revealed that hotspot mutations at the third nucleotide of U1 are present in 97% of tumors from adult patients with Sonic Hedgehog medulloblastoma (SHH-MB), 25% of tumors from adolescent patients with SHH-MB, and essentially no tumors from infant patients with SHH-MB; the mutation was also absent in tumors from patients with other medulloblastoma subtypes. Interestingly, the A-to-G mutation occurred in 10% of patients with the aggressive subtype of chronic lymphocytic leukemia, a disease that lies on the other end of the age spectrum compared with medulloblastoma. Further analysis demonstrated that adolescent patients with SHH-MB who had U1-hotspot mutations and TP53 mutations had significantly worse prognoses than those without the mutations, suggesting that prioritizing this patient group for targeted therapies may be warranted. Together, these two studies illustrate the potential value of broadening the range of genomic regions explored when searching for cancer drivers.

Shuai S, Suzuki H, Diaz-Navarro A, Nadeu F, Kumar SA, Gutierrez-Fernandez A, et al. The U1 spliceosomal RNA is recurrently mutated in multiple cancers. Nature 2019 Oct 9 [Epub ahead of print].

Suzuki H, Kumar SA, Shuai S, Diaz-Navarro A, Gutierrez-Fernandez A, De Antonellis P, et al. Recurrent non-coding U1-snRNA mutations drive cryptic splicing in Shh medulloblastoma. Nature 2019;574:707–11.

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