Genome Sequencing and RNA-Motif Analysis Reveal Novel Damaging Noncoding Mutations in Human Tumors

Babita Singh1, Juan L Trincado1, P J Tatlow2

  • 1Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), Barcelona, Spain.

Insights

A new method, MIRA, analyzes cancer mutations in noncoding RNA regions. It identifies how mutations in RNA-binding protein motifs impact RNA processing, offering insights into cancer genome variants.

Area of Science:

  • Genomics
  • Cancer Research
  • RNA Biology

Background:

  • Determining the significance of somatic mutations in noncoding cancer regions is challenging.
  • Previous studies focused on individual regulatory sites, not combinatorial effects on RNA motifs.
  • The role of mutations in common RNA regulatory motifs in cancer remains underexplored.

Purpose of the Study:

  • To develop a method for unbiased, comprehensive study of significantly mutated regions affecting RNA-binding protein (RBP) binding sites in cancer.
  • To investigate the combinatorial contribution of mutations to common RNA regulatory motifs.
  • To identify alterations in RNA expression and splicing linked to mutations on RBP binding sites.

Main Methods:

  • Developed MIRA (mutation identification for RNA alterations) for analyzing noncoding mutations.
  • Utilized RNA sequencing (RNA-seq) data alongside mutation data.
  • Identified significantly mutated regions (SMRs) impacting RBP binding sites.

Main Results:

  • Identified SRSF10, MBNL1, and HNRPLL motifs in introns and UTRs with specific mutational patterns.
  • Found mutations disrupting motifs and impacting RNA processing, including splicing.
  • Linked mutations in RBP binding sites to altered RNA expression and splicing.

Conclusions:

  • MIRA facilitates integrative analysis of multiple genome sites acting through common RBPs.
  • The study aids in interpreting noncoding variants in cancer genomes.
  • Identified novel alterations in introns, UTRs, and long noncoding RNAs affecting RNA processing.

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