Discovery of driver non-coding splice-site-creating mutations in cancer

Area of Science:

• Genomics
• Molecular Biology
• Cancer Research

Background:

• Somatic non-coding mutations' impact on RNA splicing is largely unexplored.
• Conventional annotation pipelines often overlook splice-altering mutations.

Purpose of the Study:

• To investigate the extent and consequences of non-coding mutations affecting RNA splicing.
• To introduce and utilize the MiSplice pipeline for analyzing splicing alterations.

Main Methods:

• Analysis of whole-genome sequencing (WGS) data from 783 cancer cases.
• Analysis of whole-exome sequencing (WES) data from 9494 cancer cases using the MiSplice pipeline.

Main Results:

• Discovery of 562 non-coding mutations causing splicing alterations.
• Identification that most mutations create new exons, often in larger introns.
• Observed alterations in cancer-associated genes (e.g., TP53, ATRX), leading to truncated proteins.

Conclusions:

• Non-coding splice-inducing mutations can significantly impact gene expression and protein function in cancer.
• The findings highlight the importance of studying these previously neglected mutations.
• The MiSplice pipeline is a valuable tool for future large-scale mutation analysis.