Genome-wide analysis of somatic noncoding mutation patterns in cancer

We established a genome-wide compendium of somatic mutation events in 3949 whole cancer genomes representing 19 tumor types. Protein-coding events captured well-established drivers. Noncoding events near tissue-specific genes, such as ALB in the liver or KLK3 in the prostate, characterized localized passenger mutation patterns and may reflect tumor-cell-of-origin imprinting. Noncoding events in regulatory promoter and enhancer regions frequently involved cancer-relevant genes such as BCL6, FGFR2, RAD51B, SMC6, TERT, and XBP1 and represent possible drivers. Unlike most noncoding regulatory events, XBP1 mutations primarily accumulated outside the gene's promoter, and we validated their effect on gene expression using CRISPR-interference screening and luciferase reporter assays. Broadly, our study provides a blueprint for capturing mutation events across the entire genome to guide advances in biological discovery, therapies, and diagnostics.

Automated summary

We established a comprehensive map of somatic mutation events in the whole cancer genomes, representing 19 tumor types. We found that protein-coding events and noncoding events play different roles in tumors, and noncoding events may be potential drivers. We also discovered that XBP1 mutations primarily accumulate outside the gene's promoter and impact gene expression.