Genome-wide analysis of somatic noncoding mutation patterns in cancer.

Abstract

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 <i>ALB</i> in the liver or <i>KLK3</i> 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 <i>BCL6</i>, <i>FGFR2</i>, <i>RAD51B</i>, <i>SMC6</i>, <i>TERT</i>, and <i>XBP1</i> and represent possible drivers. Unlike most noncoding regulatory events, <i>XBP1</i> 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.