Somatic Mutation Events Were Characterized Across the Whole Cancer Genome

Despite the well-studied functions of protein-coding somatic mutations in driving cancer, the role of somatic mutations in noncoding regions of the genome remain understudied. This is due, in part, to the difficulties in detecting and interpreting these mutation events. Building on the work of the Pan-Cancer Analysis of Whole Genomes and Hartwig Medical Foundation consortium studies, Dietlein and colleagues sought to address this issue by identifying events of point mutations as well as short insertions and deletions across the entire somatic genomes of 3,949 patients across 19 different cancer types. This approach classified events by their genomic location and identified 142 events in coding regions, including in oncogenes and tumor suppressors; 73 events in regulatory regions such as promoter and enhancer regions; 70 events near tissue-specific genes, such as genes expressed in a unique tissue type; and 87 events in the “other” category, which includes events with an unclear role. Mutations in coding regions of the genome included well-known cancer genes, and mutations in regulatory regions were also enriched for typical cancer-related genes. Conversely, events occurring near tissue-specific genes were not typically found in cancer-specific genes but were associated with genes that held physiologic functions within a specific tissue type. Systematic follow-up assessed this approach's ability to detect mutation events, revealing a connection between tissue-specific events and the cell of origin in tumor development as well as differential expression between mutated and nonmutated samples for a few mutation events. Furthermore, some noncoding mutations were found to exhibit direct physical interactions with established driver genes, and some events within the regulatory category were found to be associated with differences in survival. Luciferase reporter experiments and CRISPR interference screening were performed on mutations surrounding XBP1 and indicated their ability to increase its expression and activity in breast tumors. Thus, this study establishes an approach for identifying and classifying somatic mutation events across the entire genome and may allow for future evaluation of noncoding genes relevant to cancer progression and therapy development.

Dietlein F, Wang AB, Fagre C, Tang A, Besselink NJM, Cuppen E, et al. Genome-wide analysis of somatic noncoding mutation patterns in cancer. Science 2022;376:eabg5601.

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