LAUSR

Somatic rearrangements resulting in genomic structural variation drive malignant phenotypes by altering the expression or function of cancer genes. Pan-cancer studies have revealed that structural variants (SVs) are the predominant class of driver mutation in most cancer types, but because they are difficult to discover, they remain understudied when compared with point mutations. This review provides an overview of the current knowledge of somatic SVs, discussing their primary roles, prevalence in different contexts, and mutational mechanisms. SVs arise throughout the life history of cancer, and 55% of driver mutations uncovered by the Pan-Cancer Analysis of Whole Genomes project represent SVs. Leveraging the convergence of cell biology and genomics, we propose a mechanistic classification of somatic SVs, from simple to highly complex DNA rearrangement classes. The actions of DNA repair and DNA replication processes together with mitotic errors result in a rich spectrum of SV formation processes, with cascading effects mediating extensive structural diversity after an initiating DNA lesion has formed. Thanks to new sequencing technologies, including the sequencing of single-cell genomes, open questions about the molecular triggers and the biomolecules involved in SV formation as well as their mutational rates can now be addressed. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 23 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.