Translocations in normal B cells and cancers: insights from new technical approaches

Abstract

Chromosomal translocations are recurrent genetic events that define many types of cancers. Since their first description several decades ago as defining elements in cancer cells, our understanding of the mechanisms that determine their formation as well as their implications for cancer progression and therapy has remarkably progressed. Chromosomal translocations originate from double-strand breaks (DSBs) that are brought into proximity in the nuclear space and joined inappropriately by DNA-repair pathways. The frequency and pattern of translocations are influenced by perturbations of any of these events. DSB formation is heavily determined by physiologic processes, such as the activity of RAG1/2 and AID enzymes during B-cell development or maturation, or by pathologic factors, such as ionizing radiations, ROS, or fragile sites. Cellular processes of mRNA transcription, DNA replication, and repair can influence the chromosomal territories and modify the relative position and proximity of genes inside the nucleus. DNA-repair factors contribute not only to the maintenance of genome integrity but also to translocations in normal and cancer cells. Next-generation sequencing techniques provide an unprecedented and powerful tool to approach the field of chromosomal translocations. Using specific examples, we will explain how genome-wide translocation mapping methods, such as high-throughput genomic translocation sequencing (HTGTS) and translocation-capture sequencing, combined with large-scale methods to determine nuclear proximity of genes or chromosome domains, such as 4C and Hi-C, have changed our view of the factors and the rules governing translocation formation in noncancer cells. Finally, we will review chromosomal rearrangements and newly described findings, such as chromothripsis, in cancer cells based on these novel rules on translocation formation.