The role of genome composition and activation in shaping the translocation landscape in health and disease.

Translocations are rearrangements produced upon erroneous repair of double-strand breaks, fusing segments of non-homologous chromosomes. These events can cause chimeric protein expression and other transcriptional alterations, eventually driving oncogenic transformation. Despite their significance, the factors shaping the heterogeneous translocation landscape in healthy individuals and cancer patients remain incompletely understood. In this review, we focus on genomic content and activation as two fundamental factors associated with translocation formation and selection. While emphasizing the critical role of double-strand breaks and interchromosomal contacts in translocation formation, we discuss that selective advantage is likely the main driver shaping translocation landscapes in health and disease. Finally, we address that it remains difficult to disentangle the effect of translocation formation from the influence of selective pressure, and point out that unraveling their separate contribution in future studies will be key to better understand early tumorigenesis.