Structural Chromosome Instability: Types, Origins, Consequences, and Therapeutic Opportunities

SIMPLE SUMMARY: Chromosome instability (CIN) is characterized by an increased accumulation of numerical and structural changes in chromosomes and is a common feature of solid tumors and some hematological malignancies. CIN has been extensively linked to tumorigenesis, cancer progression, and tumor resistance. However, in recent years CIN phenotypes are increasingly being harnessed for therapeutic purposes. In this review, we describe the origins of structural CIN phenotypes and highlight novel pathways for their resolution. We also discuss how CIN can be avoided or enhanced and the implications of these pathways for cell survival and thus, cancer treatments. ABSTRACT: Chromosomal instability (CIN) refers to an increased rate of acquisition of numerical and structural changes in chromosomes and is considered an enabling characteristic of tumors. Given its role as a facilitator of genomic changes, CIN is increasingly being considered as a possible therapeutic target, raising the question of which variables may convert CIN into an ally instead of an enemy during cancer treatment. This review discusses the origins of structural chromosome abnormalities and the cellular mechanisms that prevent and resolve them, as well as how different CIN phenotypes relate to each other. We discuss the possible fates of cells containing structural CIN, focusing on how a few cell duplication cycles suffice to induce profound CIN-mediated genome alterations. Because such alterations can promote tumor adaptation to treatment, we discuss currently proposed strategies to either avoid CIN or enhance CIN to a level that is no longer compatible with cell survival.