LAUSR

Simple Summary Cancers have many genetic mutations such as nucleotide changes, deletions, amplifications, and chromosome gains or losses. Some of these genetic alterations directly contribute to the initiation and progression of tumors. In parallel to these genetic changes, cancer cells acquire modifications to their chromatin landscape, i.e., to the marks that are carried by DNA and the histone proteins it is associated with. These “epimutations” have consequences for gene expression and genome stability, and also contribute to tumoral initiation and progression. Some of these chromatin changes are very local, affecting just one or a few genes. In contrast, some chromatin alterations observed in cancer are more widespread and affect a large part of the genome. In this review, we present different types of large-scale chromatin rearrangements in cancer, explain how they may occur, and why they are relevant for cancer diagnosis and treatment. Abstract Epigenetic abnormalities are extremely widespread in cancer. Some of them are mere consequences of transformation, but some actively contribute to cancer initiation and progression; they provide powerful new biological markers, as well as new targets for therapies. In this review, we examine the recent literature and focus on one particular aspect of epigenome deregulation: large-scale chromatin changes, causing global changes of DNA methylation or histone modifications. After a brief overview of the one-dimension (1D) and three-dimension (3D) epigenome in healthy cells and of its homeostasis mechanisms, we use selected examples to describe how many different events (mutations, changes in metabolism, and infections) can cause profound changes to the epigenome and fuel cancer. We then present the consequences for therapies and briefly discuss the role of single-cell approaches for the future progress of the field.