Molecular and Cellular Changes During Cancer Progression Resulting From Genetic and Epigenetic Alterations

Tumorigenesis is a complex process that involves a persistent dismantling of cellular safeguards and checkpoints. These molecular and cellular changes that accumulate over months or decades lead to a change in the fundamental identity of a cell as it transitions from normal to malignant. In this chapter, we will examine some of the molecular changes in the evolving relationship between the genome and epigenome and highlight some of the key changes that occur as normal cells progress to tumor cells. For many years tumorigenesis was almost exclusively attributed to mutations in protein-coding genes. This notion that mutations in protein-coding genes were a fundamental driver of tumorigenesis enabled the development of several novel therapeutics that targeted the mutant protein or overactive pathway responsible for driving a significant portion of the tumor growth. However, because many therapeutic challenges remained in the face of these advances, it was clear that other pieces to the puzzle had yet to be discovered. Advances in molecular and genomics techniques continued and the study of epigenetics began to expand and helped reshape the view that drivers of tumorigenesis extended beyond mutations in protein-coding genes. Studies in the field of epigenetics began to identify aberrant epigenetic marks which created altered chromatin structures and enabled protein expression in tissues that defied rules governing tissue-specificity. Not only were epigenetic alterations found to enable overexpression of proto-oncogenes, they also led to the silencing of tumor suppressor genes. With these discoveries, it became clear that tumor growth could be stimulated by much more than mutations in protein-coding genes. In fact, it became increasingly clear that much of the human genome, while transcribed, did not lead to proteins. This discovery further led to studies that began to uncover the role of noncoding RNAs in regulating chromatin structure, gene transcription, and tumor biology. In this chapter, some of the key alterations in the genome and epigenome will be explored, and some of the cancer therapies that were developed as a result of these discoveries will be discussed.