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7.1 INTRODUCTION

Cancer is fundamentally driven by genetic changes in normal cells that result in the acquisition of transformative malignant properties. These mutations permit the uncontrolled replication of the transformed cancer cells, a small fraction of which ultimately gains the ability to leave their tissue of origin and invade distant parts of the body where metastatic lesions are established. The second half of the 20th century witnessed a steady stream of breakthroughs in the field of cancer research, largely spurred by an explosion of technologies facilitating the analysis of tumors at a molecular level. Recent advances in low-cost high-throughput sequencing of cancer genomes (Chap. 2) are enabling a detailed mapping of the genetic events associated with the transformation of nonmalignant cells to metastatic cancer cells.

Comprehensive surveys of cancer genomes have highlighted the complexity of the disease and are also guiding the development of targeted anticancer treatments based on discrete molecular features (see Chap. 19). These efforts are revealing the extreme genetic heterogeneity that exists among tumors originating in the same tissue and, conversely, the similarities occasionally found in cancers arising in different tissues (see Chap. 13). Although a given tumor may harbor hundreds of mutations, only a few can truly be regarded as “driver” mutations that confer a selective growth advantage to transformed cells. The remaining “passenger” mutations result from the genetic instability of cancer cells without contributing actively to oncogenesis. Distinguishing between the driver and passenger mutations is critical for the identification of therapeutic targets and the development of tailored treatment regimens designed to maximize anti-cancer activity while minimizing side effects (Fig. 7–1) (Pon and Marra, 2015).

FIGURE 7–1

Passenger and driver mutations. Recent tumor sequencing efforts have revealed that transformed cells acquire a genetic landscape marked by the accumulation of numerous mutations. Among these genetic changes, however, are a much more limited subset of driver mutations that actively impart oncogenic properties, with the remaining passenger mutations representing inert changes that are neither selected for or against during tumorigenesis. Distinguishing between driver and passenger mutations is a critical research objective as the former represent potential therapeutic targets.

7.2 DISCOVERING THE GENETIC BASIS OF CANCER

7.2.1 Historical Perspective

The pronounced age dependence of cancer onset, coupled with the more limited life expectancies of premodern times, meant that cancer was a less prevalent killer than other diseases until comparatively recently. As a result, although humans have been afflicted by the disease since the beginning, references to cancer in the historical sources are scarce, and a proper understanding of its nature has long proved elusive. Hippocrates attributed the disease to an excess of “black bile,” one of the 4 constituent fluids the ancient Greeks believed made up the human body. Remarkably, this humoral theory ...

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