Cancer is fundamentally a genetic disease. It results in expansion of a cellular population that invades and destroys surrounding organs and tissues and gains the ability to spread throughout the body. The second half of the 20th century inaugurated a steady stream of breakthroughs in the field of cancer research, largely spurred by an explosion of technologies enabling the analysis of tumors at a molecular level. Recent dramatic advancements in low-cost high-throughput sequencing of cancer genomes and the development of high-resolution genome-wide profiling of the changes in gene copy number and structure are enabling detailed mapping of the genetic events associated with cellular transformation from nonmalignant to malignant cell.
The emerging comprehensive surveys of cancer genomes are uncovering the complexity of the disease and are also beginning to guide the development of highly targeted anticancer treatments based on discrete molecular features. Importantly, these efforts are revealing the extreme genetic heterogeneity that exists amongst tumors with similar histopathology (see also Chap. 13, Sec. 13.2.2). Although a given tumor may harbor hundreds of mutations in protein coding regions, perhaps only 10 to 15 can truly be considered to be "driver" mutations that confer a selective growth advantage to transformed cells. The remaining "passenger" mutations result from the genetic instability of cancer cells without actively contributing to oncogenesis. Distinguishing between the driver and passenger mutations is critical for the identification of therapeutic targets and the development of tailored treatment regimens with the promise of maximizing anti-cancer activity whilst minimizing side effects (Fig. 7–1) (Carter et al, 2009; Carter et al, 2010).
Passenger and driver mutations. Tumor sequencing has revealed that transformed cells acquire a genetic landscape marked by the accumulation of numerous mutations. Amongst 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 THE GENETIC BASIS OF CANCER
7.2.1 Historical Perspective
The earliest recorded cases of cancer were documented in ancient Egypt around 1600 BC and described 8 cases of breast cancer along with a cauterization technique used to treat the disease. The term cancer itself was coined by the father of medicine, Hippocrates, who also advanced the theory that the origins of the disease resided in an excess of "black bile," 1 of the 4 constituent fluids the ancient Greeks believed made up the human body. Remarkably, this humoral theory persisted as the dominant explanation for cancer for nearly 2 millennia thereafter. The genesis of understanding cancer as a genetic disease is widely traced to experiments carried out more than a century ...