++
CANCER IS A GENETIC DISEASE
++
Cancer arises through a series of somatic alterations in DNA that result in unrestrained cellular proliferation. Most of these alterations involve subtle sequence changes in DNA (i.e., mutations). The somatic mutations may originate as a consequence of random replication errors or exposure to carcinogens (e.g., radiation) and can be exacerbated by faulty DNA repair processes. While most cancers arise sporadically, clustering of cancers occurs in families that carry a germline mutation in a cancer gene.
++
HISTORICAL PERSPECTIVE
++
The idea that cancer progression is driven by sequential somatic mutations in specific genes has only gained general acceptance in the past 30 years. Before the advent of the microscope, cancer was believed to be composed of aggregates of mucus or other noncellular matter. By the middle of the nineteenth century, it became clear that tumors were masses of cells and that these cells arose from the normal cells of the tissue from which the cancer originated. The molecular basis for the uncontrolled proliferation of cancer cells was to remain a mystery for another century. During that time, a number of theories for the origin of cancer were postulated. The great biochemist Otto Warburg proposed the combustion theory of cancer, which stipulated that cancer was due to abnormal oxygen metabolism. Others believed that all cancers were caused by viruses, and that cancer was in fact a contagious disease.
++
In the end, observations of cancer occurring in chimney sweeps, studies of x-rays, and the overwhelming data demonstrating cigarette smoke as a causative agent in lung cancer, together with Ames’s work on chemical mutagenesis, were consistent with the idea that cancer originated through changes in DNA. However, it was not until the somatic mutations responsible for cancer were identified at the molecular level that the genetic basis of cancer was definitively established. Although the viral theory of cancer did not prove to be generally accurate (with the exception of human papillomaviruses, which can cause cervical and other cancers), the study of retroviruses led to the discovery of the first human oncogenes in the late 1970s. Oncogenes are one of the two major classes of cancer driver genes. The study of families with genetic predisposition to cancer was instrumental to the discovery of the other major class of cancer driver genes, called tumor-suppressor genes. Current technologies permit the sequence analysis of entire cancer genomes, and provide a comprehensive view of the genetic changes that cause tumors to arise and become malignant. The field that studies the various types of mutations, as well as the consequences of these mutations in tumor cells, is now known as cancer genetics.
++
THE CLONAL ORIGIN AND MULTISTEP NATURE OF CANCER
++
Nearly all cancers originate from a single cell; this clonal origin is a critical discriminating feature between neoplasia and hyperplasia. Multiple cumulative mutational events are invariably required for the progression ...