Common cancers--genetics, origin, prevention, screening: Parts I and II

Carcinogenesis is a stepwise process that occurs through mutations of cancer-related genes. Five or more genes must be mutated before malignant transformation occurs in most adult cancers; in some childhood cancers as few as two mutated genes may be sufficient. A rare inherited mutation of a critical gene may predestine cancer to occur in one or more sites. This germline mutation is present in virtually every cell in the body, except half of the germ cells, which do not contain the mutated gene in their haploid chromosome set. These and other genes have been used to piece together a puzzle of regulatory systems that govern cell division and proliferation, as well as apoptosis or programmed cell death. Mutations of these genes result not only in increased cell proliferation but also in diminished cell death. Most genetic changes that occur during carcinogenesis are not inherited or germline. They are acquired after birth and are called somatic mutations. A somatic mutation affects only the mutated cell and its progeny. Each time a cell divides, there is a chance of somatic mutation, and therefore there always is a low, background risk for cancer and other malignant lesions. A far more prevalent cause of cancer-related death in the United States is environmental exposure. Such exposure causes somatic mutations of cancer-related genes through direct damage to DNA or through alteration of proliferation or cell death, which enhances the baseline risk for mutation. As carcinogenesis becomes understood, interventions may be designed that selectively interfere in important steps. Screening for cancer is based on the premise that one can treat a patient for a cancer that has not spread from its primary site. Nevertheless, cancer screening is controversial and often confusing. Issues of costs, risks versus benefits, physical time and effort, and patient compliance all affect the clinician's view of screening, often to the extent that the true value of this approach to cancer control is underappreciated and underutilized. A clinician should consider the following questions when assessing the priority, scope, and intensity of cancer screening. Is the cancer an important public health problem? Can preclinical stages be detected and cured? Are effective screening tests available? Are the tests feasible and acceptable? Have screening programs reduced cancer-specific mortality? Is the screening program cost effective? Is screening generally recommended? There is clear-cut evidence of benefit from screening for cancer of the cervix, breast, colon and rectum, and skin and some specific genetic syndromes. Evidence of survival benefit from screening for prostate cancer is lacking, although prostate specific antigen screening is widely used. Screening for lung and ovarian cancer is ineffective.