gene on chromosome 17 and the BRCA2 gene on chromosome 13; another example is the p53 gene, some mutant forms of which lead to the Li-Fraumeni syndrome, which has breast cancer as one feature. These genes, however, account for no more than 3 to 5 percent of cases of breast cancer. As to the genetic factors involved in causation, most cancers are the consequence of an interplay between more than one gene collaborating with one or more environmental factors. The environmental factor may be of overwhelming importance, such as cigarette smoking in lung cancer and papillomavirus infection in cervical cancer; however, even in these instances the existence of genes that make some individuals more or less vulnerable to the environmental factors are suspected or such genes can be identified.
In general, genetic factors responsible for common disorders with multifactorial causes, such as cancers, are usually "susceptibility genes," and multiple genes are often responsible for the disorder. They represent a variable form (or allele) of a particular gene and have common variations, called polymorphic alleles. Alone, each variation has little effect, but in combination with other specific polymorphic alleles or nongenetic influences, these variations give rise to a particular disorder. Figure 2-1 diagrams the contrast between disorders caused by a mutation in a single gene, such as cystic fibrosis, Huntington disease, and Li-Fraumeni syndrome on the one hand and common disorders with multifactorial causation such as hypertension, manic-depressive illness, and lung cancer on the other. Each polymorphic allele occurs relatively frequently in the general "normal" population; it is present at a higher frequency (and usually in combination with other specific alleles) in people with a particular common disorder. The variable gene is a susceptibility factor, not a causative factor.
Genetic factors in common disorders with multifactorial etiology are usually investigated by allele association studies with DNA markers. These markers are sometimes variations in the sequences of specific genes that are investigated as candidate genes; because of the known functions of the genes, implication of their association in the pathogenesis of the given disorder is plausible. Alternatively, the DNA marker may be located in an "anonymous" section of the genome, that is, in a gene with an unknown function or in a noncoding region of the genome. A common variation, or "polymorphism," of a gene may alter the function of the gene product, thereby contributing to susceptibility to a disease. In such instances, the marker itself is the disease-related change. In the case of a common variation not involving the coding or gene-regulating sequence of DNA, linkage (in which genes are located close to each other on the same chromosome) is presumed to exist between the DNA variation and a specific allelic form of a susceptibility gene. Studies of associations between allelic variants