Evidence that a particular gene might explain a specific cancer predisposition syndrome often derives initially from linkage studies that use collections of families meeting stringent clinical criteria for a specific cancer susceptibility syndrome. The demonstration of strong linkage of cancer susceptibility to a gene or genetic region in a pattern consistent with autosomal dominant inheritance provides evidence in support of both the mode of inheritance and the particular gene that might underlie the risk. Once linkage is established, a strong case for association between the genetic trait and disease can be made, even though the families used in the study may not be representative of the general population. The genetic trait measured in linkage studies is not always the causal factor itself but may be a genetic trait closely linked to it. Additional molecular studies are required to identify the specific gene associated with inherited risk, after linkage studies have determined its general chromosomal location.
Linkage studies, however, provide only limited evidence concerning either the range of cancer types associated with a mutation or the magnitude of risk and lifetime probability of cancer conferred by a mutation in less selected populations. In addressing these questions, the best information for clinical decisions comes from naturally occurring populations in which people with all degrees of risk are represented, similar to those in which clinical or public health decisions must be made. Thus, observations about cancer risk in families having multiple members with early breast cancer are applicable only to other families meeting those same clinical criteria. Ideally, the families tested should also have similar exposures to factors that can modify the expression of the gene(s) being studied. The mutation-associated risk in other populations, such as families with less dramatic cancer aggregation, or in the general population can best be assessed by direct study of those populations.
- Grann VR, Jacobson JS: Population screening for cancer-related germline gene mutations. Lancet Oncol 3 (6): 341-8, 2002.