Complex or multifactorial disease inheritance is used to describe conditions caused by genetic and environmental factors. Thus, a condition may be caused by the expression of multiple genes or by the interaction of genes and environmental factors. Therefore, a single genetic locus is not responsible for the condition. Rather, the net effect of genetic, lifestyle, and environmental factors determines a person's liability to be affected with a condition, such as cancer.
Susceptibility or resistance shows a more or less normal distribution in the population. Most people have an intermediate susceptibility, with those at the tails of the distribution curve having unusually low or unusually high susceptibility. Affected individuals are presumably those who are past a point of threshold for being affected due to their particular combination of risk factors. Outside of the few known Mendelian syndromes that predispose to a high incidence of specific cancer, most cancers are complex in etiology.
Clustering of cancer among relatives is common, but teasing out the underlying causes when there is no clear pattern is more difficult. With many common malignancies, such as lung cancer, an excess of cancers in relatives can be seen. These familial aggregations are seen as being due to combinations of exposures to known carcinogens, such as tobacco smoke, and to mutations in high penetrance genes or alterations in genes with low penetrance that affect the metabolism of the carcinogens in question.
The general practitioner is likely to encounter some families with a strong genetic predisposition to cancer and the recognition of cancer susceptibility may have dramatic consequences for a given individual's health and management. Although mutations in major cancer susceptibility genes lead to recognizable Mendelian inheritance patterns, they are uncommon. Nonetheless, cancer susceptibility genes are estimated to contribute to the occurrence of organ-specific cancers from less than 1% to up to 15%. Mutations in these genes confer high relative risk and high absolute risk. The attributable risk is low, however, because they are so rare.
In contrast, scientists now know of polymorphisms or alterations in deoxyribonucleic acid that are very common in the general population. Each polymorphism may confer low relative and absolute risks, but collectively they may account for high attributable risk because they are so common. Development of clinically significant disease in the presence of certain genetic polymorphisms may be highly dependent on environmental exposure to a potent carcinogen. People carrying polymorphisms associated with weak disease susceptibility may constitute a target group for whom avoidance of carcinogen exposure may be highly useful in preventing full-blown disease from occurring.
For more information about specific low-penetrance genes, please refer to the summaries on genetics of specific types of cancer.
Complex inheritance might be considered in a pedigree showing the following:
- Males and females affected (unless the target organ is gender-specific).
- A few cancers, without clear-cut vertical transmission or sibship clusters.
- No set pattern of inheritance.
- May appear to skip generations.