MULTIFACTORIAL GENETICS OF CANCER

27 May

As indicated above, genetic predisposition to neoplasia resulting from alteration in a single gene locus is a relatively rare cause of cancer in humans as well as in lower animals. A much greater contribution of genetics to the causation of neoplastic disease are those conditions having pat- terns of inheritance that conform to a polygenic or multifactorial mode of inheritance, recently termed complex traits (Lander and Schork, 1994). Many common chronic diseases of adults (in- cluding types of hypertension, coronary heart disease, diabetes mellitus, and schizophrenia)  as well as certain developmental defects (including cleft lip and palate, spina bifida, and congenital heart disease) are known to be more frequent in those with family histories of such disorders. A number of these diseases may be due to single gene defects and others to chromosomal abnor- malities, but most are the result of multiple genetic and environmental  factors combined.  In polygenic inheritance, multiple genes at independent loci interact in a cumulative fashion with environmental factors that move an individual beyond the “threshold of risk,” so that the disease becomes  of biological  and clinical significance,  with environmental  influences  determining whether and to what extent the individual  is actually affected by the disease (Carter, 1970). Thus, the heritability for a threshold trait is a simple measure of the degree to which the liability is inherited. Figure 5.10 shows the distribution of such a disease liability in the general popula- tion and among relatives of affected individuals. The location of the threshold (T) is the same in both populations; however, the potential for disease is higher among relatives than in the general population, in part because of the genes shared by affected individuals and their relatives. Thus, the distribution of liability or potential for disease among the relatives of affected individuals is

Figure 5.10 The distribution of the risk (liability or potential for disease) in the general population (up- per curve) and that of a family exhibiting a threshold or multigenic trait (lower curve) in which there is a fixed threshold (T) that is identical in both populations.  Individuals  that are affected with the disease are those with risks or liabilities above (to the right of) the threshold, as shown by all individuals  within the shaded  areas of the curves.  (Adapted  from Duggleby  et al., 1981, with permission  of the authors  and publisher.)

shifted to the right, that is, toward a greater risk, compared with the general population. For an- other individual in the same family to exhibit the disease syndrome, a similar combination  of affected  genes must be inherited.  Since siblings share half their genes, the probability  of a brother or sister inheriting the same combination of genes is (1/2)n, where n is the number of genes required to express the disease trait, assuming that none of the genes are linked. In con- trast disorders of single genes affect 25% or 50% of the first-degree relatives who are at genetic risk as based on mathematical inheritance patterns. On the other hand, multifactorial genetic dis- orders usually affect no more than 5% to 10% of first-degree relatives, and the recurrence risk of multifactorial disease varies from family to family. Risk estimation is significantly influenced by two factors: (1) the number of affected persons already present in the family and (2) the severity of the disorder in the index case. The greater the number of affected relatives and the more se- vere the clinical presentation of the disease, the higher the risk to remaining relatives (Beaudet et al., 1995). In general, just as with most monogenic neoplastic disease, a multifactorial genetic etiology for disease is less frequently seen with increasing age beyond adolescence.

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