Our primary topic of discussion is the role of inherited variation in gene sequence and its impact on cancer risk in the general population.
We begin by examining the evidence that genetics (inherited variation in genome sequence) actually plays a role in the risk of cancer. The strongest data involve familial aggregation, showing that rates of disease are higher in the families of cancer patients than in the population at large. Of course, families are characterized by shared environment as well as shared genes. These factors are typically disentangled by comparing rates of concordance in monozy-gotic (MZ) and dizygotic (DZ) twin pairs.7 Monozygotic twins are 100% identical in genome sequence, whereas DZ twins are identical (on average) across only 50% of their DNA; the method relies on the assumption that both types of twins share environmental influences to a similar degree. To the greatest degree possible, comparison of MZ to DZ twins separates the effects of genes and the environment.
Multiple large studies8 indicate that the risk of the most common hormone-responsive cancers (breast, prostate, and ovary) is significantly influenced by inherited differences in genome sequence. Specifically, the MZ twin of a patient with cancer is two to three times more likely to get the same cancer than a DZ twin. These studies suggest that 27%-57% of the variation in population risk is due to gene effects and the remainder to non-genetic (environmental and random) factors.9,10 While these studies show that inherited factors play a causal role, they also demonstrate that genes are far from the whole story: in MZ twins, the rate of concordance for prostate cancer is on the order of 25%, showing that even genetically identical people can have very different outcomes with regard to can-cer.9,10 Moreover, in most cases, the genetic contribution is not attributable to a single gene (which would produce a recognizable mendelian pattern of inheritance) but rather must be divided among a larger number of more modest genetic contributions.
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