ABSTRACT
Genetic predisposition to cancer has been recognized for over a century. In the last few decades, the underlying genetic basis for many of these striking familial cancer clusters has been discovered. The revolution in molecular genetic technology during this time has been instrumental in understanding how and which genetic factors influence cancer risks. Some 20% to 30% of patients presenting with common malignancies like breast or colon cancer will have a blood relative who has been diagnosed with the same disease. High-penetrance, dominantly inherited cancer predisposition syndromes are important to recognize because of the substantial risks of cancer especially at young ages. However, as the genes that lead to cancer predisposition are discovered, it is now apparent that less than 5% of all breast or colon cancers arise predominantly because of the inheritance of a single high-penetrance gene mutation (Fig. 22.1). More recently, it has become clear that much of the familial clustering of common cancers, and even many cancers where there is no family history, arise because of a combination of several genetic variants that are frequent in the population and that each increases the risk by a fractional amount above the population’s average risk (common, low penetrance alleles) (1-4). The information emerging about these common genetic variants is relevant to a much larger proportion of cancers although the individual absolute associated risks are quite small (5). However, ultimately as more is learned about interactions between this type of gene and the environment and tumor biology, there may be future opportunities to target individuals who might benefit from preventive strategies including chemoprevention (6). These polymorphic genetic variants clearly modify the risk of cancer for a carrier of a highpenetrance gene mutation (7), and variants that influence long-term prognosis are now being identified (8).
