Proceso de Infiltración

Cancer occurs because of mutations in the genes responsible for cell mul- tiplication and repair. This does not mean that the disease is heritable. Indeed, it now seems clear that even the rare so-called heritable cancers caused by genes of high penetrance, and transmitted through Mendelian laws, mostly require a particular interaction with environmental factors for induction. Although the distinction between high and low penetrance genes obscures a continuum of susceptibility at the biological level, it is possible at the operational level to identify a small number of genes (high penetrance genes) in which pathological mutations are sufficiently predictive of cancer risk to influence clinical management. In contrast, any allelic variant of the “major” genes, or alteration in other interactive genes or in environmen- tally sensitive polymorphisms that would not be sufficiently penetrant to affect clinical practice, is categorized as low penetrance. Nevertheless, as knowledge expands and the capacity to test multiple genes simultaneously becomes commonplace, high penetrance “genotypes” comprising several low penetrance genetic variations may be recognized.

Genetics may therefore eventually play an important role in the control of cancer, including:

Causes of Cancer • identification of individuals at risk for a specific cancer, leading to preven- Causes of Cancer

tive or screening strategies for an individual or family members;

• identification of cancer subtype so that treatment can be tailored to target that specific disease.

The potential role of genetics should not, however, be overstated. Studies have shown that the primary determinants of most cancers are lifestyle fac- tors, such as tobacco, dietary and exercise habits, and infectious agents, rather than inherited genetic factors. For example, probably only 5% of all breast cancers occur in women with a genetic predisposition to the disease.

At present, the major practical role for cancer genetics is the identification of individuals at high risk for cancer. Information on the history of cancer in a family should be routinely collected in all countries. Routine DNA-based genetic testing for high penetrance genes (such as BRCA 1 or 2 for breast cancer) is currently only feasible in some of the most affluent countries.

Family history and DNA screening can identify individuals at moder- ately increased risk of cancer and individuals from cancer-prone families. Identification of such people allows them to make informed decisions regarding reproduction, lifestyle and clinical risk-reduction strategies. When genetic information indicates an increased risk of a cancer, those at risk may undergo more intensive or more frequent early detection interventions than are routine, in an attempt to detect a cancer at a more treatable stage.

While cancer-prone families are quite rare, the risk of a specific cancer within such a family can be very high. Genetic testing of a person with cancer can help clarify the risk to offspring. It can also serve as the basis for subse- quent genetic counselling of the offspring or family, with a view to increasing their understanding of the medical situation and encouraging them to adopt strategies to minimize subsequent cancer risk.

In practice, the type of high risk genetic susceptibility caused by high penetrance genes transmitted in a Mendelian fashion is uncommon, and the proportion of cancers caused by such predisposition is low (about 5% for breast or colon cancer and less for most other cancers, except for retinoblas- toma in children). In contrast, it is now appreciated that so-called metabolic polymorphisms, that is differences in the way people metabolize chemical carcinogens, can explain differences in the susceptibility of individuals to cancer, and that these polymorphisms are controlled at a cellular level by mutations in specific genes. A major research endeavour is now under way to characterize these genetic polymorphisms. It is already clear that there are multiplicities of such genetic changes, that they are caused by genes of low penetrance, and that the classic Mendelian laws of inheritance do not apply. However, it seems likely that collectively these polymorphisms explain much of the innate susceptibility to cancer, and that consequently their potential

Causes of Cancer contribution to the occurrence of cancer is large. Furthermore, interactions Causes of Cancer

with environmental factors seem to be frequently associated with genetic changes. Thus it may be eventually possible to identify those individuals at special risk of tobacco or diet-associated cancers, and also those susceptible to the effects of environmental contaminants.

It is also anticipated, but not yet proven, that genetic testing may eventu- ally provide information that will be used to determine the best course of treatment for some cancers. Certain cancers currently classified as a single disease may ultimately be classified into different types, each best managed by a different therapeutic strategy. Beyond the drawback of the high costs of genetic testing, there are also potential problems associated with patient privacy and discrimination. Who should have access to genetic information and for what purposes should such information be used? The potential for discrimination regarding employment and access to health insurance is considerable. Safeguards against inappropriate use are, however, being developed. If the full potential of the human genome project is to be real- ized, it is important to avoid erecting barriers that will block the potential advances in cancer prevention, diagnosis and therapy that might be achieved through such testing.