Inherited Susceptibility to Cancer

Not everyone who is exposed to an environmental carcinogen develops cancer. This is so because, for a large number of cancers, environmental carcinogens work on a background of inherited susceptibilities. It is likely in most cases that cancers arise from a combination of hereditary and environmental factors.

Although it is difficult to define precisely which genetic traits determine susceptibility, a number of types of cancer are linked to a single mutant gene inherited from either parent. In each case a specific tissue organ is characteristically affected. These types of cancer frequently strike individuals decades before the typical age of onset of cancer. Hereditary cancer syndromes include hereditary retinoblastoma, familial adenomatous polyposis of the colon, multiple endocrine neoplasia syndromes, neurofibromatosis types 1 and 2, and von Hippel-Lindau disease.

The genes responsible for these syndromes have been cloned and characterized, which makes it possible to detect those who carry the defect before tumour formation has begun. Cloning and characterization also open new therapeutic vistas that involve correcting the defective function at the molecular level. Many of these syndromes are associated with other lesions besides cancer, and in such cases detection of the associated lesions may aid in diagnosing the syndrome.

Certain common types of cancer show a tendency to affect some families in a disproportionately high degree. If two or more close relatives of a patient with cancer have the same type of tumour, an inherited susceptibility should be suspected. Other features of these syndromes are early age of onset of the tumours and multiple tumours in the same organ or tissue. Genes involved in familial breast cancer, ovarian cancer, and colon cancer have been identified and cloned.

Although tests are being developed — and in some cases are available — to detect mutations that lead to these cancers, much controversy surrounds their use. One dilemma is that the meaning of test results is not always clear. For example, a positive test result entails a risk — not a certainty — that the individual will develop cancer. A negative test result may provide a false sense of security, since not all inherited mutations that lead to cancer are known.

Another group of hereditary cancers comprises those that stem from inherited defects in DNA repair mechanisms. Examples include Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, and xeroderma pigmentosum. These syndromes are characterized by hypersensitivity to agents that damage DNA (e.g., chemicals and radiation). The failure of a cell to repair the defects in its DNA allows mutations to accumulate, some of which lead to tumour formation.

Aside from a predisposition to cancer, individuals with these syndromes suffer from other abnormalities. For example, Fanconi anemia is associated with congenital malformations, a deficit of blood cell generation in the bone marrow (aplastic anemia), and susceptibility to leukemia. Children with Bloom syndrome have poorly functioning immune systems and show stunted growth.