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Misconceptions about the use of genetic tests in populations.

Vineis-P; Schulte-P; McMichael-AJ
Lancet 2001 Mar; 357(9257):709-712
The prospect of genetic screening for preventable or deferrable disease is becoming real. As the cataloguing of the human genome proceeds, the rate at which specific genes are being implicated in disease processes is increasing. Because of its genetic basis, much interest has centred on identification of genes for cancer and their usefulness in routine screening. Cost-benefit analysis is urgently needed for screening for single-gene diseases versus multigenetic diseases, and for genes of low versus high penetrance. Penetrance of a gene describes the frequency with which the characteristic it controls (phenotype) is seen in people who carry it. Single, highly-penetrant mutations in so-called cancer genes cause only a small proportion of cancers. Highly penetrant gene mutations confer an exceptionally high risk of cancer in the carriers. They are the tail of a distribution that includes: (a) common variants of the same cancer genes (polymorphisms) that have only a mildly disruptive effect on the protein coded for by the gene; and (b) mutations in genes that are not directly involved in the cancer process. Genes implicated in rare and cancer-inducing conditions, such as xeroderma pigmentosum, show common polymorphisms that belong to the first category (a) and whose effects on the protein function (a DNA-repair enzyme) are mild. Mild defects in DNA repair can predispose to cancer and polymorphisms in the xeroderma pigmentosum DNA repair gene have been associated with an increased risk of skin cancer. Metabolic polymorphisms are a clear example of the second category (b); these are common, low-penetrant conditions in which the function of the protein (an enzyme that metabolises toxic chemicals or carcinogens) is impaired, resulting in greater susceptibility to the effect of environmental toxicants. About 50% of the population have the GSTM1 null genotype (a polymorphism in which the entire gene is deleted), but only a slightly increased risk of some forms of cancer.
Genetic-factors; Genetic-disorders; Gene-mutation; Mutagenicity; Cancer; Cancer-rates; Carcinogens; Breast-cancer; DNA-damage; Public-health
Dr Paolo Vineis, Unit of Cancer Epidemiology, Dipartimento di Scienze Biomediche e Oncologia Umana and CPO-Piemonte, via Santena 7, 10126 Torino, Italy
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