Genetic susceptibility to cancer

Abstract

For any given level of exposure to a carcinogen, only a proportion of exposed individuals will develop cancer. Interindividual differences in susceptibility at some stage of the carcinogenic process must be postulated. One contributing factor is variation in the activity of metabolizing enzymes responsible for conversion of procarcinogens to proximate carcinogens. There is also a wide spectrum of DNA repair capability within the general population. At one end are the genetic instability syndromes characterized by extreme sensitivity to carcinogenic exposures and high rates of cancer in homozygotes of these traits. Less extreme differences in mutagen sensitivity can be demonstrated by a quantitative assay of chromosome breaks induced by in vitro mutagen exposure. Two case‐control studies of patients with previously untreated upper aerodigestive tract cancers have demonstrated mutagen sensitivity to be an independent risk factor for the disease after controlling for the effects of tobacco and alcohol. Mutagen sensitivity also may have prognostic relevance. There was a fourfold elevated risk of developing multiple primary cancers in mutagen‐sensitive patients. There are also data suggestive of familial aggregation of cancer in first‐degree relatives of mutagen‐sensitive patients (twofold risk for having one first‐degree relative with cancer and sixfold risk for having two or more relatives with cancer). The preventive implications of identifying markers of carcinogen sensitivity are manifold.

Genetic polymorphisms of metabolic enzymes CYP1A1, CYP2D6, GSTM1 and GSTT1 and leukemia susceptibility

“…Thus, interindividual variability in xenobiotic metabolism has been associated with different susceptibility to toxicity in response to a given environmental pollutant. Individuals with certain genotypes that evoke increased metabolic activation of carcinogens and decreased detoxification are inherently more susceptible to environmental carcinogens and have higher risk of cancer (Spitz and Bondy, 1993;Bartsch and Hietanen, 1996;Khoury, 1996). Therefore, the genetic polymorphisms in xenobiotic metabolizing enzymes can lead to different host phenotypes and contribute to different disease profiles (Joseph et al, 2004).…”

The L84F polymorphism in the O 6 -Methylguanine-DNA-Methyltransferase (MGMT) gene is associated with increased hypoxanthine phosphoribosyltransferase (HPRT) mutant frequency in lymphocytes of tobacco smokers

“…[3]). Consistent with these assumptions, reports from several laboratories have clearly indicated a significant association between reduced DNA repair capacity and increased risk of tobaccorelated cancers [4][5][6][7][8].…”

“…O 6 -methylguanine-DNA-methyltransferase (MGMT) is a ubiquitously expressed suicide DNA repair protein that plays a critical role in this pathway. MGMT is crucial in protecting the genome from mutations and chromosome damage because of O 6 -alkylguanine adducts resulting from exposure to alkylating agents, such as those found in tobacco smoke, with high specificity for O 6 -methylguanine (O6-meG) [18][19][20]. The MGMT protein flips the adducted guanine base out of the DNA helix and into the active site of the protein.…”

Decreased Hrad6B expression in lung cancer

“…Genetic instability, which drives tumorigenesis, is fuelled by DNA damage and by errors made by the DNA repair machinery (24). DNA repair is a ubiquitous defense (25).…”