Genetic predisposition to lung cancer

Abstract

In Britain, the life-time risk of lung cancer in men who smoke 20 or more cigarettes per day is about 15%. That most smokers never develop lung cancer has promoted interest in the role of host factors. While chance, other environmental factors and the competing effect of other diseases, some of which are also smoking related, are all likely to affect individual lung cancer risk, genetic factors may also be important. This review examines the evidence for genetic predisposition to smoking related lung cancer.The review concentrates on the numerous metabolic studies that have sought differences between individuals in the genetic control of biochemical pathways that could be involved in the metabolism of carcinogens in tobacco smoke. Insights gained are likely to have wider implications for other environmental carcinogens. Other studies that have sought simple evidence, such as familial clustering or associations of lung cancer with blood group, HLA and other naturally occurring antigens, are also examined. The field of chromosomal abnormalities in lung cancer and the difficulties in interpreting them is reviewed only briefly, since this area may not directly relate to tobacco smoking and has been reviewed elsewhere (Birrer & Minna, 1988). Various sources of bias important in the interpretation of the metabolic studies in particular are outlined. Future research is likely to be dominated by the recent advances in molecular genetics that offer the possibility of circumventing bias by the direct identification of genes, but at present this is possible only to a limited extent. Familial clustering of lung cancer casesFamilial clustering of a cancer (or indeed of any disease) is an insensitive indicator of genetic predisposition. Peto (1980) and Bodmer (1986) have pointed out that a cancer can have a major genetic component yet show no detectable familial clustering. The ratio of the incidence of the cancer in relatives of known cases to that in age-matched controls is the only measure of familial clustering (in the absence of a marker). This ratio will be much smaller than the ratio of the incidence in genetically susceptible to non-susceptible individuals, which is the direct measure of the magnitude of the genetic effect. It is a question of dilution -not all patients with cancer will be genetically susceptible individuals, fewer of their relatives will be, and tne general population contains susceptibles as well as non-susceptibles. (1980) showed that even with a very large cancer risk in susceptibles, the incidence of cancer in relatives will generally be increased by no more than 1.5-3-fold. It is difficult in a family study to show that such a modest increase could not be due to chance, shared exposure or other bias.Five studies have examined lung cancer incidence in relatives of cases, but three (Tokuhata & Lilienfeld, 1963b;

Polymorphism at Codon 72 of p53 Is Not Associated with Cervical Cancer Risk

“…Resultant loss of wild type p53 increases cellular genomic instability after DNA damage. Somatic and germ line mutations of p53 have been identified in a wide variety of human carcinomas (8). However, in cervical cancers, this mutation is rarely detected (9 -11).…”

Cytochrome P450 1A1 (CYP1A1) polymorphisms and breast cancer risk in Korean women

“…Cytochrome P450 1A1 (CYP1A1) is involved in the conversion of estrone (E1) and estradiol (E2) to 2-hydroxyestradiol (2-OHE1) (Cavalieri et al, 2001). CYP1A1 also has aryl hydrocarbon hydroxylase activity which is responsible for metabolizing polycyclic aromatic hydrocarbons (PAH) to aryl epoxides (Law, 1990).…”

Inherited predisposition to early onset lung cancer according to histological type

“…[15][16][17][18] The early reports on genetic influences in lung cancer susceptibility appeared in the early 1980s and showed that firstdegree nonsmoking relatives of lung cancer patients had an increased risk of lung cancer compared to nonsmokers with no affected relatives. 19,20 Models for lung tumorigenesis have also been developed on experimental animals. 21,22 However, the role of hereditary factors in tumor development has been less well understood in lung cancer than for many other human neoplastic diseases.…”