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Genetic susceptibility to tobacco-induced lung cancer

Institution: University of California, Los Angeles
Investigator(s): Oliver Hankinson, Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0061 Award: $406,120
Subject Area: Cancer
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
A group of chemicals, known as polycyclic aromatic hydrocarbons (PAH) probably constitute the major cancer-causing agents in cigarette smoke. PAH do not cause cancer themselves, but are converted to cancer-causing compounds by enzymes contained within cells of the lung. The principal enzyme involved is CYP1A1. Cigarette smoke greatly increases the amount of CYP1A1 in lung cells, in a process that requires the action of two other cellular proteins, known as AHR and ARNT. Considerable evidence indicates that there are genetic differences in susceptibility to cigarette-induced lung cancer between people. We hypothesize that differences in the genes coding for the CYP1A1, AHR and ARNT proteins are at least partly responsible for the differences in susceptibility. In order to investigate this possibility we will look for differences in these genes that affect either the amount or effectiveness of the proteins derived from them. Such genetic differences (or “polymorphisms”) are difficult to detect in human subjects recruited at large, so we plan to maximize our chances of identifying polymorphisms by studying several defined human populations. In each of these populations, a minority of individuals have been (or will be) identified in whom induction of CYP1A1 responds idiosyncratically to PAH. One is a Finnish population. Since the population of Finland is genetically highly similar to each other, many human recessive genetic variations have been identified among Finns. The other populations are from New York state and from Switzerland. Finally we will develop simple procedures for identifying the different forms of the CYP1A1, AHR and ARNT genes that we discover within individual persons. In future studies beyond the scope of this project, we will investigate whether any of the differences in these genes that we discover are associated with increased human susceptibility to cigarette-induced lung cancer. Those persons identified as being particularly susceptible would be particularly encouraged not to smoke. Such individuals would also be particularly good subjects to take anticarcinogens in their diets.chemotherapy.

Final Report
We proposed to identify genetic polymorphisms in the human population that confer differential susceptibility to carcinogenesis by polycyclic aromatic hydrocarbons (PAH) in cigarette smoke. We focused on three genes: CYP1A1, AHR and ARNT. PAH must be metabolized, principally by the enzyme, CYP1A1, to exert their carcinogenic effects. PAH also induce CYP1A1 in a process involving the AHR and ARNT proteins. It is likely that polymorphisms in the human population that affect activity of the AHR, ARNT genes or CYP1A1 genes would have profound affects on susceptibility to lung cancer.

We studied samples from a number of individuals who appeared to be non- or poorly inducible for CYP1A1 either in their lungs or placentas, with the expectation that these individuals would possess genetic polymorphisms negating the activity of the AHR or ARNT or CYP1A1 genes. Although we detected previously unknown polymorphisms in each of the three genes, none of these were deemed likely to affect functioning of these genes or their corresponding proteins. Thus no polymorphisms were identified that could explain the non or poor inducibility characteristics of the above persons. We also analyzed polymorphisms at four previously identified sites in the AHR and CYP1A1 genes in a large cohort of smokers who exhibited great variation in cigarette-induced CYP1A1 in their lungs. No differences were observed in the frequencies of the polymorphic genotypes between the smokers with low and those with high induction. These last results indicate that interindividual variation of CYP1A1 induction in the lung is not attributable to any of these four polymorphisms.

We are currently sequencing the CYP1A1, AHR and ARNT genes from another large human population that has been characterized with regard to expression of the AHR, ARNT and CYP1A1 genes in their blood cells. Our expectation is that we will be able to correlate the presence or absence of polymorphisms in the above genes with the degree of expression of the corresponding proteins in each case. Identification of polymorphisms in the above genes could have considerable impact on cigarette-induced lung cancer since such polymorphisms could affect susceptibility to several of the major carcinogens in cigarette smoke.
Publications

Induction of CYP1A1 in Human Lung and polymorphisms of CYP1A1 and AHR
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Anttila S, Tuominen P, Hirvonen A, Karjalainen A, Hankinson O, Elovaara E ART
Yr: 2000 Vol: 41 Nbr: Abs: Pg: 551-552

Lack of induction by tobacco smoke of CYP1A1 in the lung of rare individuals is not due to polymorphisms in the AHR, ARNT, or CYP1A1 genes
Periodical: Pharmacogenetics Index Medicus:
Authors: Anttila S, Lei X-D, Elovaara E, et al ART
Yr: 2000 Vol: 8 Nbr: Abs: Pg: 741-751

Induction of CYP1A1 in human lung and polymorphisms of CYP1A1 and AHR
Periodical: Pharmacogenetics Index Medicus:
Authors: Anttila SL, Tuominen P, Hirvonen A, Karjalainen A, Hankinson O, Elovaara E ART
Yr: 2001 Vol: 11 Nbr: Abs: Pg: 501-510