CYP1A1 and CYP1B1 polymorphisms as modifying factors in patients with pneumoconiosis and occupationally related tumours: A pilot study

Abstract

Abstract. CYP1A1 and CYP1B1 are involved in the metabolism of carcinogens. The effect of CYP1A1 and CYP1B1 polymorphisms as genetic modifiers of risk was investigated in individuals with asbestos, silica dust or ionizing radiationinduced occupational tumours compared to exposed non-cancer subjects suffering from pneumoconiosis, particularly in relation to tobacco smoking. CYP1A1 T6235C, CYP1A1 A4889G and CYP1B1 codon 432 polymorphisms were determined by realtime Pcr analysis in patients with asbestos-related lung cancer (n=39), patients with diffuse malignant mesotheliomas (n=19), lung cancer in silicosis patients (n=7), uranium miners with lung cancer (uMlc) (n=40), patients with asbestosis (n=181), and silicosis patients (n=204). The results were compared to those from a healthy unexposed control group (n=50) not exposed to carcinogenic (or fibrogenic) agents in the workplace. an additional healthy control group (n=134) comprised smokers and ex-smokers. allele frequencies were within the range described for caucasians. Multivariate analysis revealed that patients with occupational diseases with the susceptible CYP1A1 T6235C genotype had a calculated risk ranging from or=0.5 (95% ci 0.18-1.36) for uMlc to or=1.23 (95% ci 0.39-4.05) for uranium miners with silicosis. The risk for patients with the susceptible CYP1A1 A4889G allele was calculated as being between or=0.39 (95% ci 0.10-1.54) for mesothelioma patients and or=1.54 (95% ci 0.49-4.89) for uMlc. CYP1B1 Val432Leu polymorphisms were associated with a risk of or=0.56 (95% ci 0.2-1.55) for uMlc and or=1.52 (95% ci 0.68-3.39) for asbestos-exposed lung cancer patients. By analyzing the interaction between tobacco smoking, type of exposure to carcinogens and the genotypes, it was determined that smoking and the presence of the susceptible genotypes did not have a combined effect. in this pilot study, the analyzed polymorphism had no consistent modifying effect on pneumoconiosis or occupationally related tumours. Introductionindividual differences in susceptibility to occupationally induced carcinomas are in part ascribed to genetic differences in metabolic activity regarding the activation or detoxification of environmental carcinogens. Human lung cancer is caused by exposure to carcinogens such as polycyclic aromatic hydrocarbons (PaH), found mainly in cigarette smoke, but can also be caused by exposure to carcinogens in the workplace, such as asbestos, ionizing radiation or silica dust.Most environmental carcinogens require metabolic activation by Phase i enzymes, cytochrome P-450s, to their reactive electrophilic intermediates. Several forms of P-450 have been identified. CYP1A1 is involved in the bioactivation of carcinogenic PaH. in a caucasian population, an association was found between CYP1A1 homozygous Mspi rFlP and lung cancer (1,2).In vitro studies have demonstrated that asbestos fibres exert a destructive effect through the generation of reactive oxygen species (roS), which leads to alterations in mitochondrial function and the activation of several...

Association of CYP1B1 Leu432Val Polymorphism and Lung Cancer Risk: An Updated Meta-Analysis

“…Eight studies were population-based and one was hospital-based and the LC cases were histologically confirmed or cytologically confirmed in six of the eligible studies. All studies were in agreement with HWE of the genotype distribution of the controls, except for the study by Schneider et al [17], in which the HWE was unknown because it only provided the number of cases and controls for the Leu/Leu and Leu/ Val ? Val/Val genotypes.…”

“…There are two studies demonstrating a significantly increased risk of LC overall for carriers of the minor allele of CYP1B1 SNP rs1056836 among women and black ever-smoking women by Timofeeva et al [14] and Cote et al [15], respectively. However, other studies have failed to find any appreciable correlation between the CYP1B1 Leu432Val polymorphism and LC risk [16][17][18][19][20][21][22]. Moreover, two meta-analyses have investigated the same hypothesis [23,24], quite similar in methods, but the results do not appear to be the same.…”

“…The manual search for references cited in all retrieved eligible studies did not find any additional articles. Therefore, a total of nine studies meeting the inclusion criteria were included in this meta-analysis [14][15][16][17][18][19][20][21][22]. Additionally, there was an eligible study [15] conducted on two different ethnic groups (Caucasian and African-American), so we treated it independently as two studies.…”

“…Moreover, two meta-analyses have investigated the same hypothesis [23,24], quite similar in methods, but the results do not appear to be the same. Additionally, both of them contained overlapping data [25,26] and missed available studies [16,17], which make their conclusions questionable. The exact relationship between genetic polymorphisms of CYP1B1 Leu432Val and the risk of LC have not been entirely established.…”

Pleural mesothelioma and lung cancer: the role of asbestos exposure and genetic variants in selected iron metabolism and inflammation genes

“…A number of studies have compared past asbestos exposure and genetic polymorphisms using either candidate genes approaches (Betti et al, 2017;Borelli, Moura, Trevisan, & Crovella, 2015;Christiani, 2000;Crovella et al, 2016;Dianzani et al, 2006;Gemignani et al, 2009;Girardelli et al, 2012;Hirvonen et al, 1996;Landi et al, 2007;London et al, 1995;Murakami et al, 2012;Neri et al, 2008;Schabath et al, 2002;Schneider & Bernges, 2009;Tunesi et al, 2015;Wang, Neuberg, & Christiani, 2004) or whole-genome association studies for both MPM and LC (Cadby et al, 2013;Kettunen et al, 2017;Matullo et al, 2013;Wei et al, 2012). While low- (Cadby et al, 2013;Matullo et al, 2013) and high-risk (Betti et al, 2017;Ohar et al, 2016) genetic factors for MPM have been reported, even defining germline variants in BAP1 tumor suppressor gene as high-risk factor (Ohar et al, 2016), the impact individual genetic variations have on asbestos-related lung cancer risk is still poorly understood.…”