title: Coding polymorphisms in Casp5, Casp8 and DR4 genes may play a role in predisposition to lung cancer.
abstract: Apoptosis plays a role in the elimination of DNA-damaged cells thus protecting the host from cancer development. Some data indicate that normal variations within the sequence of apoptotic genes may lead to suboptimal apoptotic capacity and therefore increased cancer risk. We tested 19 coding apoptotic gene SNPs in 2-stage molecular epidemiological study. For the preliminary sorting of SNP candidates, we employed a "comparison of extremes" approach, where 111 patients with highly pronounced LC susceptibility (non-smokers or young-onset light smokers) were analyzed against 110 subjects with the evidence for LC tolerance (elderly tumor-free heavy smokers). Three genotypes demonstrated possible association with LC risk (Leu/Leu-homozygotes for Casp5 Val318Leu versus other genotypes: OR=2.47 (95% CI: 1.07-5.69), p=0.03; His-carriers for Casp8 His302Asp: OR=2.26 (95% CI: 1.18-4.31), p=0.02; Arg-carriers for DR4 Lys441Arg: OR=1.89 (95% CI: 1.05-3.40), p=0.03), and therefore were selected for the validation. The extended study included 2 case-control series, namely subjects from Russia (351 LC cases and 538 controls) and Moldova (296 LC cases and 295 controls). Interestingly, all three candidate genotypes consistently demonstrated OR above 1 both in Russian and in Moldovian groups. Although the combined Mantel-Haenszel analysis yet failed to reach statistical significance (OR=1.22 (95% CI: 0.90-1.65), p=0.21; OR=1.17 (95% CI: 0.92-1.50), p=0.21; OR=1.19 (95% CI: 0.95-1.51), p=0.14, respectively), the obtained data indicate that Casp5, Casp8 and DR4 gene polymorphisms may deserve consideration in large-scale case-control studies of LC risk modifiers.
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Yulia M
authors.initials: YM
authors.lastname: Ulybina
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Ekatherina Sh
authors.initials: ES
authors.lastname: Kuligina
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Nathalia V
authors.initials: NV
authors.lastname: Mitiushkina
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Maxim E
authors.initials: ME
authors.lastname: Rozanov
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Alexandr O
authors.initials: AO
authors.lastname: Ivantsov
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Daria N
authors.initials: DN
authors.lastname: Ponomariova
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Alexandr V
authors.initials: AV
authors.lastname: Togo
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Levchenko
authors.affiliation: Moldovian Institute of Oncology, Kishinev 2025, Republic of Moldova.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Shutkin
authors.affiliation: Moldovian Institute of Oncology, Kishinev 2025, Republic of Moldova.
authors.forename: Sergiu I
authors.initials: SI
authors.lastname: Brenister
authors.affiliation: Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.affiliation: Institute of Environmental Medicine, Karolinska Institute, Stockholm SE-17177, Sweden.
authors.forename: Boris
authors.initials: B
authors.lastname: Zhivotovsky
authors.affiliation: Finnish Institute of Occupational Health, Helsinki FIN-00250, Finland.
authors.forename: Ari
authors.initials: A
authors.lastname: Hirvonen
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia. Electronic address: evgeny@imyanitov.spb.ru.
authors.forename: Evgeny N
authors.initials: EN
authors.lastname: Imyanitov
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053181:Caspase 8 / Q000235:genetics*; D020169:Caspases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; C099217:CASP5 protein, human; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases