Coding polymorphisms in Casp5, Casp8 and DR4 genes may play a role in predisposition to lung cancer.
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.
Ulybina
Yulia M
YM
N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
Kuligina
Ekatherina Sh
ES
N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
Mitiushkina
Nathalia V
NV
N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
Rozanov
Maxim E
ME
N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
Ivantsov
Alexandr O
AO
N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
Ponomariova
Daria N
DN
N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
Togo
Alexandr V
AV
N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
Levchenko
Evgeny V
EV
N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
Shutkin
Vladimir A
VA
Moldovian Institute of Oncology, Kishinev 2025, Republic of Moldova.
Brenister
Sergiu I
SI
Moldovian Institute of Oncology, Kishinev 2025, Republic of Moldova.
Devilee
Peter
P
Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Zhivotovsky
Boris
B
Institute of Environmental Medicine, Karolinska Institute, Stockholm SE-17177, Sweden.
Hirvonen
Ari
A
Finnish Institute of Occupational Health, Helsinki FIN-00250, Finland.
Imyanitov
Evgeny N
EN
N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia. Electronic address: evgeny@imyanitov.spb.ru.
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*
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