| 1. |
- Hung, Rayjean J, et al.
(författare)
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A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25
- 2008
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 452:7187, s. 633-637
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Tidskriftsartikel (refereegranskat)abstract
- Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
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| 2. |
- Kjaerheim, Kristina, et al.
(författare)
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Absence of SV40 antibodies or DNA fragments in prediagnostic mesothelioma serum samples
- 2007
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 120:11, s. 2459-2465
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Tidskriftsartikel (refereegranskat)abstract
- The rhesus monkey virus Simian Virus 40 (SV40) is a member of the polyomavirus family. It was introduced inadvertently to human populations through contaminated polio vaccine during the years 1956-1963, can induce experimental tumors in animals and transform human cells in culture. SV40 DNA has been identified in mesothelioma and other human tumors in some but not all studies. We tested prediagnostic sera from 49 mesothelioma cases and 147 matched controls for antibodies against the viral capsid protein VP1 and the large T antigen of SV40 and of the closely related human polyomaviruses BK and JC, and for SV40 DNA. Cases and controls were identified among donors to the Janus Serum Bank, which was linked to the Cancer Registry of Norway. Antibodies were analyzed by recently developed multiplex serology based on recombinantly expressed fusions of glutathione-S transferase with viral proteins as antigens combined with fluorescent bead technology. BKV and JCV specific antibodies cross- reactive with SV40 were preabsorbed with the respective VP1 proteins. Sera showing SV40 reactivity after preabsorption with BKV and JCV VP1 were further analyzed in SV40 neutralization assays. SV40 DNA was analyzed by SV40 specific polymerase chain reactions. The odds ratio for being a case when tested positive for SV40 VP1 in the antibody capture assay was 1.5 (95% CI 0.6-3.7) and 2.0 (95% CI 0.6-7.0) when only strongly reactive sera where counted as positive. Although some sera could neutralize SV40, preabsorption with BKV and JCV VP1 showed for all such sera that this neutralizing activity was due to cross-reacting antibodies and did not represent truly SV40-specific antibodies. No viral DNA was found in the sera. No significant association between SV40 antibody response in prediagnostic sera and risk of mesothelioma was seen.
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