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  • 1
    Abstract: Genome-wide association studies have highlighted three major lung cancer susceptibility regions at 15q25.1, 5p15.33 and 6p21.33. To gain insight into the possible mechanistic relevance of the genes in these regions, we investigated the regulation of candidate susceptibility gene expression by epigenetic alterations in healthy and lung tumor tissues. For genes up or downregulated in lung tumors, the influence of genetic variants on DNA methylation was investigated and in vitro studies were performed. We analyzed 394 CpG units within 19 CpG islands in the susceptibility regions in a screening set of 34 patients. Significant findings were validated in an independent patient set (n=50) with available DNA and RNA. The most consistent overall DNA methylation difference between tumor and adjacent normal tissue on 15q25 was tumor hypomethylation in the promoter region of CHRNB4 with a median difference of 8% (P〈0.001), which resulted in overexpression of the transcript in tumors (P〈0.001). Confirming previous studies, we also found hypermethylation in CHRNA3 and telomerase reverse transcriptase (TERT) with significant expression changes. Decitabine treatment of H1299 cells resulted in reduced methylation levels in gene promoters, elevated transcript levels of CHRNB4 and CHRNA3, and a slight downregulation of TERT demonstrating epigenetic regulation of lung cancer cells. Single-nucleotide polymorphisms rs421629 on 5p15.33 and rs1948, rs660652, rs8040868 and rs2036527 on 15q25.1, previously identified as lung cancer risk or nicotine-addiction modifiers, were associated with tumor DNA methylation levels in the promoters of TERT and CHRNB4 (P〈0.001), respectively, in two independent sample sets (n=82; n=150). In addition, CHRNB4 knockdown in two different cell lines (A549 and H1299) resulted in reduced proliferation (P(A549)〈0.05;P(H1299)〈0.001) and propensity to form colonies in H1299 cells. These results suggest epigenetic deregulation of nicotinic acetylcholine receptor subunit (nAChR) genes which in the case of CHRNB4 is strongly associated with genetic lung cancer susceptibility variants and a functional impact on tumorigenic potential.Oncogene advance online publication, 3 September 2012; doi:10.1038/onc.2012.344.
    Type of Publication: Journal article published
    PubMed ID: 22945651
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  • 2
    ISSN: 1619-7089
    Keywords: Chemotherapy ; Osteosarcoma ; Technetium-99m hexakis-2-methoxyisobutylisonitrile ; Therapy evaluation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The use of gamma camera scintigraphy with technetium-99m hexakis-2-methcxyisobutylisonitrile (99mTc-MIBI) for assessment of the response of high-grade osteosarcoma to preoperative chemotherapy was evaluated. Twelve patients with osteosarcoma of the extremities underwent planar examination with99mTc-MIBI before and after preoperative chemotherapy according to the recommendations of the Scandinavian Sarcoma Group. After calculating a quotient for the tumour and the average activity of both extremities and correcting for background activity, the change in uptake between the two examinations was assessed. This was compared with histological examination of the ultimately resected specimen in 11 patients and progressive clinical disease in one. All the 11 tumours undergoing histological examination showed cellular necrosis of between 50% and 100% as well as a reduced uptake of99mTc-MIBI, while the single progressive tumour showed an increased uptake. There was a correlation between the reduction of radiopharmaceutical uptake and the histological response in the entire series, while the variation was too large to allow conclusions in individual patients. This variation may have biological reasons or may be due to the planar imaging technique, which only allows semi quantitative evaluation. The technique reflects response to therapy but is not yet clinically applicable for the identification of poor responders, which would serve as a basis for alteration of the chemotherapy regimen. In order to evaluate whether such a role could be fulfilled, further studies using single-photon emission tomography with correction for attenuation and scattering of photons are necessary.
    Type of Medium: Electronic Resource
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