| 1. |
- Ding, Li, et al.
(författare)
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Somatic mutations affect key pathways in lung adenocarcinoma
- 2008
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 455:7216, s. 1069-1075
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Tidskriftsartikel (refereegranskat)abstract
- Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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| 2. |
- Geranmayeh, Fatemeh, et al.
(författare)
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Microglia in gemistocytic astrocytomas
- 2007
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Ingår i: Neurosurgery. - 0148-396X .- 1524-4040. ; 60:1, s. 159-166
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Although gemistocytic astrocytomas, they behave more aggressively than other astrocytomas. Their proliferative potential is low, and it remains an intriguing question why these tumors are so biologically "successful". They show a high mutation rate of the P53 gene, cytological abnormalities, and frequent perivascular mononuclear infiltrates. Microglial cells, a feature of this astrocytoma variant, are of increasing interest in the context of glioma growth. Methods: We selected 23 tumor biopsies from 201 samples obtained from patients with gemistocytic astrocytomas operated at Mayo Clinic between 1985 and 1998. These tumors were formerly anaylzed for P53 mutations, P53 protein, and proliferative activity (9). Immunolabeling for three microglial markers, including CR3/43, Ki-M1P, and iba1, was performed on adjacent tissue sections. In additions, in situ hybridization for the alpha-chain of the major histocompatibility complex (MHC) Class II molecule recognized by the CR3/43 monoclonal antibody was performed. Results: A high number of microglia was detected in gemistoccytic astrocytomas. More microglia were present if the fraction of gemistocytic tumor cells was high (correlation coefficient = 0.699; P < 0.0002). Interestingly, a number of gemistocytes were immunoreactive for MHC Class II molecules, an observation confirmed by in situ hybridization. Importantly, the higher the number of Class II immunoreactive gemistocytes, the fewer Class II positive microglial cell could be detected (correlation coefficient = -0.5649; P < 0.005). Conclusion: Our results support the view that gemistocytic astrocytomas contain unusually high numbers of microglial cells. We propose that the finding of aberrant MHC Class II expression by gemistocytic tumor cells correlates with a loss of immune-competent MHC Class II-expressing microglia. This may be related to the expecially poor prognosis of gemistocytic astrocytomas for which induction of T cell anergy could provide one explanation.
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