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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Somatic mutations affect key pathways in lung adenocarcinoma. 1894 47

It has been hypothesized that oncogenesis and neurodegeneration may share common mechanistic foundations. Recent evidence now reveals a number of genes in which alteration leads to either carcinogenesis or neurodegeneration, depending on cellular context. Pathways that have emerged as having critical roles in both cancer and neurodegenerative disease include those involving genes such as PARK2, ATM, PTEN, PTPRD, and mTOR. A number of mechanisms have been implicated, and commonly affected cellular processes include cell cycle regulation, DNA repair, and response to oxidative stress. For example, we have recently shown that the E3 ubiquitin ligase PARK2 is mutated or deleted in many different human malignancies and helps drive loss on chromosome 6q25.2-27, a genomic region frequently deleted in cancers. Mutation in PARK2 is also the most common cause of juvenile Parkinson's disease. Mutations in PARK2 result in an upregulation of its substrate cyclin E, resulting in dysregulated entry into the cell cycle. In neurons, this process results in cell death, but in cycling cells, the result is a growth advantage. Thus, depending on whether the cell affected is a dividing cell or a post-mitotic neuron, responses to these alterations may differ, ultimately leading to varying disease phenotypes. Here, we review the substantial data implicating specific genes in both cancer and neurodegenerative disease.
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PMID:Genetic determinants at the interface of cancer and neurodegenerative disease. 2041 18

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common non-skin cancer in the world. Tobacco chewing is implicated with most of the cases of HNSCC but this type of cancer is increasing in non-tobacco chewers as well. This study was instigated to provide comprehensive variant and gene-level data in HNSCC subjects of the Indian population and fill the gap in the literature on comparative assessment of gene mutations in cancer subjects with a habit of tobacco and those without any habit using targeted amplicon sequencing. We performed targeted Amplicon sequencing of 409 tumor suppressor genes and oncogenes, frequently mutated across many cancer types, including head and neck. DNA from primary tumor tissues and matched blood was analyzed for HNSCC patients with a habit of tobacco and those without any habit. PDE4DIP, SYNE1, and NOTCH1 emerged as the highly mutated genes in HNSCC. A total of 39 candidate causal variants in 22 unique cancer driver genes were identified in non-habitual (WoH) and habitual (WH) subjects. Comparison of genes from both the subjects, showed seven unique cancer driver genes (KIT, ATM, RNF213, GATA2, DST, RET, CYP2C19) in WoH, while WH showed five (IL7R, PKHD1, MLL3, PTPRD, MAPK8) and 10 genes (SETD2, ATR, CDKN2A, NCOA4, TP53, SYNE1, KAT6B, THBS1, PTPRT, and FGFR3) were common to both subjects. In addition to this NOTCH1, NOTCH2, and NOTCH4 gene were found to be mutated only in habitual subjects. These findings strongly support a causal role for tobacco, acting via PI3K and MAPK pathway inhibition and stimulation of various genes leading to oncogenic transformations in case of tobacco chewers. In case of non-tobacco chewers it appears that mutations in the pathway affecting the squamous epithelial lineage and DNA repair genes lead to HNSCC. Somatic mutation in CYP2C19 gene in the non-habitual subjects suggests that this gene may have a tobacco independent role in development and progression of HNSCC. In addition to sharing high mutation rate, NOTCH gene family was found to be mutated only in habitual sample. Further, presence of mutated genes not earlier reported to be involved in HNSCC, suggest that the Indian sub-continent may have different sets of genes, as compared to other parts of the world, involved in the development and progression of HNSCC.
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PMID:Tobacco habituated and non-habituated subjects exhibit different mutational spectrums in head and neck squamous cell carcinoma. 2832 20