Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K et al.. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455: 1069-1075

The Genome Center at Washington University, Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
Nature (Impact Factor: 41.46). 11/2008; 455(7216):1069-75. DOI: 10.1038/nature07423
Source: PubMed


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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    • ". Cancers often have abnormal DNA repair capacity due to mutations in key DDR genes. For example, mutations in ATM or in its downstream target, p53, have been shown to occur in over 70% of lung adenocarcinomas [57]. This appears to cause cells to become more reliant upon ATR to mediate DNA repair. "
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    • "A detailed analysis of the data from The Cancer Genome Atlas (TCGA) consortium set for glioblastoma multiforme (GBM), the most common and lethal primary central nervous system tumor in adults, shows that 3.2% of tumours have somatic mutations in ATR, ATM, or CHK1 [217]. The tumour sequencing project (TSP), a large-scale exon-directed sequencing experiment to classify recurring somatic mutations in lung adenocarcinoma, found that 7% of 188 lung adenocarcinoma patients analysed harboured mutations in ATM [218]. The TSP identified 10 missense mutations, 2 frameshift deletions, a splice site mutation, and a nonsense mutation, consistent with loss of function. "
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