Diverse somatic mutation patterns and pathway alterations in human cancers

Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Nature (Impact Factor: 41.46). 08/2010; 466(7308):869-73. DOI: 10.1038/nature09208
Source: PubMed


The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics. Here we report the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for galpha subunits in multiple cancer types. Furthermore, our experimental analyses demonstrate the functional roles of mutant GNAO1 (a Galpha subunit) and mutant MAP2K4 (a member of the JNK signalling pathway) in oncogenesis. Our study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.

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    • "These studies have detected over 60 tumor-acquired mutations per patient. Though mutation of the p53 tumor suppressor has been identified as an almost universal characteristic (95% of ovarian tumors), all other somatic mutations have been found to occur in 3–6% of tumors or less (Kan et al, 2010; Cancer Genome Atlas Research, 2011). In combination with this diversity of somatic nucleotide variation, pervasive and recurrent copy number variation has been detected (Etemadmoghadam et al, 2009; Cancer Genome Atlas Research N, 2011), giving rise to the notion that ovarian tumor progression is driven by a " turbulent genome " . "
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    • "Oncogenic role of PI-3 kinase p110β in prostate cancer It is conceivable that all class I PI-3 kinases are oncogenic when overexpressed or overactivated in mammalian cells [37] [58]. In human cancers , the most common gain-of-function mutations in PI3K family were from PIK3CA gene/ p110α protein, whereas the los-of-function mutations were from PTEN gene/PTEN phosphatase protein [40] [59] [60]. In a small portion of human cancers, gene amplification was seen in PIK3CB gene/p110β protein although its wild-type form is also oncogenic [58] [61]. "
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    • "Many GPCRs and their cognate agonists also mediate autocrine/paracrine growth stimulation in a variety of cancer cells and dramatically synergize with insulin/IGF-1 in inducing mitogenic signaling (Rozengurt, 1986). A recent characterization of cancer genomes demonstrated frequent mutations in GPCRs and G proteins (Kan et al., 2010). Consequently, we hypothesized that crosstalk between insulin/IGF-1 receptor and GPCR signaling systems is also a mechanism for enhancing the development of pancreatic cancer (Rozengurt et al., 2010). "
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