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    Novel Somatic Mutations to PI3K Pathway Genes in Metastatic Melanoma

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    Authors
    Shull, Austin Y.
    Latham-Schwark, Alicia
    Ramasamy, Poornema
    Leskoske, Kristin
    Oroian, Dora
    Birtwistle, Marc R.
    Buckhaults, Phillip J.
    Issue Date
    2012-08-17
    URI
    http://hdl.handle.net/10675.2/820
    
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    Abstract
    Background: BRAFV600 inhibitors have offered a new gateway for better treatment of metastatic melanoma. However, the overall efficacy of BRAFV600 inhibitors has been lower than expected in clinical trials, and many patients have shown resistance to the drugâ s effect. We hypothesized that somatic mutations in the Phosphoinositide 3-Kinase (PI3K) pathway, which promotes proliferation and survival, may coincide with BRAFV600 mutations and contribute to chemotherapeutic resistance.
    Methods: We performed a somatic mutation profiling study using the 454 FLX pyrosequencing platform in order to identify candidate cancer genes within the MAPK and PI3K pathways of melanoma patients. Somatic mutations of theses candidate cancer genes were then confirmed using Sanger sequencing.
    Results: As expected, BRAFV600 mutations were seen in 51% of the melanomas, whereas NRAS mutations were seen in 19% of the melanomas. However, PI3K pathway mutations, though more heterogeneous, were present in 41% of the melanoma, with PTEN being the highest mutated PI3K gene in melanomas (22%). Interestingly, several novel PI3K pathway mutations were discovered in MTOR, IRS4, PIK3R1, PIK3R4, PIK3R5, and NFKB1. PI3K pathway mutations co-occurred with BRAFV600 mutations in 17% of the tumors and co-occurred with 9% of NRAS mutant tumors, implying cooperativity between these pathways in terms of melanoma progression.
    Conclusions: These novel PI3K pathway somatic mutations could provide alternative survival and proliferative pathways for metastatic melanoma cells. They therefore may be potential chemotherapeutic targets for melanoma patients who exhibit resistance to BRAFV600 inhibitors.
    Citation
    PLoS One. 2012 Aug 17; 7(8):e43369
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pone.0043369
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