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Heinrich & Corless Laboratories GIST Research Updates: May 2012

Heinrich & Corless Laboratories GIST Research Updates: May 2012. GIST Research Updates: May 2012. Corless Will discuss new technologies for DNA sequencing The goal is to further subclassify GISTs and better understand the genes that contribute to malignancy Heinrich

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Heinrich & Corless Laboratories GIST Research Updates: May 2012

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  1. Heinrich & Corless Laboratories GIST Research Updates: May 2012

  2. GIST Research Updates: May 2012 • Corless • Will discuss new technologies for DNA sequencing • The goal is to further subclassify GISTs and better understand the genes that contribute to malignancy • Heinrich • Will discuss studies aimed at understanding how to kill persistent GIST cells that imatinib and sunitinib cannot always control

  3. ‘Next Generation’ DNA Sequencing • Traditional DNA sequencing is limited to just one part of one gene at a time • Second- and third-generation DNA sequencers are now available at OHSU • We have been using these new technologies to study GISTs

  4. Second-Generation DNA Sequencing

  5. Sequencing GIST ‘Exomes’ • Human genome consists of 3.2 billion letters (A, C, T, G) • Genes comprise only ~2% of our DNA (about 64 million letters) • We ‘pre-select’ the genes, so that only the 64 million letters of interest get sequenced – this is the ‘exome’ • Cost: $2,000 per sample

  6. GIST ExomeSequencingSpecimen Summary Additional matched normal specimens: 19 completed; 5 in progress; 8 available

  7. Apoptosis, Cell adhesion, 5 Cell cycle, 1 DNA damage autophagy , 6 response, 4 Epigenetic regulation, 8 GTPase regulation (Ras family) , 6 Golgi, intracellular transport , 7 Kinase, adaptor, RTK regulation , 15 Ribosome biogenesis, RNA Polymerase, RNA splicing, 13 Transcription factor, 15 Tumor suppressor, TP53 - related , 6 unknown, analysis in progress, 173 Ubiquitin , 9 Misc potentially interesting , 8 Sequencing results: Mutant genes by group • 25 specimens • from 18 patients • 285 non-synonymous • mutations • 276 unique genes

  8. GIST AnalysisUsing Third-Generation DNA Sequencing • The Knight Labs have partnered with Ion Torrent/Life Tech on the development of genotyping panels using third-generation DNA sequencing technology • Sequencing is performed on a semiconductor chip

  9. Sequencing Directly On A Chip

  10. Traditional Sequence 3rd Generation Sequence ACTGGTCCTGCTGGTTAG ACTGGTCCTGCTGGTTAG ACTGGTCCTGCTGGTTAG ACTGGTCCTGCTGGTTAG ACTGGTCCTGCTGGTTAG ACTGGTCCAGCTGGTTAG ACTGGTCCAGCTGGTTAG ACTGGTCCAGCTGGTTAG ACTGGTCCAGCTGGTTAG ACTGGTCCAGCTGGTTAG

  11. Knight Diagnostic Labs GIST Panel Common GIST mutations Important in WT GISTs Predicting GIST prognosis Rare GIST mutations of research interest

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