diagnostic capabilities beyond the tumor cell genome gregory j. tsongalis, phd, hcld professor of...
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Diagnostic Capabilities Beyond the Tumor Cell Genome
Gregory J. Tsongalis, PhD, HCLD
Professor of Pathology
Director, Molecular PathologyGeisel School of Medicine at Dartmouth
Dartmouth Hitchcock Medical CenterNorris Cotton Cancer Center
Lebanon, NH
Outline
• Technology and Personalized Medicine
• miRNAs
• The liquid biopsy
• Beyond that…….
Technology and Therapeutics as Drivers of Medical Care
Basic Science
Clinical Medicine
Translational Research
Clinical Laboratory Medicine
The Genome Or The Human Karyotype
Massively Parallel or Next Generation Sequencing at DHMC
MiSeq PGM
Sequence by Synthesis
Personalized Medicine
Shaw A T and Engelman J A JCO 2013;31:1105-1111
(A) Before crizotinib; (B) after 7 weeks of crizotinib.
NucleusNucleus
CytoplasmCytoplasm
Pri-miRNAPri-miRNA Pre-miRNAPre-miRNA
miRNA:mimiRNA:miRNA* RNA*
duplexduplexUnwindingUnwinding
DroshaDroshaDGCR8DGCR8
Exportin 5Exportin 5
DicerDicer
RISCRISC
RibosomeRibosome
Translational RepressionTranslational Repression mRNA CleavagemRNA Cleavage
C. L. Bartels and G.J. Tsongalis, Clin Chem, 2009;55: 623-631
Specificity(miRNAs as Biomarkers)
miRNA Profiling from Pancreatic FNAs
Szafranska, Doleshal, Edmunds , Gordon , Luttges, Mundingv Barth Jr , Gutmann, Siriawinata , Pipas , Tannapfel , Korc, Hahn, Labourier , Tsongalis . Clin Chem 54(10):1716-1724, 2008.
5
16
4
5
*
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Hanoun, Delpu, Suriawinata, Bournet, Bureau, Selves, Tsongalis , Dufresne, Buscail, Cordelier, Torrisani. Clin Chem 56(7):1107-1118, 2010.
24 FFPE matched tumor and normal HNSCC (6 laryngeal, 6 oral tongue)
miRs: 21, 205, 12746 upregulatedmiRs:451, 125b downregulated
Issues With The Tissues
– Tumor tissue has inherent limitations– Tumor tissue is a single snapshot in time– Selection bias due to tumor heterogeneity– Invasive procedure
Resected Specimen Small Needle Core Biopsy
Exhausted Block
A Huge Problem
The Liquid Biopsy
• Cell Free DNA (cfDNA)–Cells undergoing apoptosis or necrosis–Amount of cfDNA correlates with tumor staging and prognosis
Xenograft Model
Kerrington Smith, MD
Promega PlexorHY
J. E. Hill, PhDThayer School of Engineering at Dartmouth
Breath-based Diagnostics
Breath-based Diagnostics
Conclusions
• Circulating nucleic acids become future biomarkers of choice
• More advanced analysis of simpler specimens
Molecular Pathology Laboratory and Translational Research Program
Samantha AllenPaul Burchard
Francine de Abreu, Ph.D.Leanne CookBetty Dokus
Amber ErskineTorrey Gallagher
Arnold HawkJoel Lefferts, Ph.D.
Emmeline LiuRebecca O’MearaJason Peterson
Elizabeth ReaderBarbara Soares
Heather SteinmetzLaura Tafe, M.D.Scott Turner, PhDWendy Wells, M.D.
Terri WilsonEric York