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“What I Do” Bryan Betz PhD Clinical Assistant Professor Technical Director Molecular Diagnostics Laboratory Molecular Diagnostics / Molecular Pathology Application of molecular biology techniques and knowledge to clinical laboratory diagnosis • • • • • • • Infectious disease Inherited disease Hematopathology Solid Tumors Identity Testing Forensics Pharmacogenomics Is and will continue to revolutionize the way in which diseases are diagnosed and therapeutics are employed Molecular Pathology A Universal Discipline of Laboratory Medicine INFECTIOUS DISEASE FORENSICS HEMATO PATHOLOGY Molecular Pathology IDENTITY TESTING SOLID TUMORS GENETIC DISEASE Molecular Diagnostics is a Rapidly Expanding Field • Molecular diagnostics is the fastest growing segment of the diagnostics industry • ~$34 billion world-wide market • 6-8% annual growth • New discoveries and technology platforms are leading to the development of more and increasingly sophisticated tests – – – – • DNA sequencing Expression microarrays Array CGH Detection technology/test platforms Majority of the innovation and discovery takes place in Universities UM Molecular Diagnostics Test Volume and TAT Jan 2002 – Dec 2009 Applications of Molecular Diagnostics in Clinical Laboratory Medicine Infectious Disease - Qualitative and quantitative detection - Microbial identification - Drug resistance Genetics (inherited disease) - Diagnosis of: Single gene disorders Complex polygenic disorders Chromosomal disorders Oncology – Solid Tumor and Hematologic - Diagnosis - Prognosis - Predict response to therapy - Monitor residual disease Identity Testing - Determining familial relationships - Bone marrow engraftment analysis - GVHD monitoring - Laboratory specimen identification - Forensics Pharmacogenomics - Drug metabolism - Determine drug dosage UM Molecular Diagnostics Test Menu Hematologic Malignancies Solid Tumors Quantitative BCR/ABL BCR/ABL1 Kinase Mutation Analysis FLT3 Gene Mutation NPM1 Mutation CEBPA Mutation KIT D816V Mutation t(15;17) PML/RARA Translocation t(14;18) IGH/BCL2 Translocation B Cell (IGH) Gene Rearrangement T Cell Gamma (TRG) Gene Rearrangement JAK2 V617F Mutation Detection JAK2 Exon 12 Mutations (March 2010) PAX/FOXO1 Translocation, Alveolar Rhabdomyosarcoma EWSR1/WT1 Translocation, DSRT EWS/FLI1, EWS/ERG Translocations, Ewing Sarcoma SYT/SSX Translocation, Synovial Sarcoma EWS/ATF1 Translocation, Clear Cell Sarcoma Microsatellite Instability Analysis KRAS Mutation BRAF V600E Mutation KIT Mutation in GIST KIT Mutation in Melanoma HER2 FISH, Breast cancer UroVysion FISH, Bladder cancer Genetics/Pharacogenomics Cystic Fibrosis Carrier Screening Apolipoprotein E Genotyping Hereditary Hemochromatosis Mutation Detection Factor V Leiden Mutation Detection Methylenetetrahydrofolate Reductase C677T Mutation Prothrombin 20210 Mutation UGT1A1 Promoter Genotyping Warfarin Sensitivity Analysis Identity Testing Bone Marrow Transplant Engraftment Analysis My Day to Day Activities Clinical • Direct the development, validation, and implementation of new molecular tests • Technical oversight and trouble shooting of existing tests • Maintain quality control and quality assurance standards • Daily review of test data Teaching • MGP fellows and block E residents Research/Academic • Novel molecular diagnostic tests and technologies • Collaborations with AP and HP faculty New Tests Since July 2007 Hematologic Malignancies Solid Tumor Quantitative BCR/ABL BCR/ABL1 Kinase Mutation Analysis FLT3 Gene Mutation NPM1 Mutation CEBPA Mutation KIT D816V Mutation t(15;17) PML/RARA Translocation t(14;18) IGH/BCL2 Translocation B Cell (IGH) Gene Rearrangement T Cell Gamma (TRG) Gene Rearrangement JAK2 V617F Mutation Detection JAK2 Exon 12 Mutations (March 2010) PAX/FOXO1 Translocation, Alveolar Rhabdomyosarcoma EWSR1/WT1 Translocation, DSRT EWS/FLI1, EWS/ERG Translocations, Ewing Sarcoma SYT/SSX Translocation, Synovial Sarcoma EWS/ATF1 Translocation, Clear Cell Sarcoma Microsatellite Instability Analysis KRAS Mutation BRAF V600E Mutation KIT Mutation in GIST KIT Mutation in Melanoma HER2 FISH, Breast cancer UroVysion FISH, Bladder cancer Genetics/Pharacogenomics Cystic Fibrosis Carrier Screening Apolipoprotein E Genotyping Hereditary Hemochromatosis Mutation Detection Factor V Leiden Mutation Detection Methylenetetrahydrofolate Reductase C677T Mutation Prothrombin 20210 Mutation UGT1A1 Promoter Genotyping Warfarin Sensitivity Analysis Identity Testing Bone Marrow Transplant Engraftment Analysis Molecular Diagnostics - Oncology Diagnosis Prognosis Predict response to therapy Monitor residual disease Diagnosis – Ewing Sarcoma Extract RNA Reverse transcription EWSR1/FLI1 cDNA EWSR1 primer FLI1 primer PCR ~ 1 billion copies of target cDNA PCR products Detection Capillary electrophoresis EWSR1/FLI1 (Type 1) GAPDH control Molecular Diagnostics - Oncology Diagnosis Prognosis Predict response to therapy Monitor residual disease Prognosis - Normal Karyotype AML CEBPAmut NPM1mutFLT3-ITDneg Other genotypes Schlenk RF et al. NEJM 358(18):1909, 2008 Prognostic Molecular Testing in AML – The UM Experience 90 80 Tests per Month 70 60 Total FLT3 KIT NPM1 CEBPA 50 40 30 20 10 0 Jan-04 2004 Jan-05 2005 Jan-06 2006 Jan-07 2007 Jan-08 2008 Jan-09 2009 Molecular Diagnostics - Oncology Diagnosis Prognosis Predict response to therapy Monitor residual disease Predict Response to Therapy: KIT Mutations in Melanoma (4 wk) Hodi FS et al., 2008 J Clin Oncol 26(12):2046 Molecular Diagnostics - Oncology Diagnosis Prognosis Predict response to therapy Monitor residual disease Monitoring Residual Disease – UroVysion FISH Normal Urothelial Cell CEP 3 LSI 9p21 CEP 7 CEP 17 Malignant Urothelial Cell Monitoring Residual Disease – UroVysion FISH Case 4 History of CIS (bladder), Post Resection Recurrence of CIS, BCG therapy, Monitoring Cystoscopy - Negative FISH - Positive Thanks!
