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Interactions in Genetics and Pathology

Interactions in Genetics and Pathology. CMGS/ACC Part II Study Day 22 nd November 2007 Maggie Williams MRCPath Consultant Clinical Scientist Bristol Genetics Laboratory. Interactions in Genetics and Pathology. Results from other disciplines;

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Interactions in Genetics and Pathology

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  1. Interactions in Genetics and Pathology CMGS/ACC Part II Study Day 22nd November 2007 Maggie Williams MRCPath Consultant Clinical Scientist Bristol Genetics Laboratory

  2. Interactions in Genetics and Pathology • Results from other disciplines; • inform requesting and interpretation of genetic tests • are used in conjunction with genetic tests to make a diagnosis/prognosis • Genetic technologies have wide application in pathology

  3. MODERNISATION INITIATIVES • Genetics White Paper June 03 • Modernising Pathology Services Feb 2004 • Modernising pathology: building a service responsive to patients Sept 05 • New pathology networks / new technologies • Staff skill mix • The NHS Plan • Modernisation HCS Careers, A4C, KSF, NOS, • Connecting for Health • EVOLUTION OF SERVICES • NHS improvement plan June 2004 • Patient Care Pathway (18 week target ) • Increasing overlap in service areas • Technological Advances • increasing overlap in application Drivers

  4. Drivers • FINANCIAL • EFFICIENT USE OF RESOURCES • Space • Equipment • Used to capacity – “sweat assets” • Avoid duplication • Relative Reduction in maintenance costs • Reagents • Batch throughput • Central procurement • Staff • Workforce Review and Skill mix • Skill set sharing • Explore common roles – Admin, QM… • QUALITY • RESEARCH OPPORTUNITIES

  5. Barriers • HISTORICAL • Resistance to change • Ownership • MANAGEMENT OF SERVICES • Ensuring appropriate Professional and Clinical involvement • Workforce issues – “capacity planning” • PHYSICAL SEPARATION • Poor communication – isolated working • Work patterns– Reporting times - hours vs days • ELECTRONIC SEPARATION • Incompatible IT • Demographics / Results / Combined reports

  6. Genetics and PathologyFlexibility and Pragmatism GENETICS CYTO MOL CYTO MOL A B C • Various models for Genetics • Various Models for Pathology • Local laboratory situations vary • Opportunity for Interaction • Profile of work • Constantly review local options within National Framework

  7. Bristol Genetics Laboratory • MERGER DEC 2005 ( pathology modernisation review) • OVERLAPPING SERVICES • FRAX/PWS/AS • Quantitation - QF PCR/ MLPA /Arrays • Molecular Oncology • Non-invasive prenatal testing –ffDNA, PGD • Infertility services -karyotype,FISH,CF,POF,Y deletions • COMMON ROLES • Quality Management • Administration/Office • Laboratory service manager • IT manager • Health and Safety

  8. COMMON FACILITIES • Sample Reception and booking in • DNA/RNA extraction • PCR • Electrophoresis and Imaging • Automated capillary analysis (ongoing) • IT LIMS/Q pulse • COMBINED BUDGET • Flexibility • Procurement savings • Skill mix review • TRAINING • Combined training committee • Staff rotation, programmes and competencies ( ongoing ) Bristol Genetics Laboratory

  9. NBT GENETICS PATHOLOGY MANAGEMENT

  10. HAEMATOLOGY CLINICAL BIOCHEMISTRY CELLULAR PATHOLOGY GENETICS NEURO PATHOLOGY IMMUNOLOGY MICROBIOLOGY NBT GENETICS/PATHOLOGY INTERACTIONS • OPPORTUNITIES • Integrated management structure • Close physical location ( some areas ) • Financial drivers – CRES (4%), PMF • PM Centralisation and new build for 2009/10

  11. Clinical Biochemistry • Newborn Screening CF/MCAD ( 08/09) • Antinatal Screening Biochemical test/CVS/amnio/QFPCR/karyotype • Biochemical Genetics - proteins/enzymes/metabolites PKU/Galactosaemia/MCAD/SLO • Biochemical tests contributing to diagnosis CK analysis – neuromuscular disorders CAH Alpha1 antiptypsin • Pharmacogenetics Study of (inherited) differences in Drug Metabolising Enzymes Aim to reduce adverse drug reactions • reduce morbidity and patient distress • reduce associated costs

  12. Clinical Biochemistry/Pharmacogenetics • Cholinesterase • DME metabolising certain drugs used in anaesthesia • Deficiency from genetic variations  prolonged action of drugs  prolonged stay (distress and costs) • biochemical phenotyping (National & International) and genotyping • Cytochrome p450 enzymes • Highly polymorphic family of DMEs • CYP2C9 • Metabolises the anticoagulant warfarin • Genetic variants  over coagulation • Genotyping pre-treatment  avoidance of ADRs • CYP2D6 Multiple SNP variants • anti-arrhythmics • beta-blockers • MAO inhibitors • morphine derivatives/anti-psychotics/tricyclic anti-depressants

  13. BACTERIOLOGY / VIROLOGY MICROBIOLOGY VIROLOGY Future perspectives in public health microbiology. Cath Arnold NGRL Wessex website Health Protection Agency and Public Health Laboratories BACTERIOLOGY NBT reference centre with strong R+D interest

  14. RAPID DETECTION AND IDENTIFICATION OF PATHOGENS Increased speed, efficiency, sensitivity & accuracy MORE EFFICIENT & APPROPRIATE TREATMENT - Meningitis - MRSA- pre-access testing - ESBL - Acinetobacter sp. - TB - Chlamydia - Norovirus - Flu - Non-culturable bacteria- orthopaedics Rapid diagnosis Difficult to culture Phenotypic ID specialised

  15. RAPID DETECTION OF ANTIBIOTIC RESISTANCE AND VIRULENCE GENES • Determine pathogenic potential of micro-organisms • Implementation of appropriate therapy SURVEILLANCE AND EPIDEMIOLOGY • Intra-species relatedness • Outbreak Investigations • - Source, modes and route of transmission • - Emergence of new or virulent clones eg. • C. difficile, Community associated-S. aureus / MRSA, ESBL’s • Longitudinal and Historical studies / Predicting future trends

  16. General Haematology • Hereditary Haemochromatosis – • HFE gene analysis C282Y and H63D mutations • Clotting factors • Factor V Leiden and prothrombin II • UKGTN access for specialist tests • Thalassaemia • Haemophilia

  17. Molecular Oncology • Tumour markers- acquired disease • histopathology – morphology/grade • haematology – cell/platelet counts, morphology • immunology - immunophenotyping • cytogenetics – karyotype/FISH/array • molecular genetics - clonality, mutations, • methylation, quantitation, MSI • Diagnosis • Prognosis • Therapeutic decision making

  18. Haemato oncology • AML • t(15:17), t (8;21), Inv(16), MLL 11q23 • FLT3-ITD, NPM1 • Secondary AML • del (5) EGR1, del (7) ELN) • ALL children • T(12;21) TEL/AML1, MLL, BCR-ABL, Hyperdiploidy/ploidy • ALL adults • c-myc • Lymphomas • IgH 14q32, IgH/BCL2 t(14;18), BCL6 3q27, IgH/CCND1 t(11:14) • C-myc 8q24, MALT 18q21, ALK 2p23 • Clonality studies BIOMED-2 IG and TCR gene rearrangements

  19. Haemato oncology • CML/MPD • Bcr-abl,JAK2 V617F, JAK2 exon 12 • Tefferi et al WHO revision proposals Blood August 2007 110:10912-1097 • Eosinophilia • FIPL1-PDGFRA • MDS • Del(5) EGR1, del(&) ELN), del (20)(q12) • CLL • Del(13)q14), trisomy 12, p53 (17p)loss, ATM (11q23) • BMT monitoring • X;Y sex mismatch.disease specific translocation • Research • Progression of MDS to AML and genomic instability • Cytogenetics, molecular genetics,histopathology

  20. Haemato oncology MRD UK ALL 2003 TRIAL – Childhood Acute ALL • LRF funded • NHS in April 2008 • PCR clonality – Sequencing/Specific Real Time PCR assay • 4 centres • Glasgow • Sheffield • Hammersmith • Bristol • Integration of UoB research team in NHS service laboratory

  21. Oligodendroglioma neurosurgeons, neuropathologists, oncologists, genetics • Oligodendroglia are highly specialised myelin-forming cells of the CNS. • Rare primary brain tumours, frequency ~0.53 cases/100,000 • Of these ~20% are anaplastic • Relatively good prognosis, survival of up to 10 years from diagnosis. • Median age of onset between 40 & 50 years • Treatment by surgical resection, followed by radiotherapy and PCV chemotherapy on recurrence. • Recurrence is common, often leading to disease progression and death.

  22. Molecular Aspects of Oligodendrogliomas • The combination of 1p and 19q deletions predicts a high response rate to PCV and prolonged survival. • If no 1p19q LOH, chemotherapy is not withheld, but advise that the chance of benefit from PCV is low. LOH 1p/19q McDonald et al (2005) Cancer. 1;104(7):1468-77 No LOH • Deletion of CDKN2A, PTENmutations and amplification of EGFR are indicators of poor response.

  23. D19S418 D1S2736 Blood Tumour Blood D1S214 D1S199 Tumour

  24. Glioblastoma • Commonest malignant brain tumour: ~5/100,000 per annum. • More common in elderly patients. • Highly malignant, infiltrates the brain extensively. • Median survival of 9 months • Surgical resection with concurrent radio- and chemotherapy. • <50% respond to alkylating agent temozolomide (Temodar®) • Response correlates with methylation (inactivation) of the MGMT (O6-methylguanine–DNA methyltransferase) gene

  25. Hegi ME, et al. (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. New Eng J Med;352:997-1003. Estelleret al(2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. New Eng J Med, 343, 1350 – 1354. Paz et al (2004) CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin Can Res, 10, 4933 – 4938

  26. MGMT Methylation Analysis UNMETHYLATED METHYLATED • Temozolomide has been licensed for use in Glioblastoma patients • MGMT methylation status aids therapeutic decision making • Other tumour types (melanomas, lung, bladder & oesophageal cancers)

  27. Pathology and GeneticsClinical Service Management Models • Work undertaken (whole or in part) by Genetics • Molecular Oncology • Screening • General Haematology • Cross discipline service development posts • Molecular Microbiology • House and supervise placements/training for local provision • Pharmacogenetics, immunology • Facilitate use of equipment and offer supervision support • Pharmacogenetics/histopathology • Relocation of isolated work under umbrella of Genetics • MRD group at University of Bristol

  28. Pathology and GeneticsFuture Vision- New build 2009 • DNA sequencing service • Automated Extraction facilities • PCR • Banking/freezing • Central Procurement (MSI) • Skill mix/Training/Seminars • Common Roles – Admin, quality, H+S • Integrated IT/ Combined Reporting

  29. Interactions in Genetics and Pathology Acknowledgments BGL and Pathology teams at NBT Sian and Jenny

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