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The InSiGHT-Human Variome Project Collaboration - Finlay Macrae
 

The InSiGHT-Human Variome Project Collaboration - Finlay Macrae

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The International Society for Gastrointestinal Hereditary Tumours and the Human Variome Project have had a long and fruitful collaboration. Finlay Macrae, InSiGHT's Secretary spoke at the 4th Biennial ...

The International Society for Gastrointestinal Hereditary Tumours and the Human Variome Project have had a long and fruitful collaboration. Finlay Macrae, InSiGHT's Secretary spoke at the 4th Biennial Meeting of the Human Variome Project Consortium to update delegates on the progress of the collaboration and to share some of the methods that InSiGHT has used to build their organisation and their database.

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    The InSiGHT-Human Variome Project Collaboration - Finlay Macrae The InSiGHT-Human Variome Project Collaboration - Finlay Macrae Presentation Transcript

    • Gene/Disease Specific DatabasesThe InSiGHT-Human Variome Project collaboration Finlay Macrae Secretary, International Society for Gastrointestinal Hereditary Tumours Head, Colorectal Medicine and Genetics, The Royal Melbourne Hospital Professor of Medicine, Departments of Medicine, Melbourne and Monash Universities, Victoria, Australia 4th Bi-ennial Human Variome Project Paris, June 2nd, 2012
    • Human Variome Project – InSiGHT collaboration Talk Summary• What is Lynch Syndrome?• What is InSiGHT?• What is the Human Variome Project?• Governance, Ethics, Data use policy• Indemnity, Disclaimers• The InSiGHT Mutation Interpretation Committee• Interoperability:PathoKB, Clin Var, Mutadatabase• Future Activities
    • What is Lynch Syndrome?
    • What is Lynch Syndrome?• Hereditary non Polyposis Colon Cancer Syndrome – HNPCC• Caused by a germline (inheritable) mutation in a mismatch repair gene• hMLH1, hMSH2, hMSH6 or hPMS2• LS is identified through various strategies….• The Amsterdam criteria, Bethesda criteria, Melbourne criteria, Ohio State University Criteria
    • What is Lynch Syndrome? The Amsterdam criteria 3:2:1 rule 3 first degree relatives over 2 or more generations with 1 under 50 years of age affected with Colorectal, endometrial cancer,Ovarian, small bowel, hepatobiliary, pancreatic, pelvi-ureteric, stomach, brain cancers, breast, prostate, kidney cancers
    • What is Lynch Syndrome? The Ohio State University Criteria Population screening:• Test all cancers presenting routinely by MSI or Immunohistochemistry for mismatch repair protein lossNote: Determines chemotherapy decisions inStage 2 and 3 cancers
    • What characterizes tumours within Lynch Syndrome
    • What characterizes tumours within Lynch Syndrome• Microsatellite instability• Loss of expression of MMR gene in the tumour identified through immunohistochemistry: – MLH1 and PMS2 loss = MLH1 germline (or sporadic MSI due to methylation of MLH1 somatically) – MSH2 and MSH6 loss = MSH2 (or MSH6) – MSH6 loss = MSH6 – PMS2 loss = PMS2
    • What is Lynch Syndrome?• Hereditary non Polyposis Colon Cancer Syndrome – HNPCC• Caused by a germline (inheritable) mutation in a mismatch repair gene• hMLH1, hMSH2, hMSH6 or hPMS2• LS is identified through various strategies….• The Amsterdam criteria, Bethesda criteria, Melbourne criteria, Ohio State University Criteria• How are individuals and families worked up for diagnosis of Lynch Syndrome?
    • How are patients worked up for diagnosis of Lynch Syndrome?• Suspect the diagnosis: Amsterdam, Bethesda, (Melbourne or OHSU)Amsterdam and Bethesda• Identify youngest live family member affected with CRC or other cancer• Offer IHC or MSI testingAll strategies• If loss of expression or positive MSI, proceed with mutational analysis of relevant gene indicated by IHC …sequencing and MLPA• Cascade testing through the family pedigree
    • Surveillance in LS• Colonoscopy annually (some say 2 to 3 yearly)• ?Gastroscopy• ?Annual pelvic ultrasound, endometrial sampling• ?annual urine cytology• ?Capsule endoscopyThe Dutch criteria: Screen for site with >1 cancer in family
    • Colorectal surgery for Lynch Syndrome The metachronous colorectal cancer rate after 40 years is 60%• Colectomy with ileo-rectal anastomosis• Proctocolectomy with restorative ileo-anal pouch• Segmental resection
    • What is InSiGHT?
    • What is InSiGHT• The International Society for Gastrointestinal Hereditary Tumours formed with the merger of the Leeds Castle Polyposis Group and ICG HNPCC in 2005• Followed a courtship when the two groups met in Melbourne in 1999 under LCPG chairmanship• Governed by elected Council; Non voting administrative directors• Maintains a database of MisMatch Repair (and other genes responsible for GI cancer) DNA variants through its websitewww.insight-group.org
    • What is the Human Variome Project?
    • The Human Variome ProjectHuman Variome Project International Ltd in Consultative Partnership with the United Nations Educational, Scientific and Cultural Organisation (UNESCO) as an NGOInitiated 20-23 June 2006 in Melbourne, Australia and co- sponsored by WHO Scientific Director: Professor Richard Cotton Nat Genet, 2007. 39(4): p. 433-6
    • Human Variome Project: Goals• Global inclusive initiative• Ensure the translation of genetic variation data into direct patient benefits• Facilitate the establishment and maintenance of standards, systems and infrastructure for sharing the worldwide collection of genetic variations effecting human disease• Sharing data – reducing disease
    • InSiGHT and the Human Variome Project ConsensusInSiGHT meeting Yokohama, March 2007
    • InSiGHT/HVP: Databases and curation April 2007• DNA Variant Curators and Governance: M Woods, P Peltomaki, R Sijmons, H Vasen, J den Dunnen, F Macrae• Phenotype: F Macrae, (Chair) , R Scott, S Clarke, C Burke, T Weber, P Watson, A Lindblom, P Rozen, G Moeslein, I Bernstein, A Spigelman• Virtual Histology: H Morreau, E Brazowski• Missense And Functional Assays: R Sijmons (Chair), R Hofstra, M Nystrom, N Winds, (Lene Jule Rasmussen)• Mutation Interpretation Committee: M Genuardi (Chair), J Utsunomiya, R Ramesar, J Burn, M Greenblatt, P Peltomaki, R Hofstra, R Sijmons, R Scott, M Corish, D Golgar, M Woods, B Bapat, S Tavtigian, A Spurdle, S Lipkin, M Dunlop, I Frayling, E Holinski Feder, A Lindblom, T Weber, J Wijnen, F Macrae
    • MMR mutation Identified (DNA Lab)InSiGHT Flow IHC &/or MSI data added Plan B (Histopathology)(commencing Interpretation of Virtual pathology added (Histopathology) genotypewith genotype) (Clinicians & Lab) Functional data added (Research Labs) Clinical phenotype added (Clinicians) Identified dataset stored De-identified data stored with InSiGHT locally Interpretation (Family Cancer Clinic) (InSiGHT) Data from other DbGaP (NCBI) centres can be UCSC submitted to update EBI information
    • InSiGHT LSDB Governance Committee Terms of Reference• Appointed by Council, with reference to expertise in databasing, and to an extent, geographic representation.• Consists of 6 InSiGHT members with the capacity to appoint scientists with special expertise ad hoc .• Oversees the functions the database and its supporting committees including interpretation, functional assays, phenotype, virtual pathology.• Monitors database security, back up, access and confidentiality• Reports to InSiGHT Council before Council meetings.• Ensures compliance with the LOVD Database and Usage Policy• Endorses a disclaimer on the website relating to the InSiGHT database, in line with the LOVD policy.
    • LSDB Governance Committee• Determines the Gastrointestinal Cancer genes to be included in the InSiGHT database• Approves the reference sequence for each gene• Definition of data fields that will be included• Disclosure policies per field – Fields with uninhibited exposure through public access – limited access fields – further data available through curator fields• Appoints the curator: Allocates available resources for curation• Appoints Ethics Committee
    • COMPANIES ACT 2006 COMPANY LIMITED BY GUARANTEE NOT HAVING A SHARE CAPITAL ARTICLES OF ASSOCIATION - of -THE INTERNATIONAL SOCIETY FOR GASTROINTESTINAL HEREDITARY TUMOURS As instructed to Bircham, Dyson & Bell, 50 Broadway, London, SW1H 1OL,UK Shortlisted as Charity Advisor of the Year by CityWealth Magic Circle Awards, 2010 Registered Charity in UK
    • Incorporation and Charity Registration means• Pathogenicity can be assigned with substantial medico-legal protection• InSiGHT can enter contractual arrangements with organizations, government and DNA diagnostic and research labs where needed• InSiGHT can attract funds as a tax deductible charity world-wide• Director/Office bearer roles clarified
    • InSiGHT Database: A lead LSDB for the HVP• Merge of MMR (Mike Woods), functional assay (R Sijmons) with InSiGHT databases – 2008• German HNPCC consortium data uploaded• Hicks Foundation InSiGHT curator appointed - 2010 in Melb• National submissions of diagnostic lab DNA variants (n=25,000 including 3500 unique variants)• Calibration of functional assay of missense variants R Hofstra• in silico analyses S Tavtigian• Quantitative phenotype dataset drafted• Interpretation processes implemented
    • InSiGHT LSDB database Page hits/month and unique IP addresses through LOVD• 2011 2011
    • InSiGHT/HVP database Work in progress• Data submission..France, Sweden, Denmark, Poland, Australia, US CFR, Quest Diags• MoU with MuDB: UK NHS diagnostic labs - A Devereau (UK)• InSiGHT Mutation Interpretation Committee for VUS met in San Antonio, March 2011: modus operandi established: 4 teleconferences completed (Chair: M Genuardi, Italy)• Endorsement of SNPs as clearly pathogenic or benign polymorphism as calibration tools for functional assays and Bayesian algorithm: NCI R01• Phenotype agreement, and commissioning on database: Germany• Preparation of paper describing InSiGHT pathway: F Macrae (Australia)• International Mismatch Repair Consortium: NCI R01• Microattribution: Myles Axton, ORCID, , George Patrinos (Greece)• Clin Var: NCBI Justin Paschall, Donna Maglott USA• Mutadatabase : Patrick Willems, Heidi Rehms (Belgium and USA)• Gen2Phen and PathoKB: Tony Brookes (UK)
    • The InSiGHT Hicks Foundation Curator• Check integrity of submissions Nomenclature, duplicate entries,• Promote submissions internationally• Liaison role: Travel• Assist in development of annotations• Present data on unclassified variants to Interpretation Committee: Display outcomes• Located in Melbourne JohnPaul@variome.org
    • LSDB Minimal Data Requirements (Variant) Present Derivable from other fieldsSource: Gen2Phen - D3.4 Scope and Range Requirements of Specialized Domain Models; O = Obligatory, R = RecommendedField Name D3.4 InSiGHT LOVD Examplegene Symbol O MLH1Exon R 1DNA_genomic O g.445345DNA_coding R c.125delC>TRNA O r.125c>uProtein O p.pro41argDBID O 12Reference O Chan et al., 1999DNA_published R 125 C -> TDetection/Template O DNADetection/Technique O SequencingDNA_remark R Free text commentFrequency R 1/1012 controlsOrigin R germlineAllele R 1Pathogenicity R Pathogenic
    • LSDB Minimal Data Requirements (Patient Information)Source: Gen2Phen - D3.4 Scope and Range Requirements of Specialized Domain Models; O = Obligatory, R = RecommendedField Name D3.4 InSiGHT LOVD ExamplePatient_ID O 12345Disease O CRCRemarks R Free TextGeographic R AustraliaEthnic R CaucasianGender R MaleSubmitter_ID O 5
    • LSDB Minimal Data Requirements (Patient Phenotype) Source: Gen2Phen - D3.4 Scope and Range Requirements of Specialized Domain Models• Age, Gender, Age of Diagnosis, Signs and Symptoms• Family history and pedigree:• Use of Controlled Vocabulary for Signs and Symptoms (e.g. Human Phenotype Ontology, ICD10; SNOMED)• Therapy information is optional – however, currently no ontology exists.
    • Summary Family History Statistic• Provides probability assessment based on density of phenotype across the family• Is non-identifiable, protecting privacy• Can be added in to a Bayesian Likelihood Ratio to assist in quantitation of VUSs• Requires full pedigree to derive the data, but only at source/submitter• SISA: simplified analytic technique (P Moller)
    • China establish MMR database on LOVD database platform 2010• 2006 Dr Ming Qi engages with the Human Variome Project• 2007 Dr Ming Qi joins InSiGHT• 2010 Dr Ming Qi establishes Chinese MMR database on LOVD platform• 2011 Dr Ming Qi invited to join InSiGHT Council as ad hoc Councillor• 2011 HVP China Meeting Beijing• 2012 Chinese MMR data merging with InSiGHT database
    • The International Mismatch Repair Gene Consortium• The C-CFR is keen to promote utilization of its resource (40,000 individuals)• InSiGHT and the C-CFR met at InSiGHT meeting in Dusseldorf (June 2009)and agreed to collaborate with a number of projects targeted• InSiGHT is strong on clinical collaborations and access to families with MMR mutations, and unique clinical science• C-CFR is strong on epidemiology, molecular epidemiology, molecular biology and epigenetics• C-CFR has excellent grantsmanship skills, and is well funded• Agreement in Washington April 2010 to form an InSiGHT C-CFR MMR consortium as vehicle to attract further funds from NCI, EU and Australia• 90 investigators from 45 countries representing 15000 variants• Two R01 applications on penetrance submitted in Feb 2011: not funded• Re-application planning in progressAll countries are warmly invited to join the consortium..through InSiGHT!Contact: Finlay.Macrae@mh.org.au
    • InSiGHT Interpretation Committee Modus operandi• Chair appointed by Council: Maurizio Genuardi (Italy)• Invitations for core and extended committee memberships• Qualitative approach to classification discussed, circulated, and agreed• Initial set of missense variants with discordant interpretations and 3 lines of evidence classified according to approach agreed across the committee• Variant list for discussion is circulated to extended committee – any additional available data canvassed• All data is then assembled by curator for Core Committee plus rolling other membership to classify at international teleconferences (sponsored)• One line entry to be included on InSiGHT database describing outcomes• Later, preliminary approach to all InSiGHT members to seek all available information of variants under consideration at each meeting• InSiGHT members encouraged to submit data at each contact, and signal variants of particular clinical concern for Committee consensus•
    • Interoperability• Annotation on InSiGHT databases website• ClinVar (NCBI)• Mutadatabase• Gen2Phen• DMuDB• Patho KB (data model)
    • InSiGHT Interpretation Committee Mar 2012 • R Ramesar (South Africa)• M Genuardi (Italy, Chair) • M Qi (China)• JP Plazzer (Curator) • R Hofstra (Netherlands)• F Macrae (Sec, InSiGHT) • M Vihinen (Finland)• A Spurdle (Australia) • M Nystrom (Finland) • T Weber (USA)• B Thompson (Australia) • S Tavtigian (USA)• M Woods (Canada) • D Goldgar (USA)• R Sijmons (Netherlands) • C Heinen (USA)• P Peltomaki (Finland) • S Lipkin (USA)• M Greenblatt (USA) • A Lindblom (Sweden) • K Akagi (Japan)• I Frayling (UK) • F Al-Mulla (Kuwait)• J Burn (UK) • L Rasmussen (Denmark)• M Dunlop (UK) • I Bernstein (Denmark)• S Farrington (UK) • F Wikman (Denmark)• B Royer Pokora (Germany) • T Frebourg (France) • S. Olschwang (France)• E Holinski Feder (Germany) • A Fabre (France)• G Moeslein (Germany) • M Tosi (France)• I Blanco (Spain) • S Leung (Hong Kong)• G Capella (Spain) • T Liu (Sweden)• M Pineda (Spain) • P Moller (Norway) • B Bapat (Canada)• D Du Sart (Australia) • M Farrell (Ireland)• M Kohonen Corish (Australia) • C Tops (Holland)• R Scott (Australia) • D-W Kim (Korea)• B Talseth (Australia) • J Wijnen (Netherlands) • Kristina Lagerstedt-Robinson (Sweden)
    • HVP members are welcome to join InSiGHT and contribute to our program• Join InSiGHT• Submit variant data to InSiGHT MMR and other databases• Consider membership of the InSiGHT Mutation Interpretation Committee for VUSs• Join the International Mismatch Repair Consortium• Exchange scientific personnel in training (PhDs, MDs etc)• Assist in funding the InSiGHT Mismatch Repair LSDB curator
    • CAIRNS CONVENTION CENTRE - AUSTRALIA InSiGHT Bi-Ennial Meeting August 29- 31st. 2013Join us..it will be a great meeting! Serious Business in Australia’s Most
    • CAIRNS CONVENTION CENTRE - AUSTRALIA InSiGHT Bi-Ennial Meeting August 29- 31st. 2013Join us..it will be a great meeting! Serious Business in Australia’s Most