Gene/Disease Specific DatabasesThe InSiGHT-Human Variome Project

collaborationFinlay MacraeSecretary, International Society for Gastrointestinal Hereditary TumoursHead, Colorectal Medicine and Genetics, The Royal Melbourne HospitalProfessor of Medicine, Departments of Medicine, Melbourne and Monash Universities, Victoria, Australia4th Bi-ennial Human Variome ProjectParis, June 2nd, 2012

Human Variome Project – InSiGHT collaborationTalk 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 rule3 first degree relatives over2 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 CriteriaPopulation screening:

• Test all cancers presenting routinely by MSI or Immunohistochemistry for mismatch repair protein loss

Note: Determines chemotherapy decisions in Stage 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 website

www.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 NGO

Initiated 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 theHuman 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

InSiGHT Flow Plan B (commencing

with genotype)

MMR mutation Identified

(DNA Lab)

IHC &/or MSI data added

(Histopathology)

Interpretation of genotype

(Clinicians & Lab)

Virtual pathology added

(Histopathology)

Functional data added

(Research Labs)

Clinical phenotype added

(Clinicians)

Identified dataset stored locally

(Family Cancer Clinic)

De-identified data stored with InSiGHTInterpretation

(InSiGHT)

DbGaP (NCBI)UCSC

EBI

Data from other centres can be

submitted to update information

InSiGHT LSDB Governance CommitteeTerms 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 2006COMPANY LIMITED BY GUARANTEE

NOT HAVING A SHARE CAPITALARTICLES 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 databasePage 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 InSiGHTHicks Foundation Curator

• Check integrity of submissionsNomenclature, 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

Field Name D3.4 InSiGHT LOVD Examplegene Symbol O MLH1

Exon R 1

DNA_genomic O g.445345

DNA_coding R c.125delC>T

RNA O r.125c>u

Protein O p.pro41arg

DBID O 12

Reference O Chan et al., 1999

DNA_published R 125 C -> T

Detection/Template O DNA

Detection/Technique O Sequencing

DNA_remark R Free text comment

Frequency R 1/1012 controls

Origin R germline

Allele R 1

Pathogenicity R Pathogenic

LSDB Minimal Data Requirements (Variant) Derivable from other fieldsPresent

Source: Gen2Phen - D3.4 Scope and Range Requirements of Specialized Domain Models; O = Obligatory, R = Recommended

Field Name D3.4 InSiGHT LOVD Example

Patient_ID O 12345

Disease O CRC

Remarks R Free Text

Geographic R Australia

Ethnic R Caucasian

Gender R Male

Submitter_ID O 5

LSDB Minimal Data Requirements (Patient Information)Source: Gen2Phen - D3.4 Scope and Range Requirements of Specialized Domain Models; O = Obligatory, R = Recommended

• 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.

LSDB Minimal Data Requirements (Patient Phenotype)

Source: Gen2Phen - D3.4 Scope and Range Requirements of Specialized Domain Models

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 InternationalMismatch 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 CommitteeModus 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• M Genuardi (Italy, Chair)• JP Plazzer (Curator)• F Macrae (Sec, InSiGHT)• A Spurdle (Australia)• B Thompson (Australia)• M Woods (Canada)• R Sijmons (Netherlands)• P Peltomaki (Finland)• M Greenblatt (USA)• I Frayling (UK)• J Burn (UK)• M Dunlop (UK)• S Farrington (UK)• B Royer Pokora (Germany)• E Holinski Feder (Germany)• G Moeslein (Germany)• I Blanco (Spain)• G Capella (Spain)• M Pineda (Spain)• D Du Sart (Australia)• M Kohonen Corish (Australia)• R Scott (Australia)• B Talseth (Australia)

• R Ramesar (South Africa)• M Qi (China)• R Hofstra (Netherlands)• M Vihinen (Finland)• M Nystrom (Finland)• T Weber (USA)• S Tavtigian (USA)• D Goldgar (USA)• C Heinen (USA)• S Lipkin (USA)• A Lindblom (Sweden)• K Akagi (Japan)• F Al-Mulla (Kuwait)• L Rasmussen (Denmark)• I Bernstein (Denmark)• F Wikman (Denmark)• T Frebourg (France)• S. Olschwang (France)• A Fabre (France)• M Tosi (France)• S Leung (Hong Kong)• T Liu (Sweden)• P Moller (Norway)• B Bapat (Canada)• M Farrell (Ireland)• C Tops (Holland)• D-W Kim (Korea)• 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

Serious Business in Australia’s Most Stunning Location

CAIRNS CONVENTION CENTRE - AUSTRALIA

InSiGHTBi-Ennial Meeting

August 29- 31st. 2013

Join us..it will be a great meeting!

Serious Business in Australia’s Most Stunning Location

CAIRNS CONVENTION CENTRE - AUSTRALIA

InSiGHTBi-Ennial Meeting

August 29- 31st. 2013

Join us..it will be a great meeting!