The BRCA Challenge & Exchange: Progress and Plans - Gunnar Rätsch

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PROGRESS AND PLANS Gunnar Rätsch, Ph.D. Memorial Sloan Kettering Cancer Center, New York, USA ETH Zürich, Switzerland (since May 2016) THE BRCA CHALLENGE & EXCHANGE

Transcript of The BRCA Challenge & Exchange: Progress and Plans - Gunnar Rätsch

Page 1: The BRCA Challenge & Exchange: Progress and Plans - Gunnar Rätsch

PROGRESS AND PLANS

Gunnar Rätsch, Ph.D.Memorial Sloan Kettering Cancer Center, New York, USAETH Zürich, Switzerland (since May 2016)

THE BRCA CHALLENGE & EXCHANGE

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Goals of the BRCA ChallengeTo improve the care of patients at risk of breast and ovarian cancer using global data sharing and collaboration in the analysis of BRCA1 and BRCA2

1. Share BRCA1 and BRCA2 variants publically via a web portal1. Displays a curated list of BRCA variants, interpreted by expert consensus, to

enable, without dictating, accurate clinical care

2. Includes an environment for collaborative variant curation with access to evidence (e.g. phenotypes, family history, genetic data, and functional studies)

2. Address the social, ethical, and legal challenges to global data sharing

3. Create a model for all disease genes

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BRCA Challenge Steering

Committee

Data Collection and

Interpretation Subcommittee

Evidence Gathering Group

Classified Variant

Collection Group

InterpretationGroup

Ethico-Legal and Engagement

Subcommittee

BRCA Challenge Organization

Gunnar Rätsch, MSKCC/ETHAntonis Antoniou, CRUK

Heidi Rehm, HarvardJohan den Dunnen, LUMC

Amanda Spurdle, QIMRFergus Couch, Mayo

Bob Cook-Deegan, DukeKazuto Kato, UKyotoDelyth Morgan, Br. Cancer Now

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Goals of the ChallengeTo improve the care of patients at risk of breast and ovarian cancer using global data sharing and collaboration in the analysis of BRCA1 and BRCA2

1. Share BRCA1 and BRCA2 variants publically via a web portal: The BRCA Exchange

1. Displays a curated list of BRCA variants, interpreted by expert consensus, to enable, without dictating, accurate clinical care

2. Includes an environment for collaborative variant curation with access to evidence (e.g. phenotypes, family history, genetic data, and functional studies)

2. Address the social, ethical, and legal challenges to global data sharing

3. Create a model for all disease genes

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BRCA Exchange Public Site (Tier 1)• Intended for clinicians, genetics counselors, lay public.• Show classifications only for expert panel reviewed variants• List other variants as “not yet classified”, more classifications come

soon.• Include variants from Clinvar, 1000G, BIC, LOVD, ENIGMA, ESP,

exLOVD.• Links back to databases that contain the variant (e.g., ClinVar, exLOVD).• All data is public.

Gene/Classification

Pathogenic Benign Not yet classified

BRCA1 13 483 7,230

BRCA2 31 502 5,241

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Each repository contributes distinct BRCA variations

ClinVar 1000G ExAC BIC LOVD ENIGMA ESP exLOVD

ClinVar 6959 1102 1708 3354 1950 1030 533 285

1000G 4348 562 382 295 820 247 87

ExAC 3737 1019 1049 220 600 205

BIC 3606 1581 274 382 266

LOVD 2993 301 420 283

ENIGMA 1030 146 208

ESP 687 116

exLOVD 294

Combined, BRCA Exchange has 13,500 individual, deduplicated variants.

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Different Repositories Share Same Variants Reported Differently

Two simple methods of variant comparison:

Edit variant description Genome Sequence

Repository 1 Variant after reference position 1 “GC” is inserted in this variant

AGCGCGC

Repository 2 Variant after reference position 5 “GC” is inserted in this variant

AGCGCGC

String Comparison says same variant

Direct Comparison says different variant

Keep track of different variant descriptions on the site.

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Each repository contributes distinct information on BRCA variation

Combined, BRCA Exchange soon has 15,000 individual deduplicated variants.

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brcaexchange.org

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(1)

(2)

(3)

• Simple user experience:

• (1) Enter variant

• (2) Browse related variants

• (3) Find out more and explore linked resources

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Clinical significance calls only following expert review by ENIGMA

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Goals of the BRCA ChallengeTo improve the care of patients at risk of breast and ovarian cancer using global data sharing and collaboration in the analysis of BRCA1 and BRCA2

1. Share BRCA1 and BRCA2 variants publically via a web portal: The BRCA Exchange

1. Displays a curated list of BRCA variants, interpreted by expert consensus, to enable, without dictating, accurate clinical care

2. Includes an environment for collaborative variant curation with access to evidence (e.g. phenotypes, family history, genetic data, and functional studies)

2. Address the social, ethical, and legal challenges to global data sharing

3. Create a model for all disease genes

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BRCA Exchange for Research (Tier 2 & 3)Main PurposeSupport and enable variant classification by aggregating relevant public and controlled access data in two tiers and serve as data exchange hub to receive and distribute data submissions

Tier 2 (open access, released in April 2016)• Public access, but site is available through a disclaimer• Show all available classifications from different sources• Provide additional information sources such as population frequencies, computational

predictions, etc. • Provide tools to identify disagreements (soon: support & track curation)

Tier 3 (controlled access, ongoing developments)• Links to case level & detailed clinical information and other restricted data• Controlled access: Develop approval mechanism for continuous data flow from data sources

to approved research groups• Develops input interfaces with case level data providers lab test companies, research

institutions etc. who share data for research• Provide computational tools to support variant classifications by experts

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One can download all data

Clinical significance calls from original submitters (including conflicting calls)

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Filters allow increased personalization of the research data

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Lollipops show variant distribution along the length of each gene

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BRCA Exchange is already used by curators and the public

BRCA Exchange already attracts ≈1,000 unique users per month.(currently ≈100 page views per day).

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Future Plans• More data sources! Plan to include TCGA, Quest & Haplotype Research

Consortium data.

• Contact me ([email protected]) or Rachel Liao ([email protected]) if you have variants or case level data that we can include.

• Currently data is imported to central site. Plan: Implement full GA4GH data federation for variant data sources

• Improve User Interface

• Semi-automatic variant assessment

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Currently, curators manually amass all data on a variant ...

Variant Classification

Cosegregation

Pathology

Probability calculationMore ...

Physiochemical properties

(A-GVGD Score)

Co-occurrence

Family history

SlowCumbersomeRequires great attention to prevent errors

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BRCA Exchange Research

Variant Classification

Cosegregation

Pathology

Probability calculation

More ...

Physiochemical properties (A-GVGD Score)

Co-occurrence

Family history

BRCA Exchange helps curators

➢ Near Future: Expand Research pages by (a) hosting more data and (b) pre-computing as much as possible

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AcknowledgementsMolly ZhangCharlie MarkelloBenedict PatenMary GoldmanMelissa ClineBrian CraftGunnar RätschRachel Liao

BRCA Challenge * Steering Committee * Evidence Gathering Group* Interpretation Group

BRCA Challenge Chairs: John Burn and Stephen Chanock

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Thanks!

• BRCA Challenge:• John Burn• Stephen Chanock• Antonis Antoniou• Larry Brody• Robert Cook-Deegan• Fergus Couch• Johan den Dunnen• Susan Domchek• Douglas Easton• William Foulkes• Judy Garber• David Goldgar,• Kazuto Kato

• Delyth Jane Morgan• Robert Nussbaum• Kenneth Offit• Sharon Plon• Gunnar Rätsch• Nazneen Rahman• Heidi Rehm• Mark Robson• Wendy Rubinstein• Amanda Spurdle• Dominique Stoppa-Lyonnet• Sean Tavtigian• David Haussler

BRCA-Exchange.org:• Molly Zhang• Brian Craft• Charles Markello

• Mary Goldman

• Jing Zhu• Melissa Cline• Benedict Paten• Gunnar Rätsch • Rachel Liao• GA4GH Clinical Work Group• Peter Goodhand • (And many more!)

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ClinVar

LOVD

Case data and evidence sharing

BRCAExchangeResearch

National nodesCommercial &

Research

Population Frequency Data

(EVS, ICGC, 1000G, 10KUK)

Functional Data

Segregation Co-occurrence

In silicoprediction

Options for variant submission

BRCAExchange

http://brcaexchange.orgIG

Variant Classification

BRCA Research Data & Curation

Community

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BRCA Challenge Steering Committee25

Sir John Burn, Newcastle University (United Kingdom) – Co-ChairStephen Chanock, National Cancer Institute (United States) – Co-ChairAntonis Antoniou, University of Cambridge (United Kingdom)Larry Brody, National Human Genome Research Institute (United States)Robert Cook-Deegan, Duke University (United States)Fergus Couch, Mayo Clinic (United States)Johan den Dunnen, Leiden University Medical Center (Netherlands)Susan Domchek, University of Pennsylvania (United States)Douglas Easton, University of Cambridge (United Kingdom)William Foulkes, McGill University (Canada)Judy Garber, Dana Farber Cancer Institute (United States)David Golgar, Huntsman Cancer Center (United States)Kazuto Kato, Osaka University (Japan)Baroness Delyth Morgan, Breast Cancer Now (United Kingdom)Robert Nussbaum, Invitae (United States)Ken Offit, Memorial Sloan Kettering Cancer Center (United States)Sharon Plon, Baylor College of Medicine (United States)Nazneen Rahman, Institute of Cancer Research (United Kingdom)Gunnar Rätsch, Memorial Sloan Kettering Cancer Center (United States)Heidi Rehm, Harvard Medical School (United States)Mark Robson, Memorial Sloan Kettering Cancer Center (United States)Wendy Rubinstein, National Institute of Health (United States)Amanda Spurdle, QIMR Berghofer Medical Research Institute (Australia)Dominique Stoppa-Lyonnet, Curie Institute (France)Sean Tavtigian, University of Utah (United States) Underline denotes leadership

on a subgroup

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Motivation for the BRCA Exchange

● ClinVar is incomplete:

○ European projects

○ Individual papers and submitters

○ Some organizations can't pay the cost of preparing a submission

BRCA variation is relatively common with well known medical implications

No single source for BRCA variant information

ClinVar7961 Variants

1041

2107

1191

1778

LOVD3276 Variants

UMD3675 Variants

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Motivation for the BRCA ExchangeBRCA variation is relatively

common with well known medical implications

There is no single source for BRCA variant information

High numbers of VUSs, where classification is limited by being unable to see all the data on a variant

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Each repository contributes distinct information on BRCA variation

Different databases contribute different types of information

Database Origin Allele Frequenc

y

Significance

Publications

ClinVar Y N Y N

1000 Genomes

N Y N N

ExAC N Y N N

BIC Y N Y Y

LOVD Y Y Y N

ENIGMA Y N Y Y

ESP N Y N N

exLOVD N N N Y

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Community Engagement

Involved patient advocacy groups• FORCE, BRCActivist, Brave Bosom

Community space on website• Allow networking, especially for people in developing

countries• Newsletter with updates on the BRCA Challenge and how

to share dataCase-level data• Allow people to donate their own data, similar to 1000

Genomes• Due to legal challenges, start with USA, then include more

countries

Coming soon ...