The BRCA Challenge & Exchange: Progress and Plans - Gunnar Rätsch
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Transcript of 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
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
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
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
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
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.
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.
Each repository contributes distinct information on BRCA variation
Combined, BRCA Exchange soon has 15,000 individual deduplicated variants.
brcaexchange.org
(1)
(2)
(3)
• Simple user experience:
• (1) Enter variant
• (2) Browse related variants
• (3) Find out more and explore linked resources
Clinical significance calls only following expert review by ENIGMA
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
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
One can download all data
Clinical significance calls from original submitters (including conflicting calls)
Filters allow increased personalization of the research data
Lollipops show variant distribution along the length of each gene
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).
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
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
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
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
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!)
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
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
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
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
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
(BEGIN VIDEO)
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 ...