Download - The BRCA Challenge - John Burn
the BRCA Challenge: a global initiative to facilitate
molecular diagnostics in patients with breast/ovarian cancer
Sir John Burn MD FRCP FRCPE FRCPCH FRCOG FMedSci
Professor of Clinical Genetics, Newcastle University, UK
15th May 2013
ICHG Kyoto 2016
Disclosure
I have acted as a paid advisor to Astra ZenecaIn relation to use of Lynparza (olaparib) in BRCA1&2 deficient cancers
AZ have provided a research donation to advancethe development of BRCAexchange website
PARP inhibitors: mechanism
DNA DSB
ATM/R
ERCC1XRCC3
NBS1MRE11
Rad50BRCA1gH2AX
HR repair
DNA SSB
DNA replication
BERPARP
XRCC1
Pol Lig III
FA core complex FANC
D2
Rad 52/4 RPARad 51 BRCA2
• Endogenously formed SSB are normally repaired by PARP-dependent BER.
• If PARP is inhibited SSB persist.• SSB form DSB at replication, which
are repaired by HR.• If HR is defective the breaks are not
repaired and the cell dies.• This is the first exploitation of
synthetic lethality in cancer therapy.
For internal use only
Astra Zeneca Study 19: olaparib improves survival in BRCA1 deficient ovarian cancer
6
Olaparibn=74
Placebon=62
Median(95% CI)
11.2 mo(8.3, NC)
4.3 mo(3.0, 5.4)
Probability of PFS
Time from randomisation (months)
HR=0.18 (95% CI: 0.10, 0.31)
P<0.00001
0
0.6
0.8
0.9
0
0.1
0.20.3
0.4
0.5
0.7
1.0
3 6 9 12 15
Placebo
Olaparib
gBRCA sBRCA
7
BRCA Challenge Steering CommitteeSir 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)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)Robert Nussbaum, University of California, San Francisco (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)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)
UNESCO Paris June 2015
Gunnar Ratsch
Acknowledgements• Team at UCSC Melissa Cline, Benedict
Paten, Molly Zhang, Mary Goldman, Brian Craft, Charles Markello
• Lots of feedback from everybody, in particular Mandy and Rachel.
• COGR & MSKCC/NCI provided funding for software engineers (Lshift) implementing core technical features.
Rachel Liao
ClinVar EBI / LOVD
DATA SUBMISSION
Public Access to Variants
Curation System
National nodesCommercial &
Research
Population Frequency Data
(EVS, ICGC, 1000G, 10KUK)
CuratedData
Curated Data
Functional Data
Segregation Co-occurrence
In silicoprediction
BRCAexchange
DATA SUBMISSIONFrom existing “open” sources
eg BIC and HGMD
UMD
BRCA Exchange Community
Faculty space:
Newcastle family: BRCA1 Val1736Ala
BRCA1: Valine is conserved at equivalent position 1736 in all 18 species examined
Courtesy of Sean Tavtigian
Glasgow family 31410
Breast Cancer 425207T>C ,V1736ABreast Cancer 44
Peritoneal Cancer5207T>C ,V1736A
Br Ca 29No BRCA mut
5207T>C ,V1736A
Co-occurrence caused Fanconi –like syndrome
You can start 50:50 then tilt the balance on the basis of additional information
Co-occurrence10,000 to 1 against
V1736A segregation300 to 1 in favour ofpathogenicity
“the lab says it was classified in October 2014 as a 3. However….in their opinion its not a polymorphism, they have been thinking about it already and are
concerned it may be pathogenic (a 4)”
“an 4-see John’s
email…”
“it’s pathogenic. Mark is an author on the paper…”
“we’ve seen a case…Likely
pathogenic”
“We have seen this change only once ….evidence hasn’t changed much, except: 18X in BIC still VUS,13X in DMuDB, mainly VUS except Guys designated probably pathogenic using new protein prediction
program (Mutation Taster) .. High class 3, close to4?”
About 8 hours workInconsistent reports
No correction mechanism
www.brcaexchange.org
• Pool available diagnostic data• Extract population variation• Develop a curation team• Address ethics and governance• Engage advocacy groups• Distribute to the world
BRCA Challenge Steering
Committee
Data Collection and Interpretation
Subcommittee
Evidence Gathering Group
Classified Variant Collection Group
InterpretationGroup
Ethics, Regulation and Advocacy Subcommittee
BRCA Challenge Organization
Gunnar Rätsch, MSKCCAntonis Antoniou, CRUK
Heidi Rehm, PartnersJohan den Dunnen, LUMC
Amanda Spurdle, QIMRFergus Couch, Mayo
John Burn, CRUKStephen Chanock, NCI