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