1. 100,000 genomes project and haematological malignancy
Dr Andrew Mumford
Clinical Director

4. West of England Genomics Medicine Centre

5. WEGMC Governance Structure

6. WEGMC objectives
Enable access to 100,000 genomes project for WoE patients.
Whole genome sequencing and ‘omics’ of 4,650 samples from patients and families with rare diseases or cancer.
2. Integrate genomic medicine into
standard clinical care pathways.

7. Set up timescale Launch event First RD samples 10th June
Go-live Cancer (NBT) and RD (UHB)
27th May
Designation as GMC
23rd Dec
First cancer sample
27th June
01/16
01/17
Launch event

8. Future programme
Week 21
152 RD samples
34 cancer samples

9. 1. Who is eligible. 2. Why whole genome sequencing. 3
1. Who is eligible? 2. Why whole genome sequencing? 3. How does is work for solid cancers? 4. How could it work for haematological malignancy?

10. 1. Who is eligible. 2. Why whole genome sequencing. 3
1. . Who is eligible? 2. Why whole genome sequencing? 3. How does is work for solid cancers? 4. How could it work for haematological malignancy?

11. 100,000 genomes project includes Cancer and Rare Diseases

12. Genome samples

13. Approved cancers October 2016
Ovarian cancer
Lung cancer
Prostate cancer
Colorectal cancer
Breast cancer
Sarcoma
Renal cancer
Melanoma
Upper gastrointestinal tumours
Testicular cancer
Childhood solid tumours
Adult brain tumours
Bladder cancer
Endometrial cancer
Haematological malignancy

14. 1. Who is eligible. 2. Why whole genome sequencing. 3
1. Who is eligible? 2. Why whole genome sequencing? 3. How does is work for solid cancers? 4. How could it work for haematological malignanacy?

15. Why whole genome sequencing ?
PLT 45
MPV 10.1 fl
PLT 78
PLT 64
Case 1

16. Candidate genes for genetic platelet disorders

17. Next generation sequencing:
Bait library design

18. Next generation sequencing
Coding sequence of selected genes: gene panels
Coding sequence of all genes: whole exome
While exome + regulatory regions: whole genome

19. Seelection of a candidate gene
PLT 45
MPV 10.1 fl
PLT 78
PLT 64
Case 1
CYCS
THC4
(OMIM #612004)
Case 2
RUNX1
FT-PAML
(OMIM #601399)

20. Whole genome sequencing of cancer tissue

21. 1. Who is eligible. 2. Why whole genome sequencing. 3
1. Who is eligible? 2. Why whole genome sequencing? 3. How does is work for solid cancers? 4. How could it work for haemato-oncology?

22. Defining and testing enrolment process

23. Overview schematic for cancer pathway

24. …How it works

25. Key features of Preliminary report
Domain 1: variants in ‘Actionable Genes’
annotated for gene-level and variant level actionability
variant level actionability hyper-linked to Genome Oncology (MyCancerGenome.gov)
good, contemporaneous UK clinical trials annotations (ClinicalTrials.gov)
Domain 2: variants in ‘Cancer-related Genes’
QC metrics:
per sample: % neoplastic cells (pathology), tumour purity (sequence)
per sequence: GL/tumour mapped reads, insert size, chimeric reads, median coverage, ‘eveness’ of coverage
per variant: VRF

32. 1. Who is eligible. 2. Why whole genome sequencing. 3
1. Who is eligible? 2. Why whole genome sequencing? 3. How does is work for solid cancers? 4. How could it work for haematological maliganancy?

33. Why haematological malignancy?
Fifth most common cancer in UK
Majority relapse, progress or therapy related morbidity
Molecular diagnostics to improve prognostic estimates and direct targeted therapies already standard care
GeL Steering Committee approved HM Programme 2016
Proposal developed by HM GeCIP
Funding limited to 6,000 samples (3000 patients)
Low priority for single gene disorders eg MPD, CML
Low priority for lymphoma because practical issues of collecting solid tissue
Initial proposal consultation and then modified

34. Stage 1 HM CLL, AML, Myeloma
Enrolment alongside FLAIR, AML 18/19 and MUK9/10
1. CLL
Saliva and peripheral blood sent to GMC laboratory and UK CLL BioBank
2. AML/Myeloma
Saliva and marrow sent to trial biobanks.
Marrow cell sorted and both sent back to GMC laboratory
100,000 genomes data collected from data submitted for trial
Results and clinical reports distributed by local GMCs

35. Stage 2 HM- Inclusion Newly diagnosed aggressive B and T-cell NHL
DLBCL, Burkitt, Mediastinal B cell, high grade lymphoma NOS
New AML/MDS outside trial
New myeloma outside trial
Unclassified HM (eg MDS/MPD overlap, mismatch between clinical and pathological diagnoses)
CML extreme responders (compete molecular remission or no morphological response after 3 months TKI treatment
Children with ALL with MRD>5% at day 28

36. Current position Stage 1 disorders
Agreements with Cardiff CTRU and ICR October 210
Adapt Informatics pathways October 31st
Recruitment start
CLL- Nov 15th
AML- Jan 31st
Myeloma- not specified
Stage 2 disorders
From November 15th as determined by GMC

37. Feedback?
Where are patients enrolling to FLAIR. AML18/19 and MUK9/10 ?
How many ?
Can trails infrastructure be augmented for additional workload
Who are clinical leads for stage 1 and stage 2 disorders?