Cancer Programme Update · Clare Turnbull Clinical Lead for Cancer Genomics, Genomics England Reader in Genomic Medicine, Institute of Cancer Research and ... guidelines when compared

Cancer Programme UpdateThe 100,000 Genomes Project and Forwards

Clare TurnbullClinical Lead for Cancer Genomics, Genomics England Reader in Genomic Medicine, Institute of Cancer Research and Queen Mary University of LondonHonorary Consultant in Cancer Genetics, Guys and St Thomas NHS Trust

ACGS Annual Meeting, Birmingham, June 26th 2017

To cover….

• Recruitment

• Sample Handling and Consensus statement

• Experimental work

• Haemato-oncology samples

• Return of results

• Germline Findings

• Genomics England Cancer Transition Group

210 July 2017

Phased roll-out

310 July 2017

WAVE 1 WAVE 2 WAVE 3

Breast Renal Brain

Prostate Sarcoma Upper GI

Colorectal Germ Cell Tumours

Ovarian Endometrial

Lung Melanoma

CLL Bladder

Haem Onc

Gear 1

General recruitmentSurgical resections(establish protocols)

Gear 2

BiopsiesFocused cohorts (multiple samples in space and time)

Gear 3

Individualised patient management (clinical turn-around time)

Cancer Programme

Pilot Phase: 6 CRUK sites, 5 BRC sites

Experimental Phase

2014

Main Programme

2015 2016 2017 2018

IIP

• 75x for tumour; 35x for germline• ctDNA pre-surgery

Recruitment

GMC self-reported recruitment to 2nd June (including Pilot and IIP)

• 5,176 cancer samples (inc. tumour sample and germline)

• 4 weekly average = 110 samples

5

Number of participants registered per tumour type to 8th June

6

14299

829

480

742

115

142

564

420

238

345

272

218

10 14

163121

982

62

1

839

154

456

634

52

3

279

395

318269

11 29

0

200

400

600

800

1000

1200

As of 4th May 2017 As of 8th June 2017

Sample Handling

New FFPE guideline conditions (early 2016)

SUMMARY

There are significant improvements with the new guidelines when compared to previous methods employing formal saline. However, data quality is still significantly worse than fresh-frozen (lower coverage uniformity and rate of somatic variant overcalling).

GeL402 Fresh-Frozen

GeL402 FFPE, new guidelines (NBF 80ºC)

GeL402 FFPE, previous conditions (FS 80ºC)

~ ~640,000

Confidential - Not for further distribution

Mutational burden in paired FFPE vs FF samples

• FFPE samples show increased mutational burden of small variants, both SNVs and indels• This is an artefact of FFPE samples

Monitoring quality…

Bench marking quality between centres

Bench marking quality between centres

Consensus StatementDetailed consent is still required to agree to the research aspects of the 100,000 Genomes Project and to state opinions on how a patient's germline findings should be handled. Implications of the Consensus Statement:

1.Laboratories which do not have a research HTA licence can still store tissue for the diagnostic arm of the 100,000 Genomes Project.

2.Samples can be handled in a genomic friendly way by not putting them into formalin as part of the diagnostic pathway without specific consent required to do this.

3.Consent for participation in the 100,000 Genomes Project can be taken after tissue has been sampled.

13

Proportion of biopsy/surgical resections

14

10 14

4536 31 29

40

2332

110

8 10

10

5

31

0

10

20

30

40

50

60

70

September October November December January February March April May

St George’s Hospital, South London GMCNumber of FF samples collected (Biopsy vs Resection)

Resection Biopsy

Joint Statement Implementation

• Number of biopsies as a proportion of total samples has been increasing

• After introduction of the Joint Statement – biopsies accounted for 49% of samples in May 2017

• The graph to the right provides a breakdown of biopsies by tumour type

25

5

1

0

5

10

15

20

25

30

35

Number of biopsiesN

um

ber

of

Bio

psi

es

Biopsy numbers by tumour type

Breast Colorectal Bladder

Experimental Work

Q3 2015

Initiation Implementation

phase

*Led by Prof Louise Jones. Includesmolecular pathology representation from BRC-GMC centres. Consultation with Joint Molecular Pathology Group

Main program

Q1 2016

WS 1: upstreamtumour handling

WS 2: tumour processing, fixative,

embedding

WS 3: tumour assessment

WS 5: DNAquantification and quality assessment

WS 4: DNAextraction

WS 6: Library preparation and

sequencing

EXPERIMENTAL GROUP

upo grtn epmole vdePO S

GMC implementation group

SOP

dev

elo

pm

ent

gro

up

Molecular Pathology Working Group: experiments, protocols, implementation

Alternative Freezing Strategies

• Aim: To provide flexibility in freezing samples, particularly biopsies in clinic setting

1710 July 2017

• 1,1,1,2 tetrafluoroethanesupplied in pressurised canister

• Widely used in pathology for rapid freezing for frozen section analysis

• Gives excellent morphology (for FF)

# Treatment (T:04h)

Details

1 Liquid Nitrogen onto dry ice

2 Isopentane onto dry ice

3 Cryospray (indirect)

onto dry ice

4 Cryospray (direct) onto dry ice

5 Dry ice

6 Wet ice

7 Phosphate Buffered Saline

Storage at 4C/RT

8 RPMI Culture Medium

Storage at 4C/RT

DNA Quality (Tapestation)

F1 A1 E1 B1 C1 D1 A2 E2 C2 B2 D2 S2 B3 A3 F3

X 8.5 8.3 8.7 9.0 8.7 8.9 7.4 9.1 8.8 8.7 X 8.6 8.8 6.2

Sample

DIN

N2 N2

cryospray cryospray


RNA Quality

Alternative freezing: sequencing results• No evidence of a negative impact of alternative freezing strategies

• % aligned reads

• Library insert size

• Coverage uniformity

• Numbers of somatic SV calls

• Number of small somatic variant calls and their distribution across repeat classes are similar in all conditions• See example, right

Somatic SNV number and distribution

Confidential - Not for further distribution Data courtesy of Illumina

Paxgene: Alternative Fixatives

• 8 patients from 1 GMC

• PCR-based library prep for FFPE samples

• PCR-based library prep PAXgene samples

• PCR-free library prep for FF

• PCR-free library prep PAXgene samples• Delta Cq values are good for all PAXgene samples;

• Delta Cq variable for FFPE


• PAXgene Tissue System

• Dual chamber system• Tissue fixation

• Methanol based

• Tissue Stabiliser

• Requires formalin-free processing

• Morphology, IHC and ISH reported to be comparable to FFPE (Kap M et al. PLoS ONE 2011)

Paxgene Sequencing QC runs

• PCR-free PAXgene libraries resemble FF most closely

• High-AT regions are under represented in FFPE; better with PAXgene

• High-GC regions are over represented with PAXgene (FFPE prep); FFPE samples are variable


Full build data: 217000122 (colorectal)

39%

48%

45%

purity estimate

evenness score

95.49%

94.45%

90.1%

21% 95.29%

FF

PAXgenePCR-free prep

FFPE

PAXgene PCR prep


Full build data: 217000122 (colorectal)

PA

X P

CR

-fre

e

PA

X P

CR

-fre

e

PA

X P

CR

-fre

e

PA

X P

CR

-fre

e

Somatic Indels

Somatic SNVs

Somatic small variant distribution


Haemato-oncology

Haem-onc: Myeloid DisordersDisease Eligibility Criteria Tumour / Germline samples Additional samples

High riskMyelodysplastic syndromes [MDS] / Acute myeloid Leukaemia [AML]

Newly diagnosed (i.e. untreated):- MDS (blasts 10-19%)- AML (blasts >=20%)

Tumour: DNA from pre-treatmentperipheral blood [PB] / bone marrow aspirate [BMA] (2 ug / 500 ng)Germline – intensive treatment: DNA from saliva taken at D5 of treatment (10 ug / 4 ug)Non-intensive treatment: DNA from cultured fibroblasts (10 ug / 4 ug)*alternative options being pursued

Pre-treatment RNA (in form of GTC lysate)

Chronic Myeloid Leukaemia [CML]

Extreme responders:- BCR-ABL transcript level using International

Standards [IS] of <1% or >10%Patients who present in accelerated or blast phase (>10% blasts in PB or BMA)Patients present with cytogenetic abnormality in addition to t(9;22)Patients who progress after initial response:- Progress from chronic to accelerated / blast phase- BCR-ABL transcript level using IS reduced to <1%

before increasing to >40% (on treatment)

Tumour: DNA from pre-treatment PB or BMA (2 ug / 500 ng)Germline: – good responder:DNA from saliva at time BCR-ABL <1% (10 ug / 4 ug)All other categories: DNA from cultured fibroblasts (10 ug / 4 ug)*alternative options being pursued


‘Unclassified’ Difficult to define! But examples would include- Myelodysplastic/Myeloproliferative overlap

syndromes [MDS/MPN}- Triple negative MPN- Others where mismatch between clinical diagnosis

and pathological findings – contact service desk if in doubt

Tumour: DNA from pre-treatment PB or BMA (2 ug / 500 ng)Germline: DNA from cultured fibroblasts (10 ug / 4 ug)*alternative options being pursued


26

Haem-onc: Lymphoid Disorders (1)

27

Disease Eligibility Criteria Tumour / Germline samples Additional samples

Chronic Lymphocytic Leukaemia[CLL]

- Any patient enrolled in FLAIR trial- Any untreated patient who has severe enough disease that they would meet the criteria for enrolment in the FLAIR trial and are fit enough for chemoimmunotherapy (including a purine analogue: either fludarabine or bendamustine) but have not been recruited to FLAIR for logistical, medical (e.g. poor renal function), genomic (i.e. TP53 abnormality in >20% cells) or patient choice reasons

Tumour: DNA from pre-treatment PB if lymphocytosis >25x109/L, DNA from pre-treatment BMA if lymphocytosis <25x109/L (2 ug / 500 ng)Germline: DNA from saliva taken at a time when PB lymphocytosis is lymphocytosis <25x109/L (10 ug / 4 ug)

Pre-treatment RNA (in form of GTC lysate)Baseline plasma for ctDNA Follow up plasma for ctDNA taken at 3/12 intervals for year 1, 6/12 intervals for year 2, time of any relapse

Myeloma Any newly diagnosed untreated myeloma patient from whom sufficient CD138+ cells can be isolated from the BMA to make the minimum purity (>40%) and DNA requirements (>=500 ng minimum)

Tumour: DNA from pre-treatment CD138+ selected cells (e.g. post-column enrichment)– aiming for purity >80% but will consider >40% if enrichment step undertaken (2 ug / 500 ng)Germline: DNA from PB or saliva (10 ug / 4 ug)


High grade lymphoma

- Any newly diagnosed, untreated high grade lymphoma including )but not limited to): Diffuse Large B cell Lymphoma, Burkitt’s lymphoma, Primary mediastinal B cell lymphoma, T cell lymphomas, Lymphoblastic lymphoma High grade lymphomas NOS- High grade [HG] transformation of a lower grade lymphoma or CLL

Tumour: DNA from pre-treatment fresh frozen resection / biopsy with malignant cell percentage >=40% (2 ug / 500 ng)Germline: DNA from PB or saliva (10 ug / 4 ug)

Pre-treatment RNA (in form of GTC lysate)Baseline plasma for ctDNA Follow up plasma for ctDNA taken at 3/12 intervals for year 1, 6/12 intervals for year 2, time of any relapse

Haem-onc: Lymphoid Disorders (2)

28

Disease Eligibility Criteria Tumour / Germline samples Additional samples

PaediatricAcute Lymphoblastic Leukaemia [ALL]

Children & young adults (i.e. <25 yearsold at time of diagnosis) with ALL who have failed to obtain Minimal Residual Disease [MRD] levels of <5% at the D28 BMA

Tumour: DNA from pre-treatment PB or BMA where blasts >=40% nucleated cells (NB will need to have DNA stored from diagnosis as will not know patient is eligible until post-D28 assessment (2 ug / 500 ng)Germline: DNA from saliva when there are no circulating blasts (morphological assessment of the peripheral blood) (10 ug / 4 ug)


Returning Results

‘Preliminary analysis’

Sup

ple

men

tary

an

alys

is

Structural variantsMutational densityCoverage and copy number

Mutational signatures

Hypermutation rain plotsMutation context

‘Supplementary analysis’

Cancer Analysis: FlowMain Programme (Fresh Frozen)

32

2,511

1,687

1,2761,194

584 584

362 362

90

500

1,000

1,500

2,000

2,500

3,000

1.1 Samples atGMCs

2.1 Samples atBiobanks

2.2 DNADispatched to

illumina

3.1 DNA passedQC

3.2 WGSCompleted

4.1 WGS receivedby GEL

4.2 Ready forinterpretation

6.1 Dispatched toGMCs

6.2 Feedbackreceived from

GMCs

Cancer FF DNA Sample progress

02.06.17

Return of remaining 222 reports late June

Change to SRV4

WGS with somatic small variants in 72 actionable genes

33

Median 2.4 actionable genes across tumour types

Somatic small variants in 72 actionable genes across tumour types

3410 July 2017

Breast

Ovarian

Colorectal

Lung

Renal

Sarcoma ProstateBladder

Cancer Analysis & Interpretation for Main Programme (for Fresh Frozen samples)

35

2,511

1,687

1,2761,194

584 584

362 362

90

500

1,000

1,500

2,000

2,500

3,000

1.1 Samples atGMCs

2.1 Samples atBiobanks

2.2 DNADispatched to

illumina

3.1 DNA passedQC

3.2 WGSCompleted

4.1 WGS receivedby GEL

4.2 Ready forinterpretation

6.1 Dispatched toGMCs

6.2 Feedbackreceived from

GMCs

Cancer FF DNA Sample progress

02.06.17

Return of remaining 222 reports late June

Change to SRV4

Interpretation in Cancer programme

Patient

Tumourtype

DNA

Genome sequence

Annotated VCFs

Variants Domains

Gene GroupsVariant filtering

Annotation Providers

Clinical Review

Gene Panels

NHS clinical team

GeCIP(s)

ValidationOutcomes

Reporting portal

Report QC

Knowledge Bases

● Associations Column

● On/Off Tumor Type based on matching ontology term

Illumina BaseSpace

Variant Interpreter

Four possible fields:

• Prediction: Based off ClinVar value and only possible with the Germline analysis

• Knowledge Base: only possible when in a workgroup

• BaseSpace Knowledge Network

• ClinVar

• Tiles indicate significance and number of entries:

37

Associations

Return of Germlinefindings

Proposal for expansion in return of germline variants

• Tier 1: high confidence pathogenic vars in gene set pertinent to tumour type susceptibility (current).• Pre-annotation of pathogenic vars for childhood, Haem-Onc and other rare tumour

types will be problematic

• ?Additional susceptibility variants• ?Tier 2(OPTIONAL)*:

• (a) all (low freq) vars in gene set pertinent to tumour type susceptibility

• (b) all (low freq) vars in ‘universal’ tumour type susceptibility gene set (~50 for adult solid tumours; many additional genes if expanding to haemonc and/or childhood)

• ?Addtional germline content to inform oncology management• ?Tier 3(OPTIONAL)*:

• (a) all (low freq) vars in ‘universal’ gene set relevant to therapy (DNA repair: 20-30 HRD and BER genes)

• (b) all (low freq) vars in ‘universal’ cancer gene set (eg cancer gene census; 572)

• To annotate germline var if var present in same gene or deletion spanning gene (LOH) on subtracted somatic analysis.

* for local review. Molecular pathology lab receiving cancer reports should agree approach to analysis and management of these data with their molecular genetics laboratory and clinical cancer genetics service.

Pertinent Findings: genes

40

Tumour Type Genes analysedBreast cancer BRCA1, BRCA2, PALB2, PTEN, TP53

Colorectal cancer MLH1, MSH2, MSH6, MUTYH (bi), PMS2,

POLD1, POLE, PTEN, SMAD4, STK11

Ovarian cancer BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2,

RAD51C, RAD51D

Prostate cancer BRCA2

Renal Cancer FH, FLCN, PTEN, SDHB, VHL, MET

Sarcoma TP53

Melanoma BAP1, (CDK4), CDKN2A

Endometrial cancer FH, MLH1, MSH2, MSH6, PMS2, PTEN

Adult Glioma APC, ATM (bi), MLH1, MSH2, MSH6, PMS2,

TP53

Upper GI MLH1, MSH2, MSH6, PMS2

Proposal for expansion in return of germline variants

• Tier 1: high confidence pathogenic vars in gene set pertinent to tumour type susceptibility (current).• Pre-annotation of pathogenic vars for childhood, Haem-Onc and other rare tumour

types will be problematic

• ?Additional susceptibility variants• ?Tier 2(OPTIONAL)*:

• (a) all (low freq) vars in gene set pertinent to tumour type susceptibility

• (b) all (low freq) vars in ‘universal’ tumour type susceptibility gene set (~50 for adult solid tumours; many additional genes if expanding to haemonc and/or childhood)

• ?Addtional germline content to inform oncology management• ?Tier 3(OPTIONAL)*:

• (a) all (low freq) vars in ‘universal’ gene set relevant to therapy (DNA repair: 20-30 HRD and BER genes)

• (b) all (low freq) vars in ‘universal’ cancer gene set (eg cancer gene census; 572)

• To annotate germline var if var present in same gene or deletion spanning gene (LOH) on subtracted somatic analysis.

* for local review. Molecular pathology lab receiving cancer reports should agree approach to analysis and management of these data with their molecular genetics laboratory and clinical cancer genetics service.

NHSE Cancer Transition Working Group

Single gene/Standalone test

Small panel (eg hot spot Amplicon )

Larger ‘generic’ panel (eg

Hybridisation-capture)

Genome

The molecular context: a dynamic field

‘Test’ requiredNumber of markersComplexity of markers

TechnologyCost (for depth)Chemistry/PerformanceTAT

0

50

100

150

200

250

0

20

40

60

80

100

120

140

160

180

200

2000 2010 2020 2030

0

50

100

150

200

250

0

20

40

60

80

100

120

140

160

180

200

2000 2010 2020 2030

0

50

100

150

200

250

0

20

40

60

80

100

120

140

160

180

200

2000 2010 2020 20300

50

100

150

200

250

0

20

40

60

80

100

120

140

160

180

200

2000 2010 2020 2030

Whole genome sequencing: a dynamic value proposition for each tumour context

Other non-genetic tests

Bespoke, custom-designed tumour-

specific panel

Phase I clinical trial/Experimental/compassionate use drug

Prognostic

Standard Care

Discovery

Targeted Drugs

Diagnostic

Monitoring

Clinical Trials

Single new agent vs SOC

Multi-arm umbrella/basket

Molecular genomics-drug matching

Research

Longitudinal patient studies

surgerydiagnosticbiopsy

Biopsy(diagnostic/recurrence)

neoadjuvantchemo-radioRx

Adjuvantchemo-radioRx

chemo-Rx

LOCAL/REGIONAL DISEASE METASTATIC DISEASE

chemo-Rx Phase II/III Clinical trialtargeted drug

+/-biopsy +/-biopsy

The clinical context: a dynamic fieldWhen do we undertake molecular testing on patients?

Why do we undertake molecular testing on patients?

45

CLINICAL; by tumour type• Which genes have clinical utility for testing?• What type of molecular markers in that gene?• Type of actionability? Predictive, prognostic• What is the level of evidence and impact:

“clinical (NHS)” or “research”• How widely is test implemented in NHS at the

moment ?

LABORATORY; global• What is the sensitivity of different standalone

tests/NGS approaches in testing for each type of molecular marker?

• How well does that test/NGS approach perform wrt important metrics? • Failure rate, TAT, DNA req, tolerance for

DNA quality etc

CLINICAL-LABORATORY; integrated; by tumour type• What is the total palette of markers undertaken for that tumour type?

• For standard of care clinically? If we also think about entry to clinical trials/research?• How well can different NGS-based ‘approaches’ (panels, genomes) better deliver the palette of

markers? Are standalone tests still needed?• What are the INDIRECT IMPACTS of each approach (eg molecular pathology, complexity of laboratory

workflow, ongoing requirement for redevelopment and redesign)

CLINICAL-LABORATORY-ECONOMIC; integrated; by tumour type• What is the costing for the different approaches

• IMMEDIATE COSTS: reagents, labcoats• (INDIRECT IMPACTS: (re) development, molecular pathology)• ADDITIONAL NON-LAB COSTS: data storage etc

Principles of evaluation capture

Tumour Type experts consulted

46

Sought input from >1 tumour type expertTumour type Experts approached

AML Anna Schuh, Angela Hamblin, Shirley Henderson

Haem onc other Anna Schuh, Angela Hamblin, Shirley Henderson

Sarcoma Nischalan Pillay, Adrienne Flanagan

Breast Nick Turner+ NCRI clin studies group

Colorectal

Ian Tomlinson, Gary Middleton, Phil Quirke, Nirupa

Murugaesu

Ovarian James Brenton, Iain McNneish

Prostate Johann De Bono, Mark Linch

Lung

Crispin Hiley (cc Charlie Swanton), Andrew Hudson,

Gary Middleton, Nirupa Murugaesu

Renal James Larkin, Samra Turajlic

Brain Ashkan Keyoumars, Richard Houlston

Endometrial David Church

Bladder Simon Crabb

Upper GI

John Bridgewater, Tim Meyer, Jeff Evans, Chrissie

Thirlwell

Melanoma Paul Lorigan, James Larkin

Childhood

40 different marker tests, 16 in standard of care testing

48

Gene molecular marker profile Scoring

Single fragment

molecular marker

test (e.g cobas,

pyrosequencing)

FISH karyotype

Full gene

screen (eg

sanger of

multiple

fragments)

MLPA/dosage

analysis

Single mutation(SNV, small indel) or hotpot 3 NS NS 2 NS

Oligo hot spots in same gene 3 NS NS 2 NS

All disparate mutations across a gene NS NS NS 2 NS

CNV/amplification/loss NS 1 NS NS 2

SV with known partner 3 3 2 NS NS

SV with mutiple partner 2 2 2 NS NS

SV with any partner NS NS 2 NS NS

Mutational signature NS NS NS NS NS

High (tally score 5)

Medium (tally score 3)

Low (tally score 1)Low Medium High medium Medium

tolerance of test to low quality DNA (ieFFPE)

3: Good performance using poor

quality DNA (ie FFPE)

2: Acceptable performance using

poor quality DNA

1: Equivoval performance using

poor quality DNA: high quality DNA

preferable

0: high quality DNA essential

N/A: liquid tumour

3 2 NS 2 2

3: not required

0: required

N/A: solid tumour

3 0 0 3 3

3: <3 days

2: <1 week

1: < 2 weeks

0: >2 weeks

3 2 2 2 2

3: <1%

2: 1-5%

1: 5-20%

0: >20%

3 2 2 2 2

DNA requirements (amount)

Typical TAT

Failure rate

Needs live cells

3:excellent (FP and FN rate <1%,

detection >95% for VRF<5%)

2: good (acceptable)

1: poor

0/NS: technology not suitable

Stand alone tests

Suitability/

sensitivity

Laboratory Evaluation

49

NGS DNA Amplicon

Hot spot panel (≥

200x)

NGS large gene panel

(Capture, generic) eg

Illumina 170 genes (≥

200x)

NGS bespoke

specific panel (≥

200x)

3 3 3 2 3

3 3 3 2 3

3 3 3 2 3

1 1 2 2 3

NS NS 3 2 3

NS NS 2 2 3

NS NS NS 2 3

NS 1 1 3 3

Low Medium High Very High Very High

3 2 2 1 1

3 3 3 3 3

2 1 1 0 0

3 2 2 ? ?

WGS at

(tumour

~150x)

PANELS

WGS at

(tumour ~75x)Gene molecular marker profile Scoring

Single mutation(SNV, small indel) or hotpot

Oligo hot spots in same gene

All disparate mutations across a gene

CNV/amplification/loss

SV with known partner

SV with mutiple partner

SV with any partner

Mutational signature

Very High (tally score 10)

High (tally score 5)

Medium (tally score 3)

Low (tally score 1)

tolerance of test to low quality DNA (ieFFPE)

3: Good performance using poor

quality DNA (ie FFPE)

2: Acceptable performance using

poor quality DNA

1: Equivoval performance using poor

quality DNA: high quality DNA

preferable

0: high quality DNA essential

N/A: liquid tumour

3: not required

0: required

N/A: solid tumour

3: <3 days

2: <1 week

1: < 2 weeks

0: >2 weeks

3: <1%

2: 1-5%

1: 5-20%

0: >20%

3:excellent (FP and FN rate <1%,

detection >95% for VRF<5%)

2: good (acceptable)

1: poor

0/NS: technology not suitable

Suitability/

sensitivity

DNA requirements (amount)

Typical TAT

Failure rate

Needs live cells

50

Clinical Laboratory Integrator

count

(Standard

sensitivity)

count (High

sensitivity)

Single mutation(SNV, small indel) or hotspot 6 1

Oligo hot spots in same gene 0

All disparate mutations across a gene 2

CNV/amplification/loss 0

SV with known partner 8

SV with mutiple partner 0

SV with any partner 0

Mutational signature 0

Approach1:

all

standalone

tests

Approach 2:

hotspot panel(+

additional tests)

Approach

3: generic

gene

panel(+

additional

tests)

Approach

4: bespoke

gene panel

(+

additional

tests)

Approach

5: WGS

@75x (+

additional

tests)

Approach

6: WGS

@150x (+

additional

tests)

6 3 3 1 1 0

2 2 0 0 0 0

0 0 0 0 0 0

1 1 1 0 0 0

3 3 3 0 0 0

karyotype

FISH

Single fragment molecular marker test (e.g cobas, pyro, qPCR)

Full gene screen (eg sanger of multiple fragments)

MLPA/dosage analysis

Standard Clinical Care

Count of additional tests required by this approach

STEP 1: SUMMARY OF

MOLECULAR MARKERS

FROM CLINICAL EVALUATION

STEP 2: BRINGING TESTS TOGETHER AS 5 APPROACHES

Additional stand-alone non-NGS tests

Context:

51

Adrienne Flanagan Dr Pippa Corrie Lucy Side

Andrew Protheroe Fiona Carragher Manuel Salto-Tellez

Anna Schuh Fiona Lalloo Mark Davies

Clare Verrill Gareth Thomas Martin Gore

Crispin Hiley Harpeet Wasan Nick Turner

Darren Hargrave Ian Chau Nischalan Pillay

David Church Ian Lewis Peter Clark

David Thomson Ian Tomlinson Prof Karin Oien

Dion Morton Ian Walker Rachael Hough

Dr Alison Birtle Jacquie Westwood Rachel Butler

Dr Andrew Biankin James Brenton Richard Edmondson

Dr Andrew Pettitt James Larkin Richard Stephens

Dr Colin Watts Jane Moorhead Rory Harvey

Dr Daniel Rea Jo Martin Sarah Coupland

Dr Lee Jeys Johann Debono Simon Crabb

Dr Matt Hatton John Bridgewater Tony Williams

Dr Meriel Jenney John Radford Wailup Wong

Consultation meeting: 23rd May 2017

Secondary phase of data collection

5210 July 2017

• Review of proposed marker set• Numbers, subtypes, patient journey, emerging

technologies/approaches• Key molecular targets going into Phase 3• To return by 26/6/17

GENOMICS ENGLAND CANCER TEAMLouise JonesNirupa MurugaesuClare CraigKay LawsonShirley HendersonAngela HamblinAlona SosinskyAugusto RendonSimon Thompson

CANCER WORKING GROUP

Dion Morton (pan cancer)James Brenton (ovary)Charles Swanton (lung)Johann de Bono (prostate)Nick Turner (breast)Ian Tomlinson (colorectal)Adrienne Flanagan (sarcoma)Josef Vormoor (childhood)James Larkin (renal)Anna Schuh (haem-onc)Crispin HileyMark LinchSamra TurajlicyNischalan PillayDavid Gonzalez (Imperial GMC)Frank McCaughan (SL GMC)Paul Cane (SL GMC)Tim Helliwell (NWcoast GMC)John McGrath (Wessex GMC)John Radford (Manchester GMC)Sean Grimmond (ICGC)David Cameron (clinical trials)Ian Cree (RCPath)Rowena Sharpe (CRUK)

PILOTS/EXPERIMENTSLab Leads:Anna SchuhShirley HendersonGerry ThomasAdrienne FlannaganAndrew WallaceDavid Gonzalez de CJames BrentonFrancesca CiccarelliEmily ShawLouise JonesClare Verrill

Pauline Robbe Dimitris VavoulisJames Hadfield

ILLUMINA R&D team:Mark Ross Jenn BecqZoya KingsburySean HumphrayDavid Bentley

AcknowledgementsVALIDATION, INTERPRETATION AND FEEDBACK WORKING GROUPDavid Gonzalez de Castro (ICR/RMH)Phil Bennet (UCL)Angela Hamblin (Oxford)Shirley Henderson (Oxford)Manuel Salto-Tellez (Belfast)Andrew Wallace (Manchester)Gert Attard (Imperial)Gary Middleton (Birmingham)Rachel Butler (Cardiff)

Alice Tuff LaceyJoanne MasonJason ChattooCristina Aguilera Amanda O’NeillNancy HorsemanJames HadfieldJames PeachMark CaulfieldTom Fowler

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FF vs FFPE by GMC as of 6th June

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Documents

Cancer Programme Update · Clare Turnbull Clinical Lead for Cancer Genomics, Genomics England Reader in Genomic Medicine, Institute of Cancer Research and ... guidelines when compared