ndrs molecular and genomic dataset · 7 ndrs webinar series - molecular & genomic dataset. ndrs...

NDRS Molecular and Genomic Dataset

NDRS Webinar Series – 2nd December 2020

Presenters

2

Steven HARDY PhD FRCPath

Head of Molecular Diagnostics

[email protected]

Fiona McRONALD PhD

Programme Manager –

Molecular, Genomic and

Research Data

[email protected]

Corinne MALLINSON BSc (Hons)

Molecular Liaison / Development

Lead

[email protected]

NDRS Webinar Series - Molecular & Genomic DatasetNDRS Webinar Series - Molecular & Genomic Dataset

Webinar content

3 NDRS Webinar Series - Molecular & Genomic DatasetNDRS Webinar Series - Molecular & Genomic Dataset

1. Overview of NDRS and the Molecular & Genomic programme

2. Dataset structure

3. Datasets and services

i. Cytogenetics dataset

ii. Somatic dataset

iii. Germline dataset

iv. Genetic (Family History) Enquiries service

4. Data access/availability and further information

NDRS in context…

Public Health England (Health Improvement)

4 NDRS Webinar Series - Molecular & Genomic Dataset

National Disease Registration Service (NDRS)

The National Cancer Registration &

Analysis Service (NCRAS)

The National Congenital Anomaly and

Rare Disease Registration Service

(NCARDRS)

COSD

Pathology PROMS CWT

RTDS

Other datasets

Congenital anomaly registration

Rare disease registration

Congenital anomaly legacy dataset

Screening analysis (FASP & NIPT)

Sickle cell & thalassaemia (SCT)

data collection

Molecular & genomic data

SACT


Precision

OncologyCancer

predisposition

Rare diseases

Chromosomal

abnormalities

NDRSIntegration and linkage of

genotype & phenotype data NCRAS NCARDRS

NCRAS Data Feeds NCARDRS Data Feeds

Data outputs and reports supporting

the wider clinical community, e.g….

• Variant frequency counts

• Tumour mutation profiles

• Targeted therapy prescriptions

• Prenatal detection of trisomies

• Prevalence of rare diseases and

chromosomal abnormalities

• Genotype-phenotype correlations

Cancer family history

verification service

NDRS

Data

Extraction

Germline

Mutation

Data

Tumour

Mutation

Data

LAB DATA

FEEDS

Haematology

molecular and

cytogenetics

Labs

Molecular

Pathology

Labs

Regional NHS

Cytogenetics

and Molecular

Genetics Labs

Regional

NHS

Clinical

Genetics

Services

NDRS

Molecular &

Genomics

https://thenounproject.com/term/checklist/100727https://thenounproject.com/term/dna/57372


Genomics

datasets &

services

Putting security and confidentiality first


NDRS data is highly sensitive and patient level

➢ Security and patient confidentiality are paramount

NDRS has legal permission to collect

patient information without consent

• Granted under Section 251 of the

Health and Social Care Act of

2006 (annually renewed)• Must have a medical purpose

• Be in the public interest or interest of

improving care

• Obtaining consent must be impractical

• Be compliant with DPA/GDPR

Data is aggregated, anonymised or

de-personalised wherever possible

Patient can opt out at any time

Yearly review with the Confidentiality

Advisory Group – Health Research

Authority (HRA)

Dataset structure



Molecular Data Tables


Genetic Test• Dates:

• Test Requested

• Sample Taken

• Sample received

• Report authorised date

• Reason for referral

• Hospital/Lab demographics

• Specimen type

• Tumour %

• Methodology / technology


Genetic Test Result

• Test status• Normal

• Abnormal

• Aberration type• DNA sequence variant

• Fusion

• Amplification

• Etc.

• Gene tested• EGFR

• BRAF

• KRAS

• Etc.


Genetic Sequence

Variant• Genome Build

• Transcript ID

(incl. version number)

• Sequence variant details in

HGVS where available

• Exon/intron/codon number where

specific details not given:

E.g. ‘BRAF codon 600 mutation

detected’

Cytogenetics dataset


National Congenital Anomaly and Rare Disease

Registration Service (NCARDRS)

Pre- and post-natal cytogenetic data collected from all regional genetic labs

across England as a key component of congenital anomaly registration

Relevant outputs from NCARDRS which use the cytogenetic data include:

• 2018 NCARDRS congenital anomaly statistics based on data submitted to EUROCAT

(European surveillance of congenital anomalies):

https://www.gov.uk/government/publications/ncardrs-congenital-anomaly-annual-data

• 2018/19 Fetal Anomaly Screening Programme (FASP) evaluation


https://www.gov.uk/government/publications/ncardrs-congenital-anomaly-annual-data

Infant mortality by congenital anomaly subgroup, 2018


Prevalence of Down’s syndrome, Edwards’ syndrome and

Patau’s syndrome in England- 2018


Underlying genetic mechanism in babies born in 2018 with

Down’s syndrome, Edwards’ syndrome and Patau’s

syndrome


Timing of diagnosis for babies born in 2018 with Down’s

syndrome by NCARDRS region


Number of registered tests completed in 2018 categorised

by test method


Percentage of babies with positive or negative cytogenetic

testing completed in 2018, categorised by selected structural

anomaly groups


Chromosomal anomaly type associated with cardiac

anomalies in babies with genetic tests from 2018


Anomaly type Number Percentage

Down’s syndrome 365 44.03

Edwards’ syndrome 137 16.53

Autosomal deletions 136 16.41

Autosomal duplications 53 6.39

Turner’s syndrome 40 4.83

Patau’s syndrome 32 3.86

Other autosomal anomalies 42 5.07

Other sex chromosome anomalies 24 2.90

What next for NCARDRS?

Continued support for cytogenetic data collection and registration

Supporting NIPT evaluation

Mapping case definition to reflect developments in testing (e.g. WES and NGS)

and ensure alignment to National Genomic Test Directory for rare and inherited

disease


Somatic Dataset



Data collection

• 20 laboratories – mixture of genomic, molecular

pathology and haematology laboratories

• >100 histopathology laboratories – MMR, PD-L1

As of October-20


Solid tumour spectrum

Cancer Site Count

Lung 43,964

Colorectal 22,755

Melanoma 6,577

Breast 3,610

Brain 2,444

Other 13,008


Gene spectrum

0

5,000

10,000

15,000

20,000

25,000

30,000

35,000

PD-L1

EGFR

ALK

MLH1 PMS2 MSH6 MSH2

KRASNRAS BRAF

BRAF

LUNG COLORECTAL MELANOMA

No o

f tu

mours


Results outcome

LUNG COLORECTAL MELANOMA


Variant spectrum – EGFR in lung cancer


Mutations conferring resistance to

1st generation TKIs

EGFR molecular testing / targeted treatment pathway

30

1,884 patients (diagnosed with

stage IIIB/IV non-squamous

NSCLC) harbouring 1st generation

TKI-sensitive EGFR mutations

938 patients did not go

on to develop T790M

mutation

845 patients were not

treated with a 1st

generation TKI

24 patients were not

treated with osimertinib

March 2017

Somatic testing detects

an exon 19 deletion

mutation in EGFR

April 2017

Treatment with

gefitinib begins

February 2018

Somatic testing detects

a T790M substitution

mutation in exon 20

February 2018

Treatment with

osimertinib begins

1,039 patients treated with a 1st

generation TKI

101 patients develop 1st

generation TKI-resistant T790M

mutation

77 patients treated with osimertinib

Patient

pathway

example


How is the somatic dataset being used?


1. Lynch syndrome – monitoring uptake of MMR IHC and MSI in colorectal

cancer (DG27) and endometrial cancer (DG42) – at request of NHSE/I Cancer

Programme

2. Histology-independent therapies – evaluating NTRK testing as part of the

evaluation of Entrectinib / Larotrectinib in the Cancer Drugs Fund

3. Breast cancer – evaluating performance of gene expression profiling tests to

guide adjuvant chemotherapy decisions in early breast cancers (NICE DG34)

4. Lung cancer – provision of molecular diagnostic data to National Lung

Cancer Audit planned for 2021 (RCP/HQIP)

5. Academic partnerships (see later)

Germline Dataset


Germline Data Collections

33 Hereditary Cancer - NDRS Molecular Webinar. 2nd December 2020

BRCA data received

Colorectal data received ( in progress)

Other CSG data received

Data not submitted yet

Aim of project: Linkage at patient-level of all germline

cancer predisposition tests (from England and Wales

NHS labs) to NDRS cancer registration records.

https://en.wikipedia.org/wiki/File:Hvplogo.png

Germline variants

Decrypted Demographics

NHS Number+ DOB

Demographics

Germline variants

Unique key

UniquePseudo ID+ germline

variants

Pseudonymisation interface

Cryptographic ‘salt’

One-way cryptographic hash function (SHA-256)

Reversible encryption function (AES-256)

Unique Pseudo ID

(for matching)

NHS Genetics Lab PseudonymisationOutput Files

PHE Cancer Registry (NCRAS)

NHS Number + DOB

UniquePseudo ID

+ Encrypted Demographics

Unique Pseudo ID

+

http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjo9f7QltnKAhVJXBQKHZdfAikQjRwIBw&url=http://www.freeimages.com/premium/heap-of-sea-salt-2084739&psig=AFQjCNECZJ8xcXm0jGMtFpzBm2SKwK9v_g&ust=1454505766786667http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjo9f7QltnKAhVJXBQKHZdfAikQjRwIBw&url=http://www.freeimages.com/premium/heap-of-sea-salt-2084739&psig=AFQjCNECZJ8xcXm0jGMtFpzBm2SKwK9v_g&ust=1454505766786667http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiBwa_Ml9nKAhXKuRQKHQmACW0QjRwIBw&url=http://www.drivingtesttips.biz/one-way-streets-systems-roads.html&psig=AFQjCNH8aJMHJeFi-TkSaHrsqg-zITb34A&ust=1454506076573304http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiF89X8l9nKAhXIbRQKHWT8A-8QjRwIBw&url=http://www.allpark.co.uk/road-and-traffic-signs/no-entry-road-traffic-sign.html&psig=AFQjCNFN-_KF1-FaZTKE0up1Vmfymrg_8Q&ust=1454506132321135http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjo9f7QltnKAhVJXBQKHZdfAikQjRwIBw&url=http://www.freeimages.com/premium/heap-of-sea-salt-2084739&psig=AFQjCNECZJ8xcXm0jGMtFpzBm2SKwK9v_g&ust=1454505766786667http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjo9f7QltnKAhVJXBQKHZdfAikQjRwIBw&url=http://www.freeimages.com/premium/heap-of-sea-salt-2084739&psig=AFQjCNECZJ8xcXm0jGMtFpzBm2SKwK9v_g&ust=1454505766786667http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiBwa_Ml9nKAhXKuRQKHQmACW0QjRwIBw&url=http://www.drivingtesttips.biz/one-way-streets-systems-roads.html&psig=AFQjCNH8aJMHJeFi-TkSaHrsqg-zITb34A&ust=1454506076573304http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiF89X8l9nKAhXIbRQKHWT8A-8QjRwIBw&url=http://www.allpark.co.uk/road-and-traffic-signs/no-entry-road-traffic-sign.html&psig=AFQjCNFN-_KF1-FaZTKE0up1Vmfymrg_8Q&ust=1454506132321135http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjGoMfKpeHKAhXISBQKHeHwCUEQjRwIBw&url=http://www.drivingtesttips.biz/uk-road-traffic-warning-signs.html&psig=AFQjCNEWcJbAhDOMDUVQoyDIUXJXQTnpcw&ust=1454784714587481http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjGoMfKpeHKAhXISBQKHeHwCUEQjRwIBw&url=http://www.drivingtesttips.biz/uk-road-traffic-warning-signs.html&psig=AFQjCNEWcJbAhDOMDUVQoyDIUXJXQTnpcw&ust=1454784714587481

Germline Data Submissions


62006

7249879227

88204

100554

8764 1089711303 11415

20868

5258 7532 7570 8402

16897

76028

90927

98100

108021

138319

0

20000

40000

60000

80000

100000

120000

140000

160000

0

20000

40000

60000

80000

100000

120000

140000

Dec-19 Mar-20 Jun-20 Sep-20 Nov-20

Co

un

t o

f sp

ecim

en

s s

ub

mitte

d

Quarter End

BRCA

CRC

Other

TOTAL

Total BRCA specimens submitted – by lab


Birmingham, 14799

London – Guy’s, 12365

London – St George's, 10389

Manchester, 10326

Leeds, 7951

Nottingham, 8336

Salisbury, 7886

Newcastle, 6830

London – RMH, 4571

Oxford, 4404

Cambridge, 3935

London - GOSH, 3334

Sheffield, 3169 Bristol, 1364London - KGC, 895

Restructuring the Data…


The Tower of Babel, by Pieter Brueghel the Elder, 1563

18 labs; 18 different data formats,

plus changes over time…

3 sets of genes…

One standardised format,

properly structured and

suitable for analysis

Francesco Santaniello

Bioinformatician

Ollie Tulloch

Lead Developer

Restructured data – variant counts


Variant Releases – June 2020

• BRCA variants from eight labs:

• >1700 different variants in BRCA1 / BRCA2 genes, reported in 4305 full

screens (i.e. independently ascertained families) and 9502 times in total

(i.e. including tests for a known familial mutation in relatives).

• BRCA1/BRCA2 full screen denominator estimated as 28,936.

• Colorectal variants from six labs:

• >670 different variants in MMR and other colorectal genes, reported in

1150 full screens and 1878 times in total.

• Full screen denominator varies by gene, but is >2000 for MLH1


Use of aggregate data in variant interpretation

• The problem…

• Variant of Uncertain Significance (aka VUS; ‘Very Unhelpful Statement’)

• Crowdsourcing a solution…

• Cancer Variant Interpretation Group (CanVIG-UK): monthly virtual meetings of UK NHS

geneticists (lab & clinical) to assimilate and discuss evidence around VUSs of interest.

• National-level genetic variant frequencies released from NCRAS to CanVIG-UK, and imported

into CanVar database.

• Compare variant frequency in independently-tested cancer families with that in population

control genomic databases. Is the variant more common in our high-risk cancer population?

• For full screen tests where pseudonym matched to the cancer registry, we created a data

subset of the variant counts and denominators from people of white ethnicity only – comparable

population to Non-Finnish Europeans (NFE) in gnomAD.


Collaboration with CanGene-CanVar


There was consensus that

excellent progress had been made

for WP1, which is the core of the

entire project and the one WP with

potentially practice‐changing implications for the NHS…. If

successfully achieved, this will be

a “world’s first”.

CanGene-CanVar Scientific Advisory

Committee Report, January 2020

CanVIG Variant Submission to ClinVar

PHE Germline Data Project Adopted as Work Package 1 (WP1)

New knowledge transferred for benefit of patients worldwide.

Case Study 1: PHE data and variant interpretation• IVF patient funding their own treatment by gamete sharing. Lab robot error – instead of CF

carrier status test (standard for gamete donors), MSH6 was examined, and c.3197A>G

p.(Tyr1066Cys) was identified.

• ??pathogenic variant causing Lynch syndrome. Patient now unable to donate their gametes and

fund their own assisted fertility. Potential legal action against NHS Trust. Urgent request to

InSiGHT for assistance in variant interpretation.

• Prior probability of pathogenicity as a missense = 0.153, i.e. low, but Class 3 (VUS).

• Case:control data: 0/4299 in PHE full screen data vs 4/102,672 NFE non-cancer controls in

gnomAD gives conditional probability of pathogenicity = 0.000 000 0051.

• Bayesian posterior probability (combining prior & conditional) of pathogenicity = 0.000 002 04,

which being

CaPP2 Long term follow up


IRR 0.50 (CI 0.31-0.81)p=0.005

People with Lynch

syndrome who take aspirin

for two years have a 50%

reduction in CRC over the

next two decades.

For every 25 LS patients

treated with aspirin, one

colorectal cancer is

prevented over ~15 years

(effect starts from 5 years).HR = Hazard Ratio (counts first cancer). IRR = Incident Rate Ratio (counts all cancers)

NCRAS Genetic (Family History) Enquiries Service


We respond to

375genetic enquiries

per week

That’s over

20,000cancer family

history diagnoses

checked and verified per year

We provide a vital service to NHS genetic

counselling units

and the familiesunder their care

79%match rate to

registry

“It’s a fantastic, easy to use service”

(Feedback from NHS Genetics Clinic)

99.9% of enquiries answered within 10-day target

Average case turnaround

time

2.65 days

Clinical Case 1: ‘Abdominal’ Cancer


Ca breast, 68y

‘abdominal’ ca, d. 55y

42y

Ca breast, 68y

OVARIANca, d. 55y

42y

Ca breast, 68y.BRCA1 mutation

identified

OVARIANca, d. 55y

42y Predictive BRCA1 test; mutation +ve.

Ca breast, 68y.BRCA1 mutation

identified

OVARIANca, d. 55y

42y

Manchester Score = 15(FBC>59 = 2 + OvC

Clinical Case 2: ‘Lung’ Cancer


Checked Dx

with NCRASCa pancreas,

59yCa ‘lung’, 49y

(15 years ago). Non-

smoker. Little contact

between adopted sibs.

38y

Ca pancreas, 59y

Ca BOWEL, 49y

38y

R210 Inherited MMR deficiency (Lynch syndrome) Testing Criteria 1d. [Proband has] Lynch-related cancer and ≥ 1 first degree relative has Lynch-related cancer (both occurred



Ca pancreas, 59y

Ca ‘lung’, 49y (15 years

ago). Non-smoker. Little

contact between

adopted sibs.

38y

Ca pancreas, 59y. MMR mutation identified

Ca BOWEL, 49y

38y

Eligible for colorectal

screening due to family

diagnosis of Lynch

syndrome



Ca pancreas, 59y

Ca ‘lung’, 49y (15 years

ago). Non-smoker. Little

contact between

adopted sibs.

38y

Ca pancreas, 59y. MMR mutation identified

Ca BOWEL, 49y

38y.

First colonoscopy: found large

adenoma with invasive features

Inherited Cancers – Summary


This work uses data that has been

provided by patients and collected by the

NHS as part of their care and support. The

data is collated, maintained and quality

assured by the National Cancer

Registration and Analysis Service, which

is part of Public Health England (PHE).

Genomic Laboratories

http://www.acgs.uk.com/

Data availability and access arrangements



Data access arrangements


• Formal requests to the Office for Data Release ([email protected])

• Cytogenetics – now

• Somatic – Beginning of 2021

• Germline – Late Spring/ Early Summer 2021

• Partnership working / collaborations

• Fund PHE staff

• Sponsored external staff with PHE honorary contracts

• Can also contact Steven Hardy ([email protected]) to discuss

informally

mailto:[email protected]:[email protected]


Examples of current partnerships


Partnership / disease

area

Aim(s) Partner(s) / collaborators

CanGene-CanVar (CRUK-

funded)

To establish comprehensive retrospective and prospective data submissions

of cancer susceptibility gene data from NHS labs to NDRS, production of

national variant counts to facilitate variant interpretation and linkage of the

underlying dataset to registry to facilitate analysis pertaining to cancer

genetic risk, phenotypes and outcomes

Prof Clare Turnbull, ICR

Lynch syndrome registry

(BCUK-funded)

To create a national registry of people with Lynch syndrome ascertained from

those individuals who have received testing in NHS labs and monitor cancer

development in these individuals

Prof Sir John Burn, Newcastle

Lynch syndrome Can patients who are genetically predisposed to cancers arising due to DNA mismatch repair deficiency be detected using pathology record data?

Dr Neil Rajan, Newcastle

Lung cancer and air pollution Investigating the association of air pollution with the incidence and moleculargenomics of lung cancer

Prof Charles Swanton, Crick

Mitochondrial Disease Comorbidity and mortality in mitochondrial disease: a registry-based study Prof Patrick Chinnery,

Cambridge

Wilson Disease Supporting the identification of Wilson disease patients using moleculardiagnostic data

Wilson Disease Special Interest

Group

Thanks and Acknowledgements


NHS Regional Genetics, Molecular Pathology, Haemato-

oncology and Histopathology Laboratories

Public Health England

Caroline Brook, Sophia Richardson, Esther Farmer, Sue Higgins, Margreet Luchtenborg,

Jo Pethick, Katrina Lavelle, Brian Shand, IT Development team, all registration teams

Health Data Insight CiC

Francesco Santaniello, Ollie Tulloch, Shilpi Goel, Kim Whittlestone

Cancer Variant Interpretation Group (C-VIG)

Clare Turnbull

This work uses data provided by patients and collected by the NHS as part

of their care and support

http://www.usemydata.org/index.shtmlhttp://www.acgs.uk.com/

Thank you

Steven Hardy ([email protected])

Fiona McRonald ([email protected])

Corinne Mallinson ([email protected])

ndrs molecular and genomic dataset · 7 ndrs webinar series - molecular & genomic dataset. ndrs...

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