Dr Fiona McRonald 11 th June 2019 NCRAS Public Health England National Disease Registration Service NDRS 2 NAACCRIACR Vancouver 2019 National Cancer Registration and Analysis Service NCRAS ID: 931528
Download Presentation The PPT/PDF document "Cancer Registration in the Era of Genomi..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Cancer Registration in the Era of Genomics: Integrating Germline and Somatic Genetic Data into the Cancer Registration System for England.
Dr Fiona McRonald 11th June 2019NCRAS, Public Health England
Slide2National Disease Registration Service (NDRS)
2
NAACCR-IACR, Vancouver, 2019
National Cancer Registration and Analysis Service (NCRAS)
National Congenital Anomaly and Rare Disease Registration Service (NCARDRS)
National Drug Treatment and Monitoring Service (NDTMS)
Genomics Data Programme spans these areas
Population-based registers, covering all NHS activity in England.
Slide33
Vision for NCRAS in the Genomic Era
Patient ID and Tumour Data
Germline Mutation Data
Somatic Mutation Data
NEW DATA FEEDS
Radio-therapy
Pathology Reports
PAS
Cancer Waiting Times
Chemo-therapy
Radiology
COSD / MDT
Audit
ONS Deaths
ENCORE Local Feeds (from NHS Trusts)
ENCORE National Feeds
Data Extraction
Integration of genotype and phenotype data
NAACCR-IACR, Vancouver, 2019
Precision Oncology
Cancer predisposition
Haematology molecular and cytogenetics Labs
Regional NHS Clinical Genetics Services
Molecular Pathology Labs
Regional NHS Cytogenetics and Molecular Genetics Labs
Family history confirmation
NCRAS: National Cancer Registration and Analysis Service
Slide44
NAACCR-IACR, Vancouver, 2019
Labs supplying somatic data
Birmingham
Bristol
Cambridge
Cardiff
Exeter
Leeds
Liverpool
Manchester
Newcastle (
NewGene
)
Nottingham
Royal Marsden
Sheffield
Molecular section of pathology lab
Regional Molecular Genetics lab
We have ~75-80% of solid tumour data for actionable* genes
The main gap is in London
*Genes for which a licenced targeted therapy is available
Slide5Genetics Data Schema
5NAACCR-IACR, Vancouver, 2019
Genetic TestDates, method, lab sample number, which lab carried out the test, who ordered it etc.
Genetic Test ResultWhich gene was tested, whether it was normal, type of abnormality found etc.
Genetic Sequence Variant
If a mutation was found in a gene, the exact details of the mutation can be recorded here
One genetic test can look at several genes
One gene can have several variants
Slide6Standardising and processing molecular data
Data Tables in registry – map each data feed to standard structure
6NAACCR-IACR, Vancouver, 2019
Education and training of registration staff
QA of registration process. SQL code for analysis
Slide727976
TUMOURS
TESTED
44193
GENETIC TESTS
70944
GENETIC TEST RESULTS
9
REGISTRATION STAFF
9
LABORATORIES
(Birmingham, Royal Marsden, Leeds, Cambridge, Nottingham, Liverpool, Newcastle, Sheffield, Exeter)
63900
GENES
TESTED
2.3
PER TUMOUR
20
MONTHS
Jan 2016 - Aug 2017
17.4%
ABNORMAL
TEST RESULTS
1145
COMBINATIONS
OF
GENE
AND
TUMOUR
SITE
Slide8Tumour types and genes tested
8
NAACCR-IACR, Vancouver, 2019
Registration
in progress:
2016 data >90% complete
2017 data ~25% complete
15,983
2180
3942
1409
3500
962
Slide9Lung cancer results – the Big Three
9
NAACCR-IACR, Vancouver, 2019
Figures calculated
May
2019
Slide10Aberration types
10
NAACCR-IACR, Vancouver, 2019
Gene
Test status
Genetic aberration type
Tumours tested (all sites; normal and abnormal results only)
EGFR
Normal
Wild type sequence
9411
Abnormal
Mutation (DNA sequence variant)
1234
(11.6%)
ALK
Normal
Not fused or rearranged
8559
Abnormal
Fusion / translocation
202
(2.3%)
PD-L1
Normal
Normal gene expression
3946
Abnormal/Borderline
Overexpression
4792
(54.8%)
MLH1
Normal
Normal gene expression
1372
AbnormalUnderexpression / silencing189(12.1%)
NormalNormal epigenetic status37Abnormal
Promoter methylation37(50%)
Slide11EGFR mutation spectrum in NSCLC
11
NAACCR-IACR, Vancouver, 2019
mutations conferring sensitivity to 1
st
generation TKIs
mutations conferring resistance to 1
st
generation TKIs
807 sensitivity mutations
164 resistance mutations
We estimate that ~150 of these tumours are double mutants.
Figures calculated November 2018
Response to 1
st
generation tyrosine kinase inhibitors, e.g. gefitinib, erlotinib:
Slide1212
NAACCR-IACR, Vancouver, 2019
Germline Data Collections
Pilot Project:
BRCA1
and
BRCA2
genes – Supporting the BRCA Challenge
Data received from
13
labs, covering period from 2000 onwards. Aggregated variant data from >22,000 individuals released back to NHS geneticists (Cancer Variant Interpretation Group,
CanVIG
)
Phase Two: Colorectal cancer predisposition genes (with a focus on Lynch syndrome) – Bowel Cancer UK funded
Data received from five labs so far
Data received
Data submission in progress
Awaiting data
Lab does not test BRCA1/2 genes
Slide13Diagnostic vs predictive genetic testing
NAACCR-IACR, Vancouver, 2019
Diagnostic TestingA genetic test on somebody who has a diseaseConfirms the diagnosis and the genetic basis of the diseaseFor cancer patients, PHE can collect this information under section 251
Predictive TestingA genetic test on somebody who is at risk of inheriting a disease, but is not (yet) symptomaticTells somebody whether they carry the altered genePHE cannot have identifiable information on somebody without cancer
13
Slide14NHS Number + DOB
Germline variants
Decrypted Demographics
NHS Number
+ DOB
Demographics
Germline variants
Unique key
Unique Pseudo ID
+
Unique
Pseudo ID
+ Encrypted Demographics
Unique
Pseudo 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
Pseudonymisation
Output Files
PHE Cancer Registry (NCRAS)
Slide1515
NAACCR-IACR, Vancouver, 2019
Example of raw data (Leeds)
Slide1616
NAACCR-IACR, Vancouver, 2019
Restructured data – variant counts
Slide17BRCA Variant Pathogenicity
17
NAACCR-IACR, Vancouver, 2019
ADD ONE EGG AND THE HAM
Wild type sequence
Most pathogenic BRCA mutations are truncating…
A
•
DO NEE GGA NDT HEH AM.
Frameshift deletion
ADD ON
C
EEG GAN DTH EHA M..
Frameshift
insertion
ADD ONE EGG
END THE HAM
Nonsense mutation
Variants of Unknown Significance (VUS
/
VoUS
)…
ADD ONE EGG AND THE
J
AM
Normal variant??
ADD ONE EGG AND THE HA
T
Missense mutation??
AAT GAC
GTC TAT ACC GAG GCT GAA TCA
???
Slide1818
NAACCR-IACR, Vancouver, 2019
Case Study:
BRCA2
c.9302T>G p.(Leu3101Arg)
Confirmed ethnicities in cancer registry.
Breast cancer-prone families: 10/16,600
(NHS labs’ combined counts, submitted to PHE
)
vs. population: 0/63,369 (non-Finnish Europeans in
gnomAD
database)
Fisher exact = 6.48x10
-10
Variant discussed at monthly meeting of Cancer Variant Interpretation Group (
CanVIG), and national evidence assembled.Upgraded from Class 3 (unknown significance) to Class 5 (pathogenic). Families re-contacted.
May 2018: Query from a genetic counsellor:
Variant not seen in population databases
Reported 5 times in
Clinvar
,
as a VUS.
In silico
prediction: ‘probably damaging’. Changes hydrophobic to charged residue.
Slide19Confirming family histories for genetic counselling
19
NAACCR-IACR, Vancouver, 2019
New online portal launched 1
st
January 2019
Figures from 1/1/19 – 3/6/19 inclusive:
Total requests processed
7576
Matched
5714 (75.4%)
Unmatched
1750 (23.1%)
Declined
77 (1.0%)
In Progress
35 (0.5%)
i.e. ~1500 requests per month
Slide2020
NAACCR-IACR, Vancouver, 2019
NHS Regional Genetics & Molecular Pathology Laboratories
Public Health England
Jem Rashbass,
NDR staff (R
egistration
, Analysis and IT D
evelopment
teams)
Health Data Insight CiC
Brian Shand, Nathan Bricault,
Kelvin Hunter, Shilpi Goel, Francesco Santaniello
Institute of Genetic Medicine, Newcastle
John Burn, Gill Borthwick
Cancer Variant Interpretation Group (C-VIG)
Clare Turnbull, Diana Eccles
The BRCA Challenge is supported by a generous grant from Astra Zeneca to the University of Newcastle and Health Data Insight
CiC
.
Funding to support expansion of the project to MMR genes has been provided by Bowel Cancer UK.
This work uses data provided by patients and collected by the NHS as part of their care and support
Thanks and Acknowledgements