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Dr Fiona McRonald 11 th June 2019 NCRAS, Public Health England

Cancer Registration in the Era of Genomics: Integrating Germline and Somatic Genetic Data into the Cancer Registration System for England. Dr Fiona McRonald 11 th June 2019 NCRAS, Public Health England. National Disease Registration Service (NDRS).

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Dr Fiona McRonald 11 th June 2019 NCRAS, Public Health England

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  1. 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 2019 NCRAS, Public Health England

  2. National Disease Registration Service (NDRS) Population-based registers, covering all NHS activity in England. National Congenital Anomaly and Rare Disease Registration Service (NCARDRS) • National Drug Treatment and Monitoring Service (NDTMS) National Cancer Registration and Analysis Service (NCRAS) Genomics Data Programme spans these areas NAACCR-IACR, Vancouver, 2019

  3. Regional NHS Clinical Genetics Services Regional NHS Cytogenetics and Molecular Genetics Labs Molecular Pathology Labs NCRAS: National Cancer Registration and Analysis Service Vision for NCRAS in the Genomic Era Radio-therapy Pathology Reports COSD / MDT Chemo-therapy Cancer Waiting Times ONS Deaths PAS Radiology Audit ENCORE Local Feeds (from NHS Trusts) ENCORE National Feeds Integration of genotype and phenotype data Data Extraction Patient ID and Tumour Data Somatic Mutation Data Germline Mutation Data NEW DATA FEEDS Family history confirmation Cancer predisposition Precision Oncology Haematology molecular and cytogenetics Labs NAACCR-IACR, Vancouver, 2019

  4. Birmingham Bristol Cambridge Cardiff Exeter Leeds Liverpool Manchester Newcastle (NewGene) Nottingham Royal Marsden Sheffield Labs supplying somatic data We have ~75-80% of solid tumour data for actionable* genes *Genes for which a licenced targeted therapy is available The main gap is in London Molecular section of pathology lab Regional Molecular Genetics lab NAACCR-IACR, Vancouver, 2019

  5. Genetics Data Schema Genetic Test Dates, method, lab sample number, which lab carried out the test, who ordered it etc. One genetic test can look at several genes Genetic Test Result Which gene was tested, whether it was normal, type of abnormality found etc. One gene can have several variants Genetic Sequence Variant If a mutation was found in a gene, the exact details of the mutation can be recorded here NAACCR-IACR, Vancouver, 2019

  6. Standardising and processing molecular data • Data Tables in registry – map each data feed to standard structure QA of registration process. SQL code for analysis Education and training of registration staff NAACCR-IACR, Vancouver, 2019

  7. 1145 9 COMBINATIONS OF GENE AND TUMOURSITE 9 LABORATORIES (Birmingham, Royal Marsden, Leeds, Cambridge, Nottingham, Liverpool, Newcastle, Sheffield, Exeter) REGISTRATION STAFF 20 MONTHS Jan 2016 - Aug 2017 63900 17.4% 27976 44193 70944 GENES TESTED TUMOURS TESTED GENETIC TESTS ABNORMAL TEST RESULTS GENETIC TEST RESULTS 2.3 PER TUMOUR

  8. Tumour types and genes tested • Registration in progress: • 2016 data >90% complete • 2017 data ~25% complete 3500 962 1409 15,983 3942 2180 NAACCR-IACR, Vancouver, 2019

  9. Lung cancer results – the Big Three Figures calculated May 2019 NAACCR-IACR, Vancouver, 2019

  10. Aberration types NAACCR-IACR, Vancouver, 2019

  11. EGFR mutation spectrum in NSCLC Response to 1st generation tyrosine kinase inhibitors, e.g. gefitinib, erlotinib: mutations conferring sensitivity to 1st generation TKIs mutations conferring resistance to 1st generation TKIs 807 sensitivity mutations 164 resistance mutations We estimate that ~150 of these tumours are double mutants. Figures calculated November 2018 NAACCR-IACR, Vancouver, 2019

  12. 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 NAACCR-IACR, Vancouver, 2019

  13. Diagnostic vs predictive genetic testing NAACCR-IACR, Vancouver, 2019 Diagnostic Testing • A genetic test on somebody who has a disease • Confirms the diagnosis and the genetic basis of the disease • For cancer patients, PHE can collect this information under section 251 Predictive Testing A genetic test on somebody who is at risk of inheriting a disease, but is not (yet) symptomatic Tells somebody whether they carry the altered gene PHE cannot have identifiable information on somebody without cancer

  14. One-way cryptographic hash function (SHA-256) Pseudonymisation Output Files PHE Cancer Registry (NCRAS) NHS Genetics Lab Unique Pseudo ID + Unique Pseudo ID (for matching) NHS Number + DOB NHS Number + DOB Demographics Germline variants Unique Pseudo ID + Encrypted Demographics Decrypted Demographics Reversible encryption function (AES-256) Unique key Germline variants Cryptographic ‘salt’ Unique Pseudo ID + germline variants Pseudonymisation interface

  15. Example of raw data (Leeds) NAACCR-IACR, Vancouver, 2019

  16. Restructured data – variant counts NAACCR-IACR, Vancouver, 2019

  17. BRCA Variant Pathogenicity NAACCR-IACR, Vancouver, 2019

  18. Case Study:BRCA2 c.9302T>G p.(Leu3101Arg) 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. 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. NAACCR-IACR, Vancouver, 2019

  19. Confirming family histories for genetic counselling New online portal launched 1st January 2019 Figures from 1/1/19 – 3/6/19 inclusive: i.e. ~1500 requests per month NAACCR-IACR, Vancouver, 2019

  20. NHS Regional Genetics & Molecular Pathology Laboratories Public Health England Jem Rashbass, NDR staff (Registration, Analysis and IT Development 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 Thanks and Acknowledgements This work uses data provided by patients and collected by the NHS as part of their care and support 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. NAACCR-IACR, Vancouver, 2019

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