Large-Scale Pharmacogenomics Analysis of Patients With Cancer Within the 100,000 Genomes Project Combining Whole-Genome Sequencing and Medical Records to Inform Clinical Practice
Abstract
PURPOSE As part of the 100,000 Genomes Project, we set out to assess the potential viability and clinical impact of reporting genetic variants associated with drug-induced toxicity for patients with cancer recruited for whole-genome sequencing (WGS) as part of a genomic medicine service. METHODS Germline WGS from 76,805 participants was analyzed for pharmacogenetic (PGx) variants in four genes ( DPYD , NUDT15 , TPMT , UGT1A1 ) associated with toxicity induced by five drugs used in cancer treatment (capecitabine, fluorouracil, mercaptopurine, thioguanine, irinotecan). Linking genomic data with prescribing and hospital incidence records, a phenome-wide association study (PheWAS) was performed to identify whether phenotypes indicative of adverse drug reactions (ADRs) were enriched in drug-exposed individuals with the relevant PGx variants. In a subset of 7,081 patients with cancer, DPYD variants were reported back to clinicians and outcomes were collected. RESULTS We identified clinically relevant PGx variants across the four genes in 62.7% of participants in our cohort. Extending this to annual prescription numbers in England for the drugs affected by these PGx variants, approximately 14,540 patients per year could potentially benefit from a reduced dose or alternative drug to reduce the risk of ADRs. Validating PGx associations in a real-world data set, we found a significant association between PGx variants in DPYD and toxicity-related phenotypes in patients treated with capecitabine or fluorouracil. Reported DPYD variants were deemed informative for clinical decision making in a majority of cases. CONCLUSION Reporting PGx variants from germline WGS relevant to patients with cancer alongside primary findings related to their cancer can be clinically informative, informing prescribing to reduce the risk of ADRs. Extending the range of actionable variants to those found in patients of non-European ancestry is important and will extend the potential clinical impact.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (36)
Ivone U.S. Leong
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Claudia P. Cabrera
Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom
Valentina Cipriani
Paul J. Ross
Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
Richard M. Turner
Wolfson Centre for Personalised Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
Alex Stuckey
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Sonali Sanghvi
Integrating Pharmacy & Medicines Optimisation Team, NHS North Central London Integrated Care System, UCLH NHS Foundation Trust, London
Dorota Pasko
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Loukas Moutsianas
Christopher A. Odhams
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Greg S. Elgar
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Georgia Chan
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Adam Giess
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Susan Walker
Rebecca E. Foulger
SciBite Limited, BioData Innovation Centre, Wellcome Genome Campus, Hinxton, UK
Eleanor M. Williams
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Louise C. Daugherty
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Antonio Rueda-Martin
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Daniel J. Rhodes
BenevolentAI, London, United Kingdom
Olivia Niblock
Cambridge Genomics Laboratory, United Kingdom
Alexandra Pickard
NHS England and NHS Improvement, London, United Kingdom
Lauren Marks
NHS England and NHS Improvement, London, United Kingdom
Sarah E.A. Leigh
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Matthew J. Welland
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Marta Bleda
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Catherine Snow
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Zandra Deans
NHS England and NHS Improvement, London, United Kingdom
Nirupa Murugaesu
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Richard H. Scott
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Michael R. Barnes
Matthew A. Brown
Augusto Rendon
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Sue Hill
NHS England and NHS Improvement, London, United Kingdom
Alona Sosinsky
Genomics England Ltd, Level 21 One Canada Square, London, United Kingdom
Mark J. Caulfield
Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom
Ellen M. McDonagh