A collaborative study involving the University of Liverpool has defined five new subgroups of the most common type of blood cancer, chronic lymphocytic leukaemia (CLL) and associated these with clinical outcomes.
Published in the journal Nature Genetics, this new method for risk stratifying patients could lead to more personalised patient care.
The study, which was carried out as part of the UK’s 100,000 Genomes Project, is the first to analyse all the relevant changes in DNA across the entire cancer genome, rather than targeted regions, to classify patients with cancer and link these subgroups to clinical outcomes.
It analysed the entire genome sequences from 485 patients with CLL who were enrolled in national clinical trials led by the Universities of Liverpool and Leeds, provided samples for the UK CLL Biobank in Liverpool and consented for their samples to be used in the 100,000 Genomes Project run by Genomics England.
Professor Anna Schuh from the University of Oxford, who led the study, said: “We know that cancer is fundamentally a disease caused by changes in DNA that are acquired over the lifetime of an individual. The lab tools we currently use to predict whether or not a patient is likely to respond to a given therapy usually focus on single abnormalities in the cancer DNA and do not accurately predict the patient’s clinical outcome. This is why we asked the simple question: can we increase the precision of current testing by looking at all the acquired DNA changes in cancer at once?”
By comparing the whole genome sequencing data from the cancer and healthy tissues in patients, the team were able to map known and newly identified DNA changes, structural alterations, cancer mutational signatures and other global measures associated with CLL throughout the genome. They identified 186 distinct and recurrent genomic alterations and used these to define five genomic subgroups of CLL that associate with different clinical outcomes.
Following additional validation in patients receiving a wider range of treatments than those included in this study, particularly targeted therapies, these new genomic subgroups for CLL could be used to better guide the selection of therapies for improved patient outcomes.
Professor Andrew Pettitt, founding Director of the UK CLL Biobank and Chief Investigator for two of the contributing clinical trials (RIAltO and CLL210) at the University of Liverpool, said: “This ground-breaking study is a paradigm for what can be achieved through a nationally coordinated approach to collaborative working that allows the application of cutting-edge science to a large number of high-quality samples obtained from uniform, well-defined patient cohorts and linked to high-quality clinical outcome data.
“The study findings are important for patients as CLL is one of the most common types of blood cancer and behaves very differently in individual patients in terms of how quickly it grows, how well it responds to treatment and to what extent it becomes more aggressive over time. This new study shows that the behaviour of CLL can be predicted much better by looking at all the genetic changes in the disease rather than just some of them, and it is hoped that whole genome sequencing will become routinely available and give patients and doctors more information to help with treatment decisions.”
Professor Sir Mark Caulfield, Vice Principal for Health for Queen Mary University of London and former Chief Scientist and lead of the 100,000 Genomes Project at Genomics England said: “This is the largest international genomic analysis of this blood cancer, which excitingly demonstrates the real value of whole genome sequencing from the 100,000 Genomes Project. It also harnesses the high-quality blood cancer samples from the Liverpool Chronic Lymphocytic Leukaemia Biobank and associated clinical data collected by the Clinical Trial Units at Liverpool and Leeds universities as part of multi-centre National Cancer Research Institute-supported clinical trials.
Our work shows that the entire genome is superior in classifying patients into groups compared to the conventional targeted approaches and that we can predict response to treatment more precisely and in more patients.”
Research reference:
Robbe, P., Ridout, K.E., Vavoulis, D.V. et al. Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features. Nat Genet (2022). https://doi.org/10.1038/s41588-022-01211-y
About the UK CLL Biobank
Funded by Blood Cancer UK since 2008, the UK CLL Biobank was established as a national resource to drive and facilitate translational research in CLL. Based at the University of Liverpool and overseen by a multi-stakeholder Governance Committee, the biobank contains samples from >2400 patients recruited into 12 national clinical trials and has supported research projects at laboratories around the UK. It was selected as a case study for collaborative working by the National Cancer Research Institute.