A new genome-wide analysis of chronic lymphocytic leukaemia (CLL) has defined five new sub-groups of the disease. These genomic subgroups provide a better estimation of prognosis compared to single-gene analysis, according to researchers.
The study, led by scientists at the University of Oxford, is the largest and most comprehensive analysis of the entire genomic landscape of CLL and not only defines these five subgroups but also associates these with clinical outcomes.
Writing in the latest edition of Nature Genetics, the authors say this new method for stratifying patients could lead to more personalised patient care.
Study leader Professor Anna Schuh, from the Department of Oncology at Oxford, 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?”
This study is the first to analyse all the relevant changes in DNA across the entire cancer genome, rather than targeted regions, as well as the first to classify patients with cancer and link these subgroups to clinical outcomes.
The team analysed the entire genome sequences of samples from 485 CLL patients. These patients were enrolled in clinical trials led by the Universities of Liverpool and Leeds, provided samples for the UK CLL Biobank, and consented for their samples to be used in the 100,000 Genomes project run by Genomics England.
The team compared whole genome sequencing data from cancer and healthy tissue from the participants. They mapped 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.
The team’s analysis also identified 148 new potential genetic drivers of CLL. The authors say further research may uncover new mechanisms in CLL initiation and progression.
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: “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.”
Professor Andrew Pettitt, founding director of the UK CLL Biobank and chief investigator for two of the contributing clinical trials, added: “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.”
Robbe P, Ridout KE, Vavoulis DV, Dréau H, Kinnersley B, Denny N, Chubb D, Appleby N, Cutts A, Cornish AJ, Lopez-Pascua L, Clifford R, Burns A, Stamatopoulos B, Cabes M, Alsolami R, Antoniou P, Oates M, Cavalieri D, Genomics England Research Consortium, CLL pilot consortium, Gibson J, Prabhu AV, Schwessinger R, Jennings D, James T, Maheswari U, Duran-Ferrer M, Carninci P, Knight SJL, Månsson R, Hughes J, Davies J, Ross M, Bentley S, Strefford JC, Devereux S, Pettitt AR, Hillmen P, Caulfield MJ, Houlston RS, Martín-Subero JI & Schuh A. (2022) “Whole genome landscape of chronic lymphocytic leukaemia and its association with clinical outcome.” Nature Genetics, doi: 10.1038/s41588-022-01211-y
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