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DNA abnormalities discovered in chronic lymphocytic leukaemia (CLL) may help doctors predict whether an individual patient’s disease will progress rapidly or remain indolent for years, according to research published in the New England Journal of Medicine.
Using powerful “next-generation” DNA sequencing, researchers from Dana-Farber Cancer Institute and the Broad Institute (both USA) identified nine frequently mutated genes across 91 patients.
“We have identified a new cancer pathway – aberrant RNA splicing – that has been underappreciated,” explained co-author Catherine Wu, from Dana-Farber’s Cancer Vaccine Centre.
Researchers harnessed Illumina sequencing technology at the Broad Institute to sequence leukaemia and matched normal DNA samples from 91 patients with CLL, looking for frequently mutated genes in the tumours.
They sequenced the entire genome in three patient samples, and only the protein-coding genes, collectively termed the “exome,” in the other 88 patients.
The search turned up nine genes frequently mutated in the CLL samples, and these fell into five pathways regulating DNA damage repair, cell-cycle control, Notch signalling, inflammation, and RNA splicing/processing.
Two had previously been associated with CLL and cancer in general. Another two mutations – MYD88 and NOTCH1 – were implicated in leukaemia this year (2011).
The remaining five, now identified for the first time as culprits in CLL, are SF3B1, FBXW7, DDX3X, MAPK1, and ZMYM3.
The SF3B1 gene was the second most commonly mutated gene, being found abnormal in 14 of the 91 leukaemia DNA samples.
The gene’s full name is Splicing Factor 3b, subunit 1, and the protein it makes is part of the “spliceosome” – a collection of proteins that govern the splicing out of extraneous RNA molecules (“introns”) to create the RNA message (“exons”), or molecular recipe, from which the cell manufactures proteins for the body.
“Defects in splicing have not previously been implicated in the biology of CLL,” the researchers wrote.
The researchers checked to see whether CLL samples that contained the mutated genes also had specific deletions in chromosomes (the DNA structures that carry genes) previously known to signal a poor outlook in patients.
They found that, indeed, the SF3B1 gene was often found in tandem with a particular chromosomal abnormality, consistent with a more aggressive form of CLL.
However, independent of the presence of the chromosomal deletion, the study revealed that a mutated SF3B1 gene by itself was a red flag for an aggressive case of CLL; patients harbouring the mutant SF3B1 gene were more likely to need treatment sooner than individuals lacking the gene.
Wu said that that the gene alteration might serve as a biomarker. Since these patients have more aggressive disease, knowledge of the presence of the gene alteration might prompt physicians early on to consider alternatives to conventional chemotherapy, such as earlier use of stem cell transplants to quell the disease.
The researchers said the study findings show the value of large-scale genome searches in elucidating cancers. The numerous genetic flaws uncovered by the search could not only aid in the prediction of disease course, they said, but also offer clues to the biological underpinnings of CLL, paving the way for novel targeted treatments.
New England Journal of Medicine
