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27-12-2011 | Genetics | Article

Newly identified genes predict patient prognosis in chronic lymphocytic leukemia


Free abstract

MedWire News: Researchers have identified five new genes with unestablished roles in the development of chronic lymphocytic leukemia, which could help predict patient prognosis.

The findings are of clinical importance, given that the genetic basis of chronic lymphocytic leukemia, a common and clinically heterogenous leukemia occurring in adults, is poorly understood.

"Our study defines the landscape of somatic mutations in chronic lymphocytic leukemia and highlights pre-mRNA splicing as a critical cellular process contributing to chronic lymphocytic leukemia," say Catherine Wu (Harvard Institute of Medicine, Boston, Massachusetts, USA) and colleagues.

To characterize the spectrum of somatic mutations in chronic lymphocytic leukemia, the researchers obtained DNA samples from leukemia cells in 91 patients with the disease and performed parallel sequencing of 88 whole exomes and whole genomes, together with sequencing of matched germline DNA.

In total, nine genes with mutations at significant frequencies were identified, including four with established roles in chronic lymphocytic leukemia (TP53 in 15% of patients, ATM in 9%, MYD88 in 10%, and NOTCH1 in 4%) and five with unestablished roles (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X).

These mutated genes fell into five pathways regulating DNA damage repair, cell-cycle control, Notch signaling, inflammation, and RNA splicing/processing.

In an associated press release, Wu said that mutations in one of new genes, SF3B1, interferes with gene splicing of RNA message that form a genetic template the cell uses to build a specified protein: "We have identified a new cancer pathway - aberrant RNA splicing - that has been underappreciated."

The researchers then investigated whether patient samples that contained the mutated genes also had specific deletions in chromosomes previously associated with poor prognosis. Indeed, SF3B1 occurred in 15% of patients and was often found in tandem with deletions in chromosome 11q.

"Our results suggest that SF3B1 mutations lead to mistakes in the splicing of these and other specific transcripts that affect the pathogenesis of chronic lymphocytic leukemia," write the authors in the New England Journal of Medicine.

Finally, the team found that a mutated SF3B1 gene was a marker for aggressive chronic lymphocytic leukemia, as patients harboring the mutant SF3B1 gene were significantly more likely to require treatment sooner than individuals lacking the gene. Thus, this gene alteration could serve as a potential biomarker for aggressive disease.

By Ingrid Grasmo

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