Molecular markers help reveal nature of chronic lymphocytic leukaemia
Tumour cell subnetworks of interacting proteins predict cancer progression
- Date : 06 Aug 2012
- Topic : Haematologic malignancies
Using a new assay method to study tumour cells, researchers at the University of California, San Diego School of Medicine and UC San Diego Moores Cancer Centre have found evidence of clonal evolution in chronic lymphocytic leukaemia (CLL). The assay method distinguishes features of leukaemia cells that indicate whether the disease will be aggressive or indolent in nature, a key factor in when and how patients are treated. The findings are published in the July 26, 2012 First Edition online issue of Blood.
The progression of CLL is highly variable, dependent upon the rate and effects of accumulating monoclonal B cells in the blood, marrow, and lymphoid tissues. Some patients are symptom-free for years and do not require treatment, which involves the use of drugs that can cause significant side effects and are not curative. In other patients, however, CLL is relatively aggressive and demands therapeutic intervention soon after diagnosis.
This study shows that there may not be a sharp dividing line between the more aggressive and less aggressive forms of CLL, according to Dr Thomas Kipps, Evelyn and Edwin Tasch Chair in Cancer Research and senior author of the study. Instead, it seems that over time the leukaemia cells of patients with indolent disease begin to use genes similar to those that are generally used by CLL cells of patients with aggressive disease. In other words, prior to requiring therapy, the patterns of genes expressed by CLL cells appear to converge, regardless of whether or not the patient had aggressive versus indolent disease at diagnosis.
Existing markers for aggressive or indolent disease are mostly fixed and have declining predictive value the longer the patient is from his or her initial diagnosis. When the blood sample is collected, these markers can not reliably predict whether a CLL patient will need therapy soon, particularly when the patient has had the diagnosis of CLL for many years.
A study of thousands of genes
Kipps and colleagues studied thousands of genes, particularly those that code for proteins, in a group of 130 CLL patients with different risks for disease progression. They identified 38 prognostic subnetworks of interacting genes and proteins that, at the time of sample collection, indicate the relative aggressiveness of the disease and predict when the patient will require therapy. They confirmed their work using the method on two other, smaller CLL patient cohorts in Germany and Italy.
The subnetworks offer greater predictive value because they are based not on expression levels of individual genes or proteins, but on how they dynamically interact and change over time, influencing the course of the CLL and patient symptoms. While the subnetworks abound in data, their complexity actually makes them easy to interpret and understand this issue. If researchers can find an interconnected family where most genes or proteins are expressed at higher levels, it will be more likely that these genes and proteins have functional significance.
The findings from this study help define how CLL – and perhaps other cancers – evolve over time, becoming more aggressive. The study may alter how scientists think about CLL and how clinicians treat the disease: whether it is better to wait for later stages of the disease when tumour cells are more fragile and easier to kill, or treat early-stage indolent tumour cells aggressively, when they are fewer in number but harder to find and more resistant to therapy.
Funding for this research came, in part, from the USA National Science Foundation grant NSF425926, National Institutes of Health grant ES14811, Pfizer and Agilent laboratories. Additional support came from NIH grants for the CLL Research Consortium (P01-CA081534), a Merit Award to Kipps and trainee research award to Chuang from the American Society of Haematology.
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