This article is more than 5 years old. Information may no longer be current.
Prognostic biomarker for CLL identified
Click Here to Manage Email Alerts
Researchers used quantitative DNA methylation analysis to discover a single CpG dinucleotide that plays an important role for ZAP-70 expression, a biomarker used to predict prognosis in patients with chronic lymphocytic leukemia.
ZAP-70, a zeta-chain–associated protein, was originally thought to be a valuable prognostic factor for patients with CLL, according to background information in the article. However, its practical application in laboratories has been problematic, preventing widespread use.
In order to increase the utility of ZAP-70, researchers examined the ZAP-70 regulatory region using DNA methylation profiling. They hypothesized that this would help to identify sites that were important for transcriptional control.
They collected 247 samples from patients with CLL that were used in 4 independent clinical studies. The researchers were able to identify a methylation site within the 5’ regulatory region of ZAP-70. This site had large variability in CLL samples but was universally methylated in normal B cell samples.
More specifically, analyses found that a single CpG dinucleotide and its neighboring nucleotides were highly important to the Zap-70 transcriptional process, according to the researchers.
This discovery “serves as a highly favorable biomarker in patients at diagnosis and at time of first treatment,” the researchers wrote. “In this context, narrowing to a single CpG unit dramatically simplifies analysis and allows for the potential of this test to be broadly applied across laboratories.”
In an accompanying editorial, Jean-Pierre Issa, MD, director of the Fels Institute for Cancer Research and Molecular Biology at Temple University, said ZAP-70 is one of potentially thousands of genes variably methylated in cancer.
“Arguably, it may one day be less important to see cancer (pathology and scans) and more important to know what we cannot see — the cancer genome,” Issa wrote. “It is also increasingly likely that DNA sequencing will not be sufficient for this purpose and that comprehensive DNA methylation analysis will be equally important in determining outcomes and selecting patients for various therapies.”
Perspective
Back to Top
Kanti Rai, MD
In our quest for identifying prognostic markers in CLL, which are easily performable laboratory tests with methodology or techniques that are reproducible and can be standardized, the paper by Claus and colleagues presents an extremely promising new candidate marker. This is essentially a sophisticated version of another marker, ZAP-70, which already has been widely recognized but has been known to have a rather checkered record as far as reproducibility of methodology and inter-lab standardizability are concerned.
By a meticulously performed study among some of the leading institutions in Germany, the UK and the United States, these investigators — using high-resolution quantitative DNA methylation analysis — succeeded in discovering a small area CpG Unit 1 on ZAP-70, whose level of methylation was accurately detectable, and there was a clear-cut and close relationship between the degree of methylation and the patient's prognosis. High methylation was associated with good prognosis (and ZAP-70 negativity) while low methylation was associated with worse prognosis (and ZAP-70 positivity ). This work was performed in a highly disciplined manner. However, it will take time to find out if this work is duplicated by other researchers — and confirmed and reconfirmed — before we can determine its real usefulness and practicality in incorporating it in the clinic. Nevertheless, this is a highly thought-provoking and interesting finding and, to a large extent, explains the role of ZAP-70 in pathophysiology of CLL.
Collapse
Click Here to Manage Email Alerts