Issue: June 10, 2012
Perspective from Kanti Rai, MD
Source: Claus R. J Clin Oncol. 2012;doi:10.1200/JCO.2011.39.3090.
May 29, 2012
2 min read
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Prognostic biomarker for CLL identified

Issue: June 10, 2012
Perspective from Kanti Rai, MD
Source: Claus R. J Clin Oncol. 2012;doi:10.1200/JCO.2011.39.3090.
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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.”