Genomic analysis of 37 patients with Sezary syndrome, has revealed mutations in genes that affect T-cell signaling and those that interfere with cell cycle checkpoints that govern cell division.
A key finding of the study by researchers from Baylor College of Medicine and the University of Texas MD Anderson Cancer Center and available online ahead of print in Nature Genetics (doi:10.1038/ng.3444), was evidence of activating mutations in the CCR4 and CARD11 genes in about one-third of the patients.
Already, patient studies are ongoing with experimental drugs that inhibit the CCR4 mutation, noted one of the corresponding authors, David Wheeler, PhD, Professor in the Human Genome Sequencing Center at Baylor. The studies are being carried out by Madeleine Duvic, MD of MD Anderson Cancer Center, the other corresponding author.
"These kinds of studies are taking us to the doorstep of personal genomics," Wheeler said in a news release. "We are finding particular treatment targets in some of these patients-targets for which we already have drugs or for which we can develop them."
The study's lead author, Linghua Wang, MD, PhD, Assistant Professor of Molecular and Human Genetics at Baylor, said the research is significant because it identifies genes that may be important in this rare cancer.
ZEB1, a gene essential for the differentiation of T-cells, was deleted in more than half the patients and two other immune system genes-IL32 and IL2RG-were overexpressed in nearly all cases. When the scientists analyzed two T-cell receptors (V[beta] and V[alpha]) and determined how they are expressed, they found that they were rearranged when the malignant T-cell clone expanded in one-third of patients.
Overall, the team concluded: "Our results demonstrate profound disruption of key signaling pathways in Sezary syndrome and suggest potential targets for new therapies."
Funding for the research came from National Human Genome Research Institute and the Cancer Prevention and Research Institute of Texas, the Drs. Martin and Dorothy Spatz Charitable Foundation, the Blanche Bender Professorship in Cancer Research, and the MD Anderson Cancer Center Core Grant.