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Recurrent Mutations Point to Signaling Processes Behind Some Cutaneous T Cell Lymphoma Cases

NEW YORK (GenomeWeb) – In Nature Genetics, researchers from Stanford University, Washington University in St. Louis, and the University of Pennsylvania outlined findings from a study aimed at uncovering recurrent alterations in two forms of cutaneous T cell lymphoma (CTCLs): mycosis fungoides and Sézary syndrome.

The team narrowed in on nearly 500 mutation-prone genes through exome sequencing on matched tumor and normal samples from 11 individuals affected by one of the cutaneous T cell lymphoma conditions.

When they sequenced these genes in another 91 tumor samples or CTCL cell lines, the researchers uncovered recurrent mutations in cancer genes described in the past as well as new apparent culprits such as TNFRSF1B, a gene that codes for a T cell signaling pathway regulator protein called TNFR2.

Indeed, glitches affecting either TNFR2 or related signaling pathways such as the NF-kappa-B pathway turned up in more than one-third of the cutaneous T cell lymphoma cases considered, suggesting a subset of individuals with these conditions might benefit from targeted treatments aimed at staunching NF-kappa-B pathway activity.

While the team's cell line experiments support that notion, additional work is needed to determine which patients, if any, would benefit from therapies that include such inhibitors, the researchers said.

"Future studies are needed to investigate the efficacy of targeted agents in patients with mycosis fungoides and Sézary syndrome prospectively selected on the basis of their genomic profiles," they wrote.

Most CTCL cases are classified as either mycosis fungoides or Sézary syndrome, the study's authors explained. But the blood cell malignancy can manifest itself in different ways, sometimes appearing first in the peripheral blood and other times occurring in an affected individual's skin.

In an effort to better understand mycosis fungoides or Sézary syndrome and perhaps come up with targeted treatment options, the team started by using the Illumina HiSeq to do exome sequencing on matched normal and tumor samples from 11 individuals affected by one of the conditions.

Based on alterations identified in these exomes, together with existing information on potential contributors to T cell malignancy, the researchers then selected 494 genes for targeted deep sequencing in 91 patient samples or cell lines. They also searched for chromosomal abnormalities using a fusion-finding bioinformatics method known as FACTERA.

Along with frequent mutations in well-known cancer contributors such as TP53, MLL3, KRAS, and PLCG1, one particular codon of the TNFRSF1B gene was prone to point mutations or gains in the tumor samples, they noted.

The team decided to delve into the TNFRSF1B alterations further, given the resulting protein's expression in mature T cells and its apparent role in T cell signaling, survival, and proliferation — processes that seem to be carried out with the help of non-canonical signaling by NF-kappa-B and other members of that pathway.

Somatic mutations tended to turn up in genes from the NF-kappa-B pathway itself and in components of the PI3-kinase signaling pathway, which can also impact T cell function, the researchers reported. And roughly 11 percent of individuals tested had structural variants falling in or around genes from pathways known to impact T cell proliferation or survival.

Many of these chromosomal abnormalities appeared to occur in tumors lacking glitches in the TNFR2 coding gene, they noted, suggesting these mutations may be mutually exclusive.

In cases where tumor samples contained digital droplet PCR-confirmed copy number gains affecting TNFRSF1B, meanwhile, the team saw higher-than-usual levels of the TNFR2 protein.

And at least one of the recurrent mutations detected in TNFRSF1B was linked to juiced-up NF-kappa-B signaling in Jurkat cell lines — activity that could be stanched with proteasome inhibiting compounds that's been tested in CTCL cases with enhanced NF-kappa-B activity in the past.