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Comprehensive Sequencing IDs Genes Involved in Cutaneous T Cell Lymphoma Pathogenesis

NEW YORK (GenomeWeb) – Researchers from Yale University have used a comprehensive sequencing strategy involving whole-genome, transcriptome, and exome sequencing to identify genes involved in the pathogenesis of cutaneous T cell lymphoma. Their findings could have implications for new therapeutics.

Reporting in Nature Genetics this week, the team found mutations in 17 genes involved in T cell activation and apoptosis, chromatin remodeling, the nuclear factor kappa beta pathway, and DNA damage response.

The researchers studied 40 patients with stage IV disease, 37 of whom had been treated with extracorporeal photopheresis. For all patients, they sequenced the exomes of tumor and matched normal samples. They also performed RNA-seq on 11 patients and whole-genome sequencing on two individuals.

Exome sequencing uncovered a mean of 63 somatic SNVs and 27 copy number variants per sample. Whole-genome sequencing called 99 percent and 98 percent of the SNVs and CNVs, respectively, and the researchers also confirmed a select number of them by PCR and Sanger sequencing.

To narrow down their focus on genes involved in pathogenesis, the researchers looked for genes with recurrent SNVs that altered the same amino acid more often than would be expected by chance, which pointed to three genes: CD28, RHOA and PLCG1.

Next, they looked for genes with SNVs previously identified as recurrent, identifying BRAF and STAT5B. The team also looked for genes with an increased burden of protein altering SNVs, which highlighted TP53, DNMT3A, and FAS.

And finally, they looked for copy number alterations that occurred more often than expected by chance, which identified 29 recurrent focal deletions and seven recurrent focal amplifications, as well as four broad deletions and eight broad amplifications. Using gene localization data, the researchers narrowed down those CNVs to implicate seven genes — TP53, DNMT3A, FAS, NFKB2, ARID1A, ZEB1, and CDKN2A. Additional analyses identified five other genes related to the CNVS — TNFAIP3, ATM, CTCF, PRKCQ, and IRF4.

"We find frequent deletions and damaging SSNVs in chromatin-modifying genes," the authors wrote, including ARID1A, which was mutated in 62.5 percent of cases; CTCF, mutated in 12.5 percent of cases; and DNMT3A, mutated in 42.5 percent of cases.

In addition, five of the genes implicated in cutaneous T cell lymphoma also contribute to other T cell neoplasms, like peripheral T cell lymphoma, T cell large granular lymphocytic leukemia, and adult T cell lymphoma, "underscoring the importance of these genes for the malignant transformation of mature T cells," the authors wrote.

Some of the findings also have therapeutic implications. For instance, activating mutations in the nuclear factor kappa beta pathway suggest that bortezomib, which inhibits that pathway, may be useful. In addition, mutations to CD28 suggest that inhibitors of binding, like the CTLA-4-immunoglobulin, abatacept, which is used to treat some autoimmune diseases, should be tested. And finally, cutaneous T cell lymphoma has previously been shown to respond to histone deacetylase inhibitors, and the identification of frequent mutations to chromatin-modifying genes may now explain that sensitivity, the authors noted.