Genomic Alterations in Cutaneous T-Cell Lymphoma

Kenneth Y. Tsai, MD, PhD reviewing Choi J et al. Nat Genet 2015 Sep.

Mutations in genes involved in CTCL have implications for new therapeutic approaches.

Although many tumors have now been subjected to genomic profiling, cutaneous T-cell lymphoma (CTCL) has remained relatively unexplored, and currently no biomarkers have been identified to help determine therapy or outcome.

To address this issue, investigators performed a genomic-level study of CTCL mutations in 40 patients with stage IVA1–B disease and CTCL cells in the blood. Of these, 37 had undergone extracorporeal photopheresis. The mean time from disease diagnosis to CTCL sampling was 2.5 years.

A combination of exome sequencing and RNA sequencing confirmed that TP53 deletions or mutations were the most common alteration, with a mean of 63 total single nucleotide variants per tumor sample, dominated by UVB signature C→T mutations. In contrast to many other cancers, CTCL possesses a large number of complex chromosomal rearrangements, with tumor suppressor such as TP53 and CDKN2A preferentially removed by deletion. Other commonly inactivated genes included DNMT3A, ARID1A, and CTCF — all involved in gene regulation — and FAS, involved in controlling cell death in T-cells. In addition, genes implicated in other cancers were reported to be mutated in CTCL for the first time, including activating mutations in BRAF and STAT5B and a dominant negative mutation in RHOA. Mutations in CD28, necessary for full activation of T-cells, was a novel finding. These mutations confer hyperactive signaling in T-cells after stimulation with IL2.

Citation(s):

Choi J et al. Genomic landscape of cutaneous T cell lymphoma. Nat Genet 2015 Sep; 47:1011; [e-pub].