Mycosis fungoides (MF) is the most common cutaneous T‐cell lymphoma (CTCL).,Causative genetic alterations in MF are unknown.,The low recurrence of pathogenic small‐scale mutations (ie, nucleotide substitutions, indels) in the disease, calls for the study of additional aspects of MF genetics.,Here, we investigated structural genomic alterations in tumor‐stage MF by integrating whole‐genome sequencing and RNA‐sequencing.,Multiple genes with roles in cell physiology (n = 113) and metabolism (n = 92) were found to be impacted by genomic rearrangements, including 47 genes currently implicated in cancer.,Fusion transcripts involving genes of interest such as DOT1L, KDM6A, LIFR, TP53, and TP63 were also observed.,Additionally, we identified recurrent deletions of genes involved in cell cycle control, chromatin regulation, the JAK‐STAT pathway, and the PI‐3‐K pathway.,Remarkably, many of these deletions result from genomic rearrangements.,Deletion of tumor suppressors HNRNPK and SOCS1 were the most frequent genetic alterations in MF after deletion of CDKN2A.,Notably, SOCS1 deletion could be detected in early‐stage MF.,In agreement with the observed genomic alterations, transcriptome analysis revealed up‐regulation of the cell cycle, JAK‐STAT, PI‐3‐K and developmental pathways.,Our results position inactivation of HNRNPK and SOCS1 as potential driver events in MF development.
Histopathology alone cannot predict outcome of patients with CD30+ primary cutaneous lymphoproliferative disorders (CD30CLPD) and early mycosis fungoides (MF).,To test the hypothesis that serum cytokines/cytokine receptors provide prognostic information in these disorders, we measured soluble CD30 (sCD30), sCD25, and selected cytokines in cell cultures and sera of 116 patients with CD30CLPD and 96 patients with early MF followed up to 20 years.,Significant positive correlation was found between sCD30 levels and sCD25, CD40L, IL-6, and IL-8, suggesting CD30+ neoplastic cells secrete these cytokines, but not Th2 cytokines.,In vitro studies confirmed sCD30, sCD25, IL-6 and IL-8 are secreted by CD30CLPD-derived cell lines.,CD30CLPD patients with above normal sCD30 and sCD25 had worse overall and disease-related survivals, but only sCD30 retained significance in Cox models that included advanced age.,High sCD30 also identified patients with worse survival in early MF.,Increased IL-6 and IL-8 correlated with poor disease-related survival in CD30CLPD patients, We conclude that: (1) neoplastic cells of some CD30CLPD patients do not resemble Th2 cells, (2) high serum sCD30, sCD25, IL-6, and perhaps IL-8 levels may provide prognostic information useful for patient management.