Targeted deep sequencing of mycosis fungoides reveals intracellular signaling pathways associated with aggressiveness and large cell transformation

Abstract

Introduction: Large‐cell transformation (LCT) of mycosis fungoides (MF) has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis. Its molecular pathogenesis has not been elucidated yet. Materials and Methods: In order to address molecular mechanisms of LCT, we performed hybrid capture panel‐based sequencing of skin biopsies from 10 patients suffering from MF with LCT versus 17 patients without LCT including follow‐up biopsies during clinical course, respectively (51 samples in total). The analyzed patients were at-tributed to three different groups based on the presence of LCT and clinical behavior. Results: While indolent MF cases without LCT did not show pathogenic driver mutations, a high rate of oncogenic alterations was detected in patients with LCT and aggressive clinical courses. Various genes of different oncogenic signaling pathways, including the MAPK and JAK‐STAT signaling pathways, as well as epigenetic modifiers were affected. A high inter‐individual and distinctive intra‐individual mutation diversity was observed. Oncogenic RAS mutations were exclusively detected in patients with LCT. Conclusion: Our data demonstrate that LCT transition of MF is associated with increased frequency of somatic mutations in cancer‐associated genes. In particular, the activation of RAS sig-naling—together with epigenetic dysregulation—may crucially contribute to the molecular patho-genesis of the LCT phenotype, thus conveying its adverse clinical behavior.