Recurrent Oncogenic JAK and STAT Alterations in Cutaneous CD30-Positive Lymphoproliferative Disorders

Area of Science:

• Oncology
• Dermatology
• Molecular Biology
• Genetics

Background:

• Cutaneous CD30-positive lymphoproliferative disorders (LPD) include lymphomatoid papulosis (LyP) and cutaneous anaplastic large T-cell lymphoma (cALCL).
• The molecular pathogenesis of LyP and cALCL remains largely unknown.
• LyP is characterized by benign lymphoproliferation with spontaneous regression, while cALCL presents as skin tumors with low metastatic potential.

Purpose of the Study:

• To elucidate the molecular pathogenesis of LyP and cALCL.
• To identify common genetic aberrations driving lymphomagenesis in LPD.
• To explore potential personalized treatment strategies based on molecular findings.

Main Methods:

• Comprehensive next-generation sequencing was performed on a cohort of 12 patients with LPD.
• Targeted sequencing with hybrid capture DNA library preparation was used, considering the low tumor cell content in LyP.
• Anchored multiplex PCR enrichment was employed for the identification of fusion transcripts.

Main Results:

• Genetic events implying a constitutively activated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway were detected in 50% of LPD cases.
• Molecular aberrations included pathogenic STAT mutations or oncogenic fusion transcripts involving JAK effector domains.
• Previously unreported genetic aberrations were identified in LyP, suggesting shared driving mechanisms with cALCL.

Conclusions:

• Convergent aberrations within the JAK-STAT pathway suggest common molecular drivers for lymphomagenesis in LyP and cALCL.
• The identification of these oncogenic alterations provides a basis for developing novel, personalized treatment strategies for LPD.
• Understanding the molecular pathogenesis is crucial for advancing therapeutic options in cutaneous lymphomas.