JAK and STAT alterations in CD30 positive LPD

The group of cutaneous CD30-positive lymphoproliferative disorders (LPD) comprises two different entities, namely lymphomatoid papulosis (LyP) and cutaneous anaplastic large T-cell lymphoma (cALCL). LyP constitutes a benign lymphoproliferation with spontaneously regressing papules, whereas cALCL presents with solitary or multiple skin tumors with a low propensity to disseminate.
To elucidate the hitherto largely unknown molecular pathogenesis of these entities, we performed comprehensive next generation sequencing in a well-characterized cohort of 12 patients. Considering the low tumor cell content of LyP, we applied targeted sequencing technologies with a hybrid capture-based DNA library preparation approach and for the identification of fusion transcripts an anchored multiplex PCR enrichment kit.
As the major finding, we detected in 50% of LPD genetic events that imply a constitutively activated JAK-STAT pathway in these entities. The identified molecular aberrations comprised either pathogenic STAT mutations or oncogenic fusion transcripts comprising effector domains of JAK. With respect to LyP, we are the first to demonstrate such genetic aberrations in this specific entity, respectively.
The detection of these convergent aberrations within the JAK-STAT signaling pathway deciphers common potential driving mechanisms of lymphomagenesis within LPD being shared between LyP and cALCL. Moreover, the presence of these oncogenic alterations paves the way to develop novel personalized treatment strategies.EGA study EGAS00001004181