Friday, May 9, 2025
5/9/2025
Genomic Analysis of Cutaneous CD30+ Lymphoproliferative Disorders - PROJECT SUMMARY/ABSTRACT ALK-negative systemic anaplastic large cell lymphoma (sALCL) is an aggressive disease requiring intense chemotherapy. The primary cutaneous CD30+ lymphoproliferative disorders (CD30+LPD) of lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (pcALCL) are indolent, less well recognized entities. Distinguishing sALCL, LyP, and pcALCL histologically is difficult; this often leads to misdiagnosis and overaggressive treatment of patients with CD30+ LPD. The 5-year survival rate is 92% for LyP and 90% for pcALCL when managed with standard of care, non-targeted, skin-directed therapies. The 5-year survival rate is 15-45% for ALK-negative sALCL and requires aggressive treatment with potentially fatal side- effects. Thus, there is a critical clinical need to differentiate the LyP and pcALCL CD30+ LPD from ALK- negative sALCL since each has distinct prognoses and requires different treatment plans. In the era of personalized medicine, physicians and scientists are looking to characterize tumors molecularly with the goal of developing markers for diagnosis and directing therapy at the underlying mutation(s). Molecular characterization is incomplete for CD30+ LPD. The clinical application of whole genome sequencing (WGS), whole exome sequencing (WES) and RNA sequencing (RNA-seq) will help differentiate among these entities. Through upstream analysis of genomic variability and pathway changes by WGS and WES integrated with RNA- seq to identify expressed mutations, we anticipate that completion of the proposed research will yield molecular signatures of LyP, pcALCL, and sALCL. This will change the current paradigm of relying solely on clinical pathologic correlation by a few experts at large academic centers, which delays achievement of the correct diagnosis beyond the point of treatment selection. However, a significant barrier is obtaining a statistically significant number of specimens to complete a meaningful analysis, since CD30+ LPD are rare entities. To overcome this obstacle, City of Hope has already established a consortium of five tertiary referral centers to contribute not only tissue but also clinical information. The consortium is unique in that it leverages multiple experienced investigators in the clinical, pathologic, and translational areas of lymphoma research who analyze the largest group of specimens to date. By facilitating more accurate diagnosis of LyP and pcALCL, the proposed studies will potentially help prevent over-treatment of patients with CD30+ LPD with chemotherapy, thus eliminating the unnecessary side-effects of chemotherapy, including shortened overall survival due to treatment.
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