Characterising the genomic landscape of two clinical risk groups in CD30+ T-cell lymphoproliferative disorders with cutaneous involvement: a multi-institutional retrospective study

BACKGROUND: CD30+ T cell lymphoproliferative disorders (CD30+ T LPD) with cutaneous involvement comprise a diverse group of neoplasms with variable clinical outcomes. The molecular mechanisms underlying the prognostic differences in these diseases are poorly understood. METHODS: In this multi-institutional retrospective study, 79 patients with CD30+ T LPD were evaluated. DNA and RNA sequencing were performed on skin biopsy samples to characterise molecular features. Patients were assigned to low- and high-risk groups based on treatment recommendations in clinical records. Pathogenic pathways, immune microenvironments, transcriptomic profiles, driver mutations, and mutation signatures were compared between the risk groups. FINDINGS: Across risk groups, there was high mutational recurrence in genes involved in epigenetic regulation and intracellular signalling pathways. Mutational signature analysis revealed a shared prevalence of 5-methylcytosine deamination, UV exposure, defective mismatch repair, and POLE-associated proofreading deficiency. In contrast, gene set enrichment analysis showed that the high-risk group was enriched in pathways governing cell cycle progression, DNA damage response, and immune activation compared to the low-risk group. Furthermore, immune microenvironment deconvolution showed a higher abundance of resting dendritic cells in the low-risk group. Finally, high-risk patients exhibited significant overexpression of clinically relevant proteins, highlighting potential alternative treatment approaches for this population. INTERPRETATION: Mutation analyses suggest diverse pathogenesis in these diseases. The high-risk and low-risk groups diverge in gene expression profiles and immune microenvironment, suggesting that these biological differences hold prognostic significance. Molecularly informed therapeutic strategies should be investigated prospectively through clinical trials. FUNDING: This work was supported by developmental funds of the Duke Cancer Institute as part of the P30 Cancer Center Support Grant. Data generation was supported in an unrestricted fashion by the NIH, Data Driven Bioscience, Amazon and Google. SSD was supported by the Wellcome Trust Foundation and the NIH.

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Journal
EBioMedicine
Published
2026-10-27
DOI
https://doi.org/10.1016/j.ebiom.2026.106532
Primary Topic
Cutaneous lymphoproliferative disorders research
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article
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article

Characterising the genomic landscape of two clinical risk groups in CD30+ T-cell lymphoproliferative disorders with cutaneous involvement: a multi-institutional retrospective study

Payal Sojitra, Dennis Owusu, Alexandra E. Kovach, Ayush Batra et al.
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EBioMedicine
Cutaneous lymphoproliferative disorders research
article

Characterising the genomic landscape of two clinical risk groups in CD30+ T-cell lymphoproliferative disorders with cutaneous involvement: a multi-institutional retrospective study

Payal Sojitra, Dennis Owusu, Alexandra E. Kovach, Ayush Batra, Devang Thakkar, Matthew Stuart McKinney, Chad M. McCall, Eric D. Hsi, Clay Parker, Lanie E. Happ, Elizabeth Thacker, Kikkeri N. Naresh, Caroline Roth, Yuri D. Fedoriw, Magdalena Czader, Sarah Lynn Ondrejka, Sirpa Leppä, Jennifer R. Shingleton, Rohit Gulati, Andrew M. Evens, Veronica S. Russell, David L. Jaye, Raju K. Pillai, Emily Ferguson Mason, Amir Behdad, J. Wang, Cassandra Love, Carlos Galvez, Jean Louise Koff, Sandeep S. Davé, Maria Angelica Selim, Andrew Evans, Leonardo P. A. Biral, Shelby Bettoney, Catalina Amador, Chee Leong Cheng
article en

Abstract

BACKGROUND: CD30+ T cell lymphoproliferative disorders (CD30+ T LPD) with cutaneous involvement comprise a diverse group of neoplasms with variable clinical outcomes. The molecular mechanisms underlying the prognostic differences in these diseases are poorly understood. METHODS: In this multi-institutional retrospective study, 79 patients with CD30+ T LPD were evaluated. DNA and RNA sequencing were performed on skin biopsy samples to characterise molecular features. Patients were assigned to low- and high-risk groups based on treatment recommendations in clinical records. Pathogenic pathways, immune microenvironments, transcriptomic profiles, driver mutations, and mutation signatures were compared between the risk groups. FINDINGS: Across risk groups, there was high mutational recurrence in genes involved in epigenetic regulation and intracellular signalling pathways. Mutational signature analysis revealed a shared prevalence of 5-methylcytosine deamination, UV exposure, defective mismatch repair, and POLE-associated proofreading deficiency. In contrast, gene set enrichment analysis showed that the high-risk group was enriched in pathways governing cell cycle progression, DNA damage response, and immune activation compared to the low-risk group. Furthermore, immune microenvironment deconvolution showed a higher abundance of resting dendritic cells in the low-risk group. Finally, high-risk patients exhibited significant overexpression of clinically relevant proteins, highlighting potential alternative treatment approaches for this population. INTERPRETATION: Mutation analyses suggest diverse pathogenesis in these diseases. The high-risk and low-risk groups diverge in gene expression profiles and immune microenvironment, suggesting that these biological differences hold prognostic significance. Molecularly informed therapeutic strategies should be investigated prospectively through clinical trials. FUNDING: This work was supported by developmental funds of the Duke Cancer Institute as part of the P30 Cancer Center Support Grant. Data generation was supported in an unrestricted fashion by the NIH, Data Driven Bioscience, Amazon and Google. SSD was supported by the Wellcome Trust Foundation and the NIH.

EBioMedicineVol. 133
Rutgers, The State University of New Jersey (US), University of North Carolina at Chapel Hill (US), University of Nebraska at Omaha (US), City Of Hope National Medical Center (US), Cleveland Clinic (US), Mayo Clinic (US), University of Helsinki (FI), Emory University (US), Duke University (US), Vanderbilt University (US), Singapore General Hospital (SG), Helsinki University Hospital (FI), University of Rochester Medical Center (US), University of Illinois Chicago (US), Fred Hutch Cancer Center (US), Cleveland Clinic Florida (US), City of Hope (US), Indiana University Indianapolis (US), Winship Cancer Institute (US), Rutgers Cancer Institute (US), University of Rochester (US)
Google, National Institutes of Health, Duke Cancer Institute
Good health and well-being
Openalex Percentile: Top 10%
Cutaneous lymphoproliferative disorders research
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