Whole-genome sequencing of Reed-Sternberg cells identifies outcome determinants in Hodgkin lymphoma

Abstract Classical Hodgkin lymphoma (cHL) is a B-cell-derived malignancy characterized by rare Hodgkin and Reed–Sternberg (HRS) cells within an extensive inflammatory microenvironment. Although most patients achieve durable remission with first-line therapy, a subset relapse or experience disease progression. We performed whole-genome sequencing (WGS) of purified HRS-cell pools isolated from diagnostic biopsies of 76 cHL patients using DEPArray™ technology. Somatic copy number variations (CNVs), structural variants (SVs), and COSMIC mutational signatures were correlated with clinical characteristics, treatment response, and progression-free survival (PFS). HRS genomes displayed marked chromosomal instability with recurrent CNVs. Several CNV peaks were associated with baseline features and treatment response, while 2p11.2 amplification and 11q25 and 2p13.2 deletions were linked to inferior PFS. Mutational spectra were dominated by SBS5, SBS8, SBS84, SBS9 and SBS1, with an inverse SBS5–SBS9 axis and an AID-like SBS9-high/SBS5-low profile enriched in nodular sclerosis cHL. SV patterns were largely represented by SV2, with specific signatures associated with disease stage and treatment-related toxicity. TRACER-HL, integrating a Genomic Instability Score with relapse-associated CNVs, achieved an AUC of 0.81 and an NPV of 95%. These findings identify candidate genomic features associated with outcome and support further evaluation of genomically informed risk stratification strategies in cHL.

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Publication Details

Journal
Scientific Reports
Published
2026-09-04
DOI
https://doi.org/10.1038/s41598-026-69457-8
Primary Topic
Lymphoma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
0.00

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article

Whole-genome sequencing of Reed-Sternberg cells identifies outcome determinants in Hodgkin lymphoma

Javier Pascual, María Casanova-Espinosa, Silvia Sequero-Lopez, Jesús Velasco-Suelto et al.
Scientific Reports
Lymphoma Diagnosis and Treatment
article

Whole-genome sequencing of Reed-Sternberg cells identifies outcome determinants in Hodgkin lymphoma

Javier Pascual, María Casanova-Espinosa, Silvia Sequero-Lopez, Jesús Velasco-Suelto, Luis de la Cruz‐Merino, Marcos Melián-Sosa, Rocío Lavado-Valenzuela, Mariano Provencio-Pulla, Emilio Alba, Martina Álvarez, Antonio Rueda‐Domínguez, Esperanza López-López, Francisco R. García-Arroyo, Daniel Prieto, Laura Gálvez, Iñaki Comino‐Méndez, Antonio Cantarero-Cuenca, Natividad Martínez-Banaclocha, Natalia Palazón-Carrión
article en

Abstract

Abstract Classical Hodgkin lymphoma (cHL) is a B-cell-derived malignancy characterized by rare Hodgkin and Reed–Sternberg (HRS) cells within an extensive inflammatory microenvironment. Although most patients achieve durable remission with first-line therapy, a subset relapse or experience disease progression. We performed whole-genome sequencing (WGS) of purified HRS-cell pools isolated from diagnostic biopsies of 76 cHL patients using DEPArray™ technology. Somatic copy number variations (CNVs), structural variants (SVs), and COSMIC mutational signatures were correlated with clinical characteristics, treatment response, and progression-free survival (PFS). HRS genomes displayed marked chromosomal instability with recurrent CNVs. Several CNV peaks were associated with baseline features and treatment response, while 2p11.2 amplification and 11q25 and 2p13.2 deletions were linked to inferior PFS. Mutational spectra were dominated by SBS5, SBS8, SBS84, SBS9 and SBS1, with an inverse SBS5–SBS9 axis and an AID-like SBS9-high/SBS5-low profile enriched in nodular sclerosis cHL. SV patterns were largely represented by SV2, with specific signatures associated with disease stage and treatment-related toxicity. TRACER-HL, integrating a Genomic Instability Score with relapse-associated CNVs, achieved an AUC of 0.81 and an NPV of 95%. These findings identify candidate genomic features associated with outcome and support further evaluation of genomically informed risk stratification strategies in cHL.

Scientific Reports
Hospital Costa del Sol (ES), Fundación Instituto Valenciano de Oncología (ES), Hospital Universitario Puerta de Hierro Majadahonda (ES), Instituto de Investigación Biosanitaria de Granada (ES), Instituto de Biomedicina de Sevilla (ES), Hospital General Universitario de Alicante Doctor Balmis (ES), Centro de Investigación del Cáncer (ES), Spanish Head & Neck Cancer Cooperative Group (ES), Hospital Clínico Universitario Virgen de la Victoria (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Complejo Hospitalario de Pontevedra (ES), Instituto de Investigación Biomédica de Málaga (ES), Universidad de Sevilla (ES), Universidad de Málaga (ES)
Universidad de Málaga, Agencia Estatal de Investigación
Openalex Percentile: Top 40%
Lymphoma Diagnosis and Treatment
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