Back
2025BIOMED007.pdf
Doctoral thesis

The genetics of classic Hodgkin lymphoma

  • 2025

PhD: Università della Svizzera italiana

Classic Hodgkin lymphoma
Circulating tumor DNA
Molecular markers
Whole-genome doubling
Chromosomal instability
Tumor microenvironment
Prognostic biomarkers
English Classic Hodgkin lymphoma (cHL) is a lymphoid malignancy characterized by rare malignant Hodgkin and Reed–Sternberg (HRS) cells embedded within a complex inflammatory microenvironment. Although cHL displays distinctive histological and clinical features, its genomic landscape remains incompletely understood, largely due to the scarcity of HRS cells in tumor biopsies. This thesis addresses this limitation by applying circulating tumor DNA (ctDNA) profiling to perform a comprehensive genetic characterization of cHL. Using deep targeted sequencing of ctDNA from treatment-naïve patients, somatic mutations and somatic copy number alterations (SCNAs) were detected in the majority of cases, with strong concordance to previously reported tumor-based genomic studies. Unsupervised clustering of genomic features revealed two biologically distinct molecular subtypes of cHL. One subtype exhibited a hypermutated profile enriched for mutational signatures associated with microsatellite instability (MSI) and activation-induced cytidine deaminase (AID) activity. The second subtype was characterized by a lower mutational burden but greater chromosomal instability, reflected by an increased SCNA load. A major finding of this study is the frequent occurrence of whole-genome doubling (WGD), observed in 24% of patients. WGD was strongly associated with CCNE1 gain and correlated with inferior progression-free survival, identifying it as an independent prognostic biomarker. These results provide molecular insight into the characteristic polyploid and multinucleated morphology of HRS cells and support a mechanistic role for cyclin E dysregulation in cHL pathogenesis. Characterization of the tumor microenvironment, based on gene expression profiling and immunohistochemical analyses, identified two dominant immune classes: one enriched for macrophage and stromal signatures, and another enriched for T-cell–related and immune checkpoint pathways. While these immune classes were not associated with genetic subtype or Epstein–Barr virus (EBV) status, they correlated with predicted neoantigen burden, suggesting that immune selection may contribute to tumor evolution in cHL. In summary, this work provides new insights into the molecular heterogeneity of cHL, highlights the prognostic relevance of whole-genome doubling, and demonstrates the potential of ctDNA profiling to support future precision oncology approaches in this disease.
Collections
Language
  • English
Classification
Medicine
License
License undefined
Open access status
green
Identifiers
Persistent URL
https://n2t.net/ark:/12658/srd1335006
Statistics
Document views: 0 File downloads:
  • 2025BIOMED007.pdf: 0