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2026BIOMED001.pdf
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17/03/2028
Doctoral thesis

Integrative molecular and gene expression profiling to identify high-risk follicular lymphoma

  • 2026

PhD: Università della Svizzera italiana

Follicular lymphoma
Prognostication
Molecular profiling
Genetics
Gene expression profiling
Transcriptomics
English Follicular lymphoma (FL) is a biologically and clinically heterogeneous B-cell malignancy classically defined by the t(14;18) translocation (BCL2-R). Recent classifications have broadened this landscape to include entities such as duodenal-type FL, pediatric-type FL, and primary cutaneous follicle center lymphoma (PCFCL), each with distinct clinical and molecular features. However, how genomic and microenvironmental traits delineate clinically meaningful FL subsets—particularly those at risk of early progression—remains incompletely understood, motivating this study amid the increasing complexity of FL taxonomy. In this study, we characterized 415 patients using targeted deep sequencing (mutations and somatic copy number abnormalities) and HTG-based gene expression profiling. Unsupervised clustering resolved three major genetic subtypes: a BCL2-Rneg-like group enriched for t(14;18)-negative FL and JAK/STAT pathway mutations; a Chromosomal unstable group defined by extensive copy-number aberrations and strong adverse prognostic associations; and a BCL2-Rpos-like group dominated by t(14;18)-positive FL with an aberrant somatic hypermutation footprint. Transcriptomic analysis identified two B-cell differentiation states – germinal center B-like and memory B cell-like – the latter overrepresented in grade 3B and Chromosomal unstable FL and associated with inferior outcomes. Gene set variation analysis further distinguished three microenvironmental programs: a stromal/macrophage-rich subtype enriched in grade 3B FL, PCFCL, and Chromosomal unstable FL; a B-cell/proliferative subtype enriched in BCL2-Rneg-negative FL and high-risk expression profiles, and a T/NK-cell–enriched subtype associated with BCL2-Rpos-positive FL and immune-high-risk signatures. Together, these data refine the molecular taxonomy of FL by showing that genetic architecture and microenvironmental programs provide complementary, clinically relevant layers of disease heterogeneity. While genetic subtypes capture the foundational biology of FL, copy-number burden and transcriptional states more closely align with clinical aggressiveness, underscoring the need to integrate these features into future prognostic models and therapeutic stratification frameworks.
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  • English
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Medicine
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green
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https://n2t.net/ark:/12658/srd1335007
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