Novel genetic insights: follicular lymphoma subtypes and ASXL1-related disease

The Swiss Cancer Institute’s Young Oncology Academy (YOA) is a support and mentorship program for young oncologists. Academy participants are supervised by a renowned faculty member for almost a year and are required to write a review paper on a topic of interest. Today we present Dr. med. Annaïse Julie Jauchʼs review paper on the ESID EHA SIOPE Focused Symposium 2025 (Vienna, 18.–20.11.2025). The scientific meeting was dedicated to the interplay of immunology and hematology, with particular emphasis on the somatic and germline genetic landscapes shaping malignancies. Dr.med. Jauchʼs tutor is Prof. Dr. med. Urban Novak.

Whole-genome sequencing reveals three follicular lymphoma subtypes¹

Follicular lymphoma (FL) is a malignancy of germinal-center B-cells and a common non-Hodgkin lymphoma subtype in Western Europe.² While FL typically follows an indolent course and recent advances in treatment avenues have significantly improved patient survival, the disease remains incurable and demonstrates a considerable clinical heterogeneity. A patient subset experiences early progression, treatment refractoriness, or histological transformation.³

The WHO 2022 classification recognizes four FL-subtypes: classical FL, FL with unusual cytological features, follicular large B-cell lymphoma and FL with a predominantly diffuse growth pattern.⁴ Although this classification enhances our understanding of FL biology, genetic-based subclassification remains challenging. The m7-FLIPI risk model integrates seven somatic mutations with clinical parameters to predict progression free survival,⁵ however, the algorithm does not incorporate FL hall-mark translocations (BCL-2::IGH, BCL-6 associated rearrangements).

The work by Ren et al. aimed to define clinically relevant genetic FL subtypes, through whole-genome and transcriptomic sequencing of 131 primary FL samples. Using integrated clustering of copy number variants (CNVs), somatic mutations, and structural variants, they identified three genetic subtypes: Cluster 1 (C1) was characterized by recurrent BCL-6 translocations and mutations in NOTCH and NF-κB. C2 on the other hand was defined by high frequency of BCL2 translocations and genetic alterations in chromatin modifier genes (CREBBP, KMT2D, EZH2). C3 lacked BCL2/BCL6 translocations but exhibited a high CNV burden. Clinically, C1 was associated with a favorable prognosis, while C3 correlated with inferior progression-free survival and overall survival.

In summary, the work by W. Ren and colleagues proposes three genetic FL subtypes with distinct biological features, genetic propensities and clinical outcome. Future work will have to validate the proposed risk stratification, and define its clinical use in view of the current and future therapeutic options.

ASXL1 deficiency: epigenetic dysfunction, immunodeficiency, and EBV-associated lymphoma⁶

Inborn errors of immunity (IEI) are germline disorders affecting immune system development and/or function.⁷ Malignancy is the second leading cause of death in IEI patients.⁸ Notably, one third of newly identified monogenetic disorders are established by studying a single case,⁹ following methodical validation to establish causality.

Fu and colleagues described a female patient, with recurrent pneumonia requiring hospitalization, including one severe EBV-related episode. At the age of three, she developed vaccine-strain rubella-positive granulomas following live-attenuated MMR vaccination that persisted over ten years. Laboratory findings revealed erythrocytic macrocytosis, T-cell lymphopenia and hypogammaglobulinaemia. Chronic EBV replication was noted. At the age of 14 years, she developed EBV-associated advanced Hodgkin lymphoma (stage IVA, mixed cellularity subtype). Following polychemotherapy and checkpoint inhibitors, persistent disease necessitated allogeneic hematopoietic stem cell transplantation from a matched-unrelated donor. The patient remained well 18 months post-transplantation.

Given the severe clinical phenotype and young age, a genetic cause was assumed, and whole genome and exome sequencing was performed. Two novel compound heterozygous missense mutations in ASXL1 were identified. While somatic alterations in the epigenetic modifier ASXL1 are well-characterized in clonal hematopoiesis and hematological malignancies, germline variants have not been previously associated with immune dysfunction.

The authors demonstrated reduced ASXL1 protein levels in patient derived T-cells and fibroblasts. Cells transfected with the ASXL1 variants recapitulated the low protein levels. This was paralleled with the loss of differentially methylated sites and accelerated epigenetic aging compared to healthy controls. To address causality, the authors transduced patient-derived T-cells with wild-type ASXL1, partially rescuing the methylation defects and epigenetic aging.

Profound T-cell exhaustion, reduced T- and NK-cell numbers as well as impaired cytotoxicity suggested that chronic viral replication and impaired immunosurveillance lead to Hodgkin lymphoma development.

In summary, the authors identified biallelic germline ASXL1 missense mutations as a novel IEI. They suggest genetic testing in patients with chronic viral infections, viral-associated malignancy and combined immunodeficiency. Allogeneic bone marrow transplantation in such rare cases will likely cure the immunodeficiency and the related hematologic malignancy.