Gustaf Leijonhufvud: Molecular studies in paediatric cancer with focus on paediatric leukaemias

Abstract

Introduction: Genetic processes and viral infections influence disease development and progression in children with cancer. Certain subtypes of pediatric acute lymphoblastic leukemia (ALL), such as KMT2A rearrangements, ETV6::RUNX1 fusion arise in utero, while the timing of other lesions, including iAMP21 and STIL::TAL1 fusions, remains unclear. Children with malignancies are particularly vulnerable to viral infections, as disease and treatment-induced immunosuppression can affect viral replication and immune function. Within the human virome, Torque teno virus (TTV) and Human pegivirus (HPgV) are of interest due to their persistence and potential influence on immune status. Knowledge of these viruses in children at diagnosis is limited.

Methods: Neonatal blood spots (NBS) from eight children with ALL were retrospectively analyzed to determine whether genetic lesions were present at birth. Genetic findings at diagnosis were compared with NBS samples using molecular genetic techniques. Serum viromes of children with leukemia or newly diagnosed cancer were characterized using metagenomic sequencing and compared with quantitative PCR for TTV, allowing detailed assessment of viral burden and immune status.

Results: In two patients with iAMP21, several clonal genetic alterations were detected in NBS, consistent with germline predisposition, while driving rearrangements arose postnatally. STIL::TAL1 fusions were absent in NBS, indicating postnatal acquisition. Metagenomic sequencing demonstrated higher sensitivity than PCR for TTV detection. A broad diversity of viruses, including TTV and HPgV, was present in serum at diagnosis, suggesting that viral burden may already reflect altered immune status in newly diagnosed children.

Conclusion: Both prenatal and postnatal genetic events contribute to pediatric ALL development, and children with cancer frequently exhibit a complex viral burden at diagnosis. Metagenomics provides a powerful tool to map the virome and understand how persistent viruses may influence immune function and disease progression. Overall, the findings highlight the interplay between genetic predisposition, clonal evolution, and viral infections in childhood cancer.