Children with B-cell non-Hodgkin lymphoma (B-NHL) have an excellent chance of survival, however, current clinical risk stratification places as many as half of patients in a high-risk group receiving very intensive chemo-immunotherapy. TP53 alterations are associated with adverse outcome in many malignancies; however, whilst common in paediatric B-NHL, their utility as a risk classifier is unknown. We evaluated the clinical significance of TP53 abnormalities (mutations, deletion and/or copy number neutral loss of heterozygosity) in a large UK paediatric B-NHL cohort and determined their impact on survival. TP53 abnormalities were present in 54.7% of cases and were independently associated with a significantly inferior survival compared to those without a TP53 abnormality (PFS 70.0% vs 100%, p < 0.001, OS 78.0% vs 100%, p = 0.002). Moreover, amongst patients clinically defined as high-risk (stage III with high LDH or stage IV), those without a TP53 abnormality have superior survival compared to those with TP53 abnormalities (PFS 100% vs 55.6%, p = 0.005, OS 100% vs 66.7%, p = 0.019). Biallelic TP53 abnormalities were either maintained from the presentation or acquired at progression in all paired diagnosis/progression Burkitt lymphoma cases. TP53 abnormalities thus define clinical risk groups within paediatric B-NHL and offer a novel molecular risk stratifier, allowing more personalised treatment protocols.

CEITEC Masaryk University Brno Czech Republic

Department of Cellular Pathology Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK

Department of Paediatric and Adolescent Haematology and Oncology The Great North Children's Hospital Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK

Department of Paediatric Haematology Oncology and Palliative Care Addenbrooke's Hospital Cambridge University Hospitals NHS Foundation Trust Cambridge UK

Department of Paediatric Oncology Royal Marsden Hospital Sutton Surrey UK

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Addenbrooke's Hospital Cambridge UK

National Horizons Centre Teesside University 38 John Dixon Lane Darlington UK

Newcastle Genetics Laboratory Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK

School of Health and Life Sciences Teesside University Middlesbrough UK

Wolfson Childhood Cancer Research Centre Translational and Clinical Research Institute Newcastle University Newcastle upon Tyne UK

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