Investigation of somatic genomic abnormalities and the tumour microenvironment in paediatric B-cell non-Hodgkin lymphoma

Abstract

Over 90% of children diagnosed with B-cell non-Hodgkin lymphoma (B-NHL) respond well to front-line therapy. However, survival for patients with primary refractory or relapsed disease remains dismal and treatment options limited. This project aimed to investigate the genomics and microenvironment of newly identified B-NHL subtypes associated with poor (tumours with TP53 abnormalities) and good (Burkitt-like lymphoma with 11q aberration (BLL-11q)) outcomes to identify prognostic biomarkers and gain insight into the biology of paediatric B-NHL. Genomic analysis of sporadic Burkitt lymphoma (sBL) patients identified TP53 abnormalities associated with inferior overall (p=0.016) and progression-free (p=0.0047) survival. Analysis of matched diagnostic and relapse samples revealed TP53 abnormalities in all cases at diagnosis which were maintained at relapse, indicating a role for TP53 in sBL relapse. TP53 abnormalities were present within a cohort of endemic BL (eBL) but were not associated with outcome. Care pathway analysis involving semi-structured interviews with UK clinicians indicated positive responses to our TP53 study and recommended validation within a prospective clinical trial. BLL-11q tumours harbour copy number gain and loss patterns on chromosome 11q. Previous studies identified genes of interest within the loss region but the gene/s of interest within 11q gain remain unclear. Copy number analysis redefined the minimum region of gain on 11q, which included IL10RA. Gene expression analysis revealed significantly higher expression of IL-10 pathway members – IL10, IL10RA, JAK2, STAT3 – in BLL-11q samples compared to sBL. High surface expression of IL10RA in cell-lines with 11q gain/loss abnormalities was confirmed by flow cytometry. In contrast, sBL cell-lines had low/absent IL10RA surface expression. Together, this project has shown that TP53 abnormalities offer substantial clinical utility as a potential prognostic biomarker in sBL but not eBL, and has identified IL10RA as a candidate gene of interest warranting further investigation as a potential novel treatment target for patients with BLL-11q.