Investigating chemoresistance in relapsed/refractory B cell non-Hodgkin Lymphoma

Abstract

Paediatric B-cell non-Hodgkin Lymphoma (B-NHL), namely Burkitt lymphoma and diffuse large B cell lymphoma, is successfully treated in the majority of patients in the UK at the cost of debilitating toxicity. For patients who undergo disease progression the prognosis is dire, with salvage rates as low as 20%. Previous studies have identified putative markers of disease progression, but none are currently used in the clinic. There is a clear need for usable markers of relapse/refractory disease at diagnosis for paediatric B-NHL with the aim to stratify patients and identify new potentially targetable genes and pathways. Copy number analysis of 162 patients from the CCLG and published data identified genomic aberrations associated with disease progression: 17p copy number neutral loss of heterozygosity (CNN-LOH), 3q29 amplification and 17q CNN-LOH. 17p CNNLOH was a prognostic marker with a hazard-ratio of 5.6 (95% CI 2-16, p=0.001, Cox proportional hazard method). TP53 was investigated further using a combination Sanger sequencing and whole-exome sequencing. TP53 aberrations were present in 52/95 cases, with biallelic abnormalities conferring poorer outcomes. Biallelic TP53 aberrations were also associated with complex chromosomal abnormalities, including a novel aberration termed 13qplex. Copy number analysis of 105 endemic BL patients treated in Malawi showed that prognostic aberrations in sporadic BL are present but not prognostic in endemic BL. TP53 aberrations were identified in endemic BL and were not associated with relapse, however biallelic cases had an inferior overall survival. Investigating 11 diagnostic and relapse pairs demonstrated that TP53 status drives evolution of chemo-resistant disease. BLs with TP53 aberrations at diagnosis exhibited linear evolution, while TP53 normal cases had early-diverging patterns of progression and acquired TP53 aberrations at relapse. We report TP53 as an important prognostic marker in paediatric B-NHL that confers higher risk of disease progression and may help inform treatment decisions allowing for the possibility of new treatments.