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Lookup NU author(s): Alex Newman, Dr Masood Zaka, Dr Peixun Zhou, Dr Amy Erhorn, Dr Rachel CrosslandORCiD, Sara Wilkinson, Dr Amir EnshaeiORCiD, Karl Wood, Dr Despoina Televantou, Professor Christine Harrison, Dr Simon BomkenORCiD, Dr Christopher BaconORCiD, Dr Vikki Rand
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Background: Current frontline therapies for paediatric B-cell non-Hodgkin lymphoma (B-NHL) are very effective, achieving >90% survival, but attempts to reduce the very intensive therapy have been unsuccessful. Although potential prognostic biomarkers have been identified, including gain of 7q, loss of 13q and gain of MIR17HG, they are not used in the clinic. Furthermore, little is currently known about the biology of relapsed disease. Better understanding is essential to identify risk factors to stratify patients and to inform the next generation of relapse strategies. Objectives: To identify genomic abnormalities associated with an increased risk of relapsed disease in paediatric B-NHL. Design/Methods: We included 162 paediatric B-NHL cases in this study; 110 samples were obtained from the Children’s Cancer and Leukaemia Group (CCLG) Tumour bank and 52 cases were identified from the literature. Matched relapse samples were obtained for 9/18 relapse cases. High-resolution copy number data were generated using Affymetrix Cytoscan or Oncoscan arrays. TP53 mutations were detected using next-generation and Sanger sequencing. Univariate and multivariate analyses examined the association of abnormalities with time to progression and overall survival. Results: Twenty-six recurrent copy number abnormalities (CNAs) and regions of copy number neutral loss of heterozygosity (CNN-LOH) were detected by GISTIC2.0. Recurrent CNAs involved known cancer genes including MCL1, REL, CDKN2A/B and TP53. Genomic analysis identified aberrations enriched in the genome of cases who failed treatment; gain of 3q29, 17p loss and CNN-LOH, gain of MYC and FAS. In contrast, 6q loss involving PRDM1 was only identified in non-relapsing cases. Investigation of the 17p candidate gene, TP53, identified mutations in 46% (37/80) of samples, resulting in biallelic inactivation in 68% (25/37) of cases. Survival analysis demonstrated that TP53 biallelic inactivation is a prognostic factor identifying children with an increased risk of disease progression (HR 3.51, 95% CI 1.22-10.14, p=0.02). Of the nine matched relapse samples, 6/9 (67%), representing 6/6 (100%) Burkitt cases, had TP53 biallelic inactivation at relapse; four maintained the abnormalities from diagnosis and two acquired TP53 inactivation at relapse. Notably, MIR17HG gain correlated with 17p and TP53 aberrations, however, it was not associated with outcome. Conclusion: Genome-wide analysis revealed that 3q29 gain, 17q CNN-LOH and TP53 inactivation are associated with an increased risk of relapse in paediatric B-NHL. Our findings have potential to contribute to patient stratification and therapy personalisation.
Author(s): Newman AM, Zaka M, Zhou P, Erhorn A, Crossland RE, Wilkinson S, Enshaei A, Taj M, Wood K, Televantou D, Turner SD, Burke A, Harrison CJ, Bomken S, Bacon CM, Rand V
Publication type: Conference Proceedings (inc. Abstract)
Publication status: Published
Conference Name: Sixth International Symposium on Childhood, Adolescent and Young Adult Non‐Hodgkin Lymphoma
Year of Conference: 2018
Pages: 60-60
Print publication date: 26/09/2018
Online publication date: 19/09/2018
Acceptance date: 19/09/2018
Date deposited: 24/04/2019
ISSN: 1365-2141
Publisher: John Wiley and Sons Ltd
URL: https://doi.org/10.1111/bjh.15536
DOI: 10.1111/bjh.15536
PubMed id: 30230525
Series Title: British Journal of Haematology
