TP53 status as a biomarker in children with aggressive lymphoma: the power of a retrospective cohort and collaboration

In this study we used integrated genomics data to evaluate the clinical significance of TP53 abnormalities in a large UK paediatric B-cell non-Hodgkin lymphoma cohort and determined that TP53 status is a biomarker to define clinical groups with both a high- and low-risk of therapeutic failure.

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This paper was driven by two key clinical questions: (1) how can we reduce treatment-related toxicity and (2) how do we treat children with B-cell non-Hodgkin lymphoma (B-NHL) who don’t respond to current first-line treatment?

B-cell non-Hodgkin lymphomas (B-NHL) are a heterogeneous group of aggressive tumours with Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) the most common subtypes in children. Children with mature B-NHL are treated with the same protocols based on the FAB/LMB96 protocol despite subtype diagnosis1. Currently children with mature B-NHL in the UK and other high-income countries have a very good chance of cure. However, this comes at the cost of significant treatment-related toxicities, long-term morbidities and disruption to a normal childhood with many months spent in hospital and on ICU away from family and friends. In addition, for those children with primary refractory or relapsed disease, treatment options are limited, and outcome remains very poor.

Unlike other cancers, such as leukaemias, there are currently no molecular biomarkers that can risk stratify children with B-NHL. Importantly, genomic analyses of B-NHL subtypes have identified a number of highly recurrent coding mutations but their clinical importance in paediatric disease has not been investigated. Our knowledge of the underlying biology of primary refractory or relapsed disease is also limited.

Our laboratory focusses on understanding the role of the underlying genomic alterations in aggressive cancers and evaluating their potential as biomarkers and/or therapeutic targets. Our group has previously identified FOXO1 as a potential therapeutic target for paediatric BL patients2. We identified FOXO1 mutation in a 1/3rd of BL cases and cluster in and adjacent to the AKT recognition motif. We show nuclear localisation of FOXO1 in patient samples and cell lines and provide CRISPR/Cas9 functional knockout data supporting an important role for FOXO1 as an oncogenic factor in the pathogenesis of BL. However, they were not associated with outcome.

In this paper we aimed to evaluate the potential utility of TP53 status as a prognostic biomarker in paediatric B-NHL. Genomic alterations of TP53 are one of the most common alterations in paediatric B-NHL3-7. It is well established that TP53 alterations are associated with poor outcome in many malignancies but their utility as a prognostic biomarker is unknown.

Using a combination of next-generation sequencing and copy number microarrays, we identified TP53 abnormalities in over half of cases and, importantly, showed they were associated with a significantly inferior survival. One of the strengths of our retrospective cohort was that most patients were not treated with the anti-CD20 monoclonal antibody rituximab. Rituximab has recently been added to first-line protocols to treat clinically high-risk patients8, which has further increased that intensity of treatment for children with B-NHL. In our study we were able to stratify the cohort to identify those who were clinically high-risk (stage III with high LDH or stage IV) and show that high-risk cases without TP53 abnormalities had a significantly superior survival compared those with TP53 abnormalities.

Our study identifies, for the first time, a clinically actionable genomic factor associated with a high risk of disease recurrence and, critically, identifies a sub-group with an extremely low risk of relapse. The next step is to validate these findings in an international clinical trial designed to consider therapy reduction. At the National Horizons Centre at Teesside University, UK, we are using our cutting-edge facilities to develop a test to be used in a trial to screen for TP53 abnormalities in different healthcare settings. We are also working in partnership with colleagues at Newcastle University to further our understanding of the underlying mechanisms of primary refractory and relapsed disease to develop new strategies to prevent or treat therapy resistant disease.

Paediatric B-NHL is a rare cancer which brings several challenges. Rare cancers are defined as affecting fewer than 6 in 100,000 people each year and equate to almost a quarter of all cancer cases. Studying rare cancers is often a multi-institutional and more frequently an international effort to obtain sufficient cases and biological material for research. The cohort in this paper is a retrospective cohort collected with the support of Children’s Cancer and Leukaemia Group (CCLG) Tissue Bank. This work could not have been done without the support of CCLG and all of the clinical teams across the UK. Without their passion and enthusiasm for such studies we would not be able to investigate rare cancers and make meaningful discoveries.

In short, working in partnership is key to studying rare cancers and is central to improve risk stratification in paediatric B-NHL and other rare cancers in order to reduce treatment-related toxicity and improve outcome for patients who currently do not respond to first-line or subsequent treatment.  

References

  1. Patte C, Auperin A, Gerrard M, Michon J, Pinkerton R, Sposto R, et al. Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 2007 Apr 1; 109(7): 2773-2780.
  2. Zhou P, Blain AE, Newman AM, Zaka M, Chagaluka G, Adlar FR, et al. Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif. Blood Adv 2019 Jul 23; 3(14): 2118-2127.
  3. Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A 2012 Mar 6; 109(10): 3879-3884.
  4. Love C, Sun Z, Jima D, Li G, Zhang J, Miles R, et al. The genetic landscape of mutations in Burkitt lymphoma. Nat Genet 2012 Dec; 44(12): 1321-1325.
  5. Morin RD, Mungall K, Pleasance E, Mungall AJ, Goya R, Huff RD, et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood 2013 Aug 15; 122(7): 1256-1265.
  6. Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 2011 Jul 31; 43(9): 830-837.
  7. Schmitz R, Young RM, Ceribelli M, Jhavar S, Xiao W, Zhang M, et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 2012 Oct 4; 490(7418): 116-120.
  8. Minard-Colin V, Auperin A, Pillon M, Burke GAA, Barkauskas DA, Wheatley K, et al. Rituximab for High-Risk, Mature B-Cell Non-Hodgkin's Lymphoma in Children. N Engl J Med 2020 Jun 4; 382(23): 2207-2219.

 

 

Professor Vikki Rand

Professor of Biosciences , Teesside University