The genomic landscape of two Burkitt lymphoma cases and derived cell lines: comparison between primary and relapse samples

Abstract

Relapse occurs in 10–40% of Burkitt lymphoma (BL) patients that have completed intensive chemotherapy regimens and is typically fatal. While treatment-naive BL has been characterized, the genomic landscape of BL at the time of relapse (rBL) has never been reported. Here, we present a genomic characterization of two rBL patients. The diagnostic samples had mutations common in BL, including MYC and CCND3. Additional mutations were detected at relapse, affecting important pathways such as NFκB (IKBKB) and MEK/ERK (NRAS) signaling, glutamine metabolism (SIRT4), and RNA processing (ZFP36L2). Genes implicated in drug resistance were also mutated at relapse (TP53, BAX, ALDH3A1, APAF1, FANCI). This concurrent genomic profiling of samples obtained at diagnosis and relapse has revealed mutations not previously reported in this disease. The patient-derived cell lines will be made available and, along with their detailed genetics, will be a valuable resource to examine the role of specific mutations in therapeutic resistance.

Keywords:

• Lymphoma and Hodgkin disease
• lymphocytes
• cell cycle and apoptosis changes
• drug resistance
• molecular genetics

Acknowledgements

We acknowledge the support of the patients and their families who have consented to participate in lymphoma tissue banking within the LCBQ. We thank the Jewish General Hospital Foundation, the Cole Foundation, and the Fonds de Recherche du Québec en Santé for financially supporting the LCBQ. We also thank the Letai laboratory for teaching us how to perform the BH3 profiling protocol, Dr. Volker Blank’s laboratory (Lady Davis Institute) for the Namalwa and Raji cell lines, Dr. Raquel Aloyz’s laboratory (Lady Davis Institute) for the OCI-Ly8 cell line, and Sami Chaaban for critical review of the manuscript.

Ethics approval and consent to participate: This research was approved by the REB at the Jewish General Hospital (protocols 11-047, 12-052) and is in accordance with the declaration of Helsinki.

Consent for publication: Both patients consented to the LCBQ project (protocol 11-047), which includes the consent to publish the data generated from their samples.

Availability of data and materials: The datasets generated and/or analyzed during the current study will be made available upon article acceptance. Requests to have access to the cell lines should be made to Dr. Nathalie Johnson at [email protected].

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2017.1413186.

Additional information

Funding

This research was supported by the Canadian Institute for Health Research (CIHR) (operating grants 300738 awarded to RDM and NAJ and 299607 awarded to NAJ) and the Terry Fox Foundation (Canada) (grant no. 2390b02f443001b62e3fe0408dccc681, project #1043, awarded to RDM). CMW and DG received salary awards from the Cole Foundation and CIHR, respectively. NAJ has received research funding from Roche Canada and consulting fees/honoraria from Roche, Abbvie, Lundbeck, Seattle Genetics, Janssen, and Gilead. CMW has equity shares in Gilead, and Bristol Myers Squibb.