Relapse timing is associated with distinct evolutionary dynamics in DLBCL

Abstract

Diffuse large B-cell lymphoma (DLBCL) is cured in over 60% of patients, but outcomes are poor for patients with relapsed or refractory disease (rrDLBCL). Here, we performed whole genome/exome sequencing (WGS/WES) on tumors from 73 serially-biopsied patients with rrDLBCL. Based on the observation that outcomes to salvage therapy/autologous stem cell transplantation are related to time-to-relapse, we stratified patients into groups according to relapse timing to explore the relationship to genetic divergence and sensitivity to salvage immunochemotherapy. The degree of mutational divergence increased with time between biopsies, yet tumor pairs were mostly concordant for cell-of-origin, oncogene rearrangement status and genetics-based subgroup. In patients with highly divergent tumors, several genes acquired exclusive mutations independently in each tumor, which, along with concordance of genetics-based subgroups, suggests that the earliest mutations in a shared precursor cell constrain tumor evolution. These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naive disease.

Competing Interest Statement

CLF reports honoraria/consulting for BMS, Seattle Genetics, Celgene, Abbvie, Sanofi, Incyte, Amgen, ONK therapeutics and Janssen; research funding from BMS, Janssen and Roche/Genentech. DV reports reports honoraria/advisory boards for Roche and institutional research funding from Roche. MC reports honoraria from Kyte/Gilead and Novartis. AEH reports research funding from Roche, AbbVie, Janssen, Merck, Seattle Genetics, Karyopharm and Incyte. KJS reports honoraria/consulting for Abbvie, AstraZeneca, BMS, Janssen, Merck and Seattle Genetics; Steering committee for Beigene; Data and safety monitoring committee for Regeneron. RK reports research funding from Abbvie. CS reports consultancy for AbbVie, Bayer, and Seattle Genetics; research funds from Trillium Therapeutics, BMS, and Epizyme. DWS reports consultancy for AbbVie, AstraZeneca, Incyte, and Janssen; research funds from Janssen and Roche/Genentech; named inventor on a patent describing the use of gene expression to subtype aggressive B-cell lymphomas, one of which is licensed to NanoString Technologies. All other authors declare no competing financial and/or non-financial interests in relation to the work described.

Funding Statement

This study was supported by a Large Scale Applied Research Project funded by Genome Canada (13124), Genome BC (271LYM), Canadian Institutes of Health Research (CIHR) (GP1-155873), the British Columbia Cancer Foundation (BCCF) and the Provincial Health Services Authority (PHSA). It was also supported by Terry Fox Research Institute (TFRI) Program Project Grants (1061, 1108), TFRI Marathon of Hope Cancer Centre Network, the Genome BC Marathon of Hope Cancer Centre program (MOH001), and grant 1P01CA229100 from the National Cancer Institute. RDM and CS are supported by Michael Smith Foundation for Health Research, Career Investigator Awards. DWS is supported by a Michael Smith Foundation for Health Research, Health Professional Investigator Award. BC is supported by a CIHR Canada Graduate Scholarship Doctoral Award.

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Ethics Board of University of British Columbia-BC Cancer Research gave ethical approval for this work.

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