Relapse timing is associated with distinct evolutionary dynamics in DLBCL.
Laura K HiltonHenry S NguBrett J CollingeKostiantyn DrevalSusana Ben-NeriahChristopher K RushtonJasper Chun Hei WongManuela CruzAndrew J RothMerrill BoyleBarbara MeissnerGraham W SlackPedro FarinhaJeffrey W CraigAlina S GerrieCiara L FreemanDiego VillaMichael CrumpLois ShepherdAnnette E HayJohn KuruvillaKerry J SavageRobert KridelAly KarsanMarco A MarraLaurie H SehnChristian SteidlRyan D MorinDavid W ScottPublished in: medRxiv : the preprint server for health sciences (2023)
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-naïve disease.
Keyphrases
- diffuse large b cell lymphoma
- end stage renal disease
- stem cell transplantation
- newly diagnosed
- ejection fraction
- chronic kidney disease
- epstein barr virus
- genome wide
- cell therapy
- prognostic factors
- acute myeloid leukemia
- high dose
- type diabetes
- clinical trial
- randomized controlled trial
- squamous cell carcinoma
- gene expression
- dna methylation
- low dose
- skeletal muscle
- stem cells
- transcription factor
- insulin resistance