Whole-genome and transcriptome analysis in relapsed/refractory non-Hodgkin lymphoma: Results from a multicentre...

Comprehensive genome and transcriptome profiling can inform the diagnosis, prognosis and management of relapsed/refractory (R/R) solid malignancies, yet its integration into clinical care has lagged despite strong biological rationale. We evaluated the clinical utility of whole genome and transcriptome analysis (WGTA) in 65 patients (37 paediatric, 14 adolescents and young adults, 14 adults) with R/R non-Hodgkin lymphomas enrolled in Canadian precision oncology initiatives (Personalized Oncogenomics, Precision Oncology for Young People, Personalized Targeted Therapy in Refractory or Relapsed Cancer in Childhood, SickKids' Cancer Sequencing). WGTA provided clinically potentially useful findings in 89% of patients including therapy selection, diagnostic clarification, prediction of resistance, minimal residual disease marker identification and discovery of germline cancer predisposition. Results altered management in 15% of patients. Barriers to implementation included clinical deterioration, availability of standard therapies reducing the need for sequence-informed therapies and limited access to targeted agents. Transcriptome-based clustering delineated five biologically distinct subgroups independent of age or histological subtype with convergent oncogenic pathways. Mutational signature analysis identified hypermutation patterns consistent with genomic damage associated with prior cytotoxic therapies. While our findings support the integration of WGTA into the care of patients with R/R lymphomas and identify opportunities for sequence-guided treatment, drug access, systematic barriers and delayed timing of testing currently limit clinical uptake and the potential of precision oncology in lymphoid malignancies.