LymphGen molecular subtyping reveals therapeutic heterogeneity beyond cell-of-origin classification in Indian DLBCL

Diffuse large B-cell lymphoma (DLBCL) is molecularly heterogeneous, yet standard cell-of-origin (COO) classification fails to capture actionable biology. Systematic genetic profiling remains unmapped in South Asian populations, who exhibit a decade-younger age of onset. We performed targeted next-generation sequencing on pre-treatment diagnostic biopsies from 186 Indian DLBCL patients to evaluate LymphGen molecular subtyping against COO classification. LymphGen re-stratification showed that every COO category contained multiple genetic subtypes with distinct driver genes, co-mutation patterns, and mutation types. This COO–genotype mismatch persisted even when we modelled perfect COO assignment, indicating it is structural, not a artefact of imperfect immunohistochemistry. The MCD subtype (18.8%) was missense-predominant (71.3% missense), characterised by recurrent MYD88 and CD79B mutations consistent with proximal NF-kB/BCR activation, whereas EZB (22.6%) and BN2 (18.3%) were truncation-predominant, consistent with tumour-suppressor loss. This cohort demonstrated enrichment of N1 (9.1% vs ∼3% Western) and A53 (15.6% vs ∼12% Western) subtypes. A53 carried the highest LOH/biallelic signature (21.3% of mutations at VAF >50%), consistent with TP53 biallelic inactivation and known poor prognosis under standard immunochemotherapy. Independent of COO, VAF-based clonal ordering identified TP53 and MYD88 as early founding events versus late BCL2/SGK1 acquisition. Furthermore, genetic subtyping reassigned risk biology in 17% of non-GCB and 23% of GCB cases, resolving all 32 COO-unclassified cases. Overall, 72% of patients carried at least one actionable lesion. These data provide an early Indian molecular reference and support integrating targeted molecular classifiers as adjuncts to comprehensive LymphGen and FISH in frontline workflows.