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<p>Non-Hodgkin lymphoma (NHL) exhibits marked interpatient heterogeneity in treatment response, yet links between tumor genotype and pharmacologic phenotype in primary samples remain incompletely defined. We integrate whole-genome sequencing of patient-derived tumor tissue with ex vivo drug sensitivity profiling across standard chemotherapeutics in a cohort of 32 patients encompassing aggressive and indolent NHL, and relate these data to clinical outcomes. Ex vivo sensitivities span more than 1,000-fold IC₅₀ ranges across drugs. HLA-DQB1 is the most frequently mutated with recurrent co-mutations in immune-regulatory genes. Mutation-wise association analyses reveal gene-specific drug effects, including increased actinomycin sensitivity with EGFR mutations, resistance to dexamethasone, prednisone and mechlorethamine with ITK mutations, and multi-drug resistance patterns linked to epigenetic regulators (KMT2D, SETD2). EP300 mutations are associated with enhanced prednisone sensitivity across subtypes. Clinically, FAT4 and CD22 mutations correlate with inferior progression-free survival. FAT4-mutated samples show reduced ex vivo sensitivity to cyclophosphamide while CD22-mutated samples demonstrate enhanced sensitivity to vinblastine, suggesting opportunities for regimen optimization. These data define an integrative functional-genomic framework that uncovers mutation–drug interactions with outcome correlates and motivate prospective studies testing genotype-informed therapy selection in NHL.</p>

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Integrating genomic and ex vivo drug sensitivity profiling to predict treatment outcomes in Korean patients with non-Hodgkin lymphoma

  • 期刊论文

  • 发表日期：

    2026年5月26日

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  • Ji Won Kim,
  • Yongchel Ahn,
  • Haeryung Lee,
  • Myung Woul Han,
  • Myung-Soo Kim,
  • Ilona Holcomb,
  • Josephine Tsang,
  • George Courcoubetis,
  • Karim Mrouj,
  • Hyoju Yi,
  • Sungwon Lim,
  • Jong Cheol Lee,
  • Jamin Koo

摘要

Non-Hodgkin lymphoma (NHL) exhibits marked interpatient heterogeneity in treatment response, yet links between tumor genotype and pharmacologic phenotype in primary samples remain incompletely defined. We integrate whole-genome sequencing of patient-derived tumor tissue with ex vivo drug sensitivity profiling across standard chemotherapeutics in a cohort of 32 patients encompassing aggressive and indolent NHL, and relate these data to clinical outcomes. Ex vivo sensitivities span more than 1,000-fold IC₅₀ ranges across drugs. HLA-DQB1 is the most frequently mutated with recurrent co-mutations in immune-regulatory genes. Mutation-wise association analyses reveal gene-specific drug effects, including increased actinomycin sensitivity with EGFR mutations, resistance to dexamethasone, prednisone and mechlorethamine with ITK mutations, and multi-drug resistance patterns linked to epigenetic regulators (KMT2D, SETD2). EP300 mutations are associated with enhanced prednisone sensitivity across subtypes. Clinically, FAT4 and CD22 mutations correlate with inferior progression-free survival. FAT4-mutated samples show reduced ex vivo sensitivity to cyclophosphamide while CD22-mutated samples demonstrate enhanced sensitivity to vinblastine, suggesting opportunities for regimen optimization. These data define an integrative functional-genomic framework that uncovers mutation–drug interactions with outcome correlates and motivate prospective studies testing genotype-informed therapy selection in NHL.