Division of Hematology, Mayo Clinic Rochester, Rochester, Minnesota, USA.
Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
Hematol Oncol. 2025 Jan;43(1):e70006. doi: 10.1002/hon.70006.
Diffuse large B-cell lymphoma (DLBCL) patients that fail to achieve a complete metabolic response with frontline immunochemotherapy have a poor prognosis. Genomic profiling has led to a broader understanding of the molecular drivers in DLBCL, but it is unknown how well current classifiers identify patients that will experience primary treatment resistance (PTR). Using whole exome and RNA sequencing data from newly diagnosed DLBCL patients, we evaluated the genomic landscape of PTR and compared it to that of non-PTR DLBCL. We found a significant increase in the frequency of TP53 (34% vs. 15%, p = 0.005) and ARID1A mutations (21% vs. 7%, p = 0.007) in PTR cases, with pathway analysis further demonstrating a downregulation of TP53 and an increase in chromatin modifying pathways. These results suggest that TP53 and ARID1A may be key mediators of PTR and important pathways contributing to the poor outcomes. We found that the current molecular classifiers were unable to identify PTR cases at diagnosis. However, our newly identified high-risk signature identified 46% of PTR cases at diagnosis. Overall, these results contribute to our understanding of the genomic landscape of patients with primary treatment resistance.
未能在前线免疫化疗中达到完全代谢缓解的弥漫性大 B 细胞淋巴瘤 (DLBCL) 患者预后较差。基因组分析使人们对 DLBCL 中的分子驱动因素有了更广泛的了解，但目前尚不清楚分类器在多大程度上能识别出将经历原发治疗抵抗 (PTR) 的患者。我们使用新诊断的 DLBCL 患者的全外显子组和 RNA 测序数据，评估了 PTR 的基因组图谱，并将其与非 PTR DLBCL 进行了比较。我们发现 PTR 病例中 TP53（34% 比 15%，p=0.005）和 ARID1A 突变的频率显著增加，通路分析进一步表明 TP53 下调和染色质修饰途径增加。这些结果表明，TP53 和 ARID1A 可能是 PTR 的关键介质，也是导致不良预后的重要途径。我们发现，目前的分子分类器无法在诊断时识别 PTR 病例。然而，我们新发现的高危特征在诊断时识别出了 46%的 PTR 病例。总的来说，这些结果有助于我们了解原发性治疗抵抗患者的基因组图谱。
