Up to 40% of diffuse large B-cell lymphoma (DLBCL) patients do not experience a durable response to frontline immunochemotherapy, and prospective identification of high-risk cases that may benefit from personalized therapeutic management remains an unmet need. Molecular phenotyping techniques have established a landscape of genomic variants in diagnostic DLBCL; however, these have not yet been applied in large-scale studies of relapsed/refractory DLBCL, resulting in incomplete characterization of mechanisms driving tumor progression and treatment resistance. Here, we performed an integrated multiomic analysis on 228 relapsed/refractory DLBCL samples, including 24 with serial biopsies. Refined cell-of-origin subtyping identified patients harboring GCB and DZsig+ relapsed/refractory tumors in cases with primary refractory disease with remarkably poor outcomes, and comparative analysis of genomic features between relapsed and diagnostic samples identified subtype-specific mechanisms of therapeutic resistance driven by frequent alteration to MYC, BCL2, BCL6, and TP53 among additional strong lymphoma driver genes. Tumor evolution dynamics suggest innate mechanisms of chemoresistance are present in many DLBCL tumors at diagnosis, and that relapsed/refractory tumors are primarily comprised of a homogenous clonal expansion with reduced tumor microenvironment activity. Adaptation of personalized therapeutic strategies targeting DLBCL subtype-specific resistance mechanisms should be considered to benefit these high-risk populations.
高达40%的弥漫大B细胞淋巴瘤（DLBCL）患者对一线免疫化疗无法产生持久应答，而前瞻性识别可能受益于个性化治疗管理的高危病例仍是未满足的临床需求。分子分型技术已初步描绘了初诊DLBCL的基因组变异图谱，但这些技术尚未广泛应用于复发/难治性DLBCL的大规模研究，导致对驱动肿瘤进展和治疗抵抗机制的认知尚不完整。本研究对228例复发/难治性DLBCL样本（其中24例包含连续活检样本）进行了整合多组学分析。通过精细的细胞起源分型，我们在原发性难治性疾病中识别出携带GCB亚型和DZsig+特征的复发/难治性肿瘤患者，其预后显著不良；通过对初诊与复发样本的基因组特征比较，发现MYC、BCL2、BCL6、TP53等关键淋巴瘤驱动基因的频繁改变，构成了不同亚型特异性治疗抵抗机制。肿瘤进化动态分析表明，许多DLBCL在初诊时已存在固有的化疗抵抗机制，且复发/难治性肿瘤主要表现为同质性克隆扩增，同时肿瘤微环境活性减弱。针对DLBCL亚型特异性耐药机制制定个性化治疗策略，将有望使这些高危人群受益。
肿瘤(癌症)患者之家