Background: Mantle Cell Lymphoma (MCL) is an aggressive malignancy with variable clinical behavior, largely reflecting the underlying molecular heterogeneity. The genomic landscape of MCL encompasses gene mutations with strong prognostic implications and secondary genetic events, which are also implicated in the pathogenesis and prognosis of the disease.Methods: We evaluated the diagnostic samples of 73 patients with relapsed/refractory MCL that were enrolled in the Fondazione Italiana Linfomi Mantle First-BIO study. All patients had available data for correlating CNVs with the presence ofTP53mutation. Time to first relapse or progression of disease (POD) was used as the primary outcome measure.Results: We identified CNVs associated with MCL, with Del 9p21.3 (CDKN2A) being the strongest predictor of shorter time to POD (p= 0.01), independently ofTP53mutation in multivariable analysis. Unsupervised clustering identified molecularly defined clusters that were associated with significantly different times to POD (p= 0.01). Pairwise log-rank tests confirmedTP53mutated vs. wild-type (WT) as the strongest prognostic factor, with cluster assessment improving the prognostic predictivity among patients: clustersTP53-mut vs.TP53-WT,p= 0.001, HR = 3.92; andp= 0.014, HR = 2.23, respectively. In conclusion, CNV-based molecular clusters might represent a novel approach to identify patients at higher risk of treatment failure, further contributing to the prognostic predictivity ofTP53mutation.
背景：套细胞淋巴瘤（MCL）是一种具有异质性临床行为的侵袭性恶性肿瘤，其表现主要反映潜在的分子异质性。MCL的基因组图谱包含具有显著预后意义的基因突变及继发性遗传事件，这些因素均与疾病的发病机制及预后相关。 方法：本研究评估了73例参加意大利淋巴瘤基金会Mantle First-BIO研究的复发/难治性MCL患者的诊断样本。所有患者均具备可用于关联拷贝数变异（CNV）与TP53突变状态的数据。研究以首次复发或疾病进展时间作为主要结局指标。 结果：我们鉴定出与MCL相关的CNV，其中Del 9p21.3（CDKN2A）在多变量分析中被证实是预测疾病进展时间缩短的最强独立因素（p=0.01），且该关联独立于TP53突变状态。通过无监督聚类分析，我们识别出与显著不同疾病进展时间相关的分子聚类（p=0.01）。配对时序检验证实TP53突变型与野生型（WT）是最强的预后因素，而聚类评估进一步提升了患者间的预后预测能力：TP53突变型聚类与TP53野生型聚类的风险比分别为HR=3.92（p=0.001）和HR=2.23（p=0.014）。结论：基于CNV的分子聚类可能为识别治疗失败高风险患者提供新方法，从而进一步增强TP53突变的预后预测价值。
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