Integrative Molecular Analysis Reveals Determinants of Clinical Outcomes in TP53-Mutated Diffuse Large B-Cell Lymphoma.

However, clinical outcomes among patients with TP53-mutant disease vary, with some patients showing treatment responses similar to those with wild-type TP53.

然而，携带TP53突变疾病的患者的临床结果存在差异，有些患者的治疗反应与野生型TP53患者相似。

This study aims to understand the clinical and molecular determinants underlying poor outcomes in TP53-mutant DLBCL.

本研究旨在理解TP53突变弥漫性大B细胞淋巴瘤（DLBCL）不良预后的临床和分子决定因素。

Methods

Clinical and molecular data for 3,091 patients were derived from 10 cohorts of patients with newly diagnosed DLBCL treated with frontline rituximab-based immunochemotherapy regimens.

3,091名患者的临床和分子数据来自10个队列，这些队列包括接受前线利妥昔单抗为基础的免疫化疗方案治疗的初诊DLBCL患者。

Targeted or whole-exome/whole-genome sequencing was available for all patients.

所有患者均可进行靶向或全外显子组/全基因组测序。

Bulk RNA-seq was analyzed for 591 patient samples.

对591个患者样本进行了批量RNA测序分析。

The primary outcome measures were progression-free survival(PFS) and overall survival(OS).

主要结果指标为无进展生存期（PFS）和总生存期（OS）。

Results

TP53-mutant DLBCL differed from wild-type disease in pattern and number of genetic lesions, malignant B-cell expression states, and tumor microenvironment composition.

TP53突变型弥漫大B细胞淋巴瘤（DLBCL）在遗传病变的模式和数量、恶性B细胞表达状态以及肿瘤微环境组成方面与野生型疾病存在差异。

TP53 mutations were 6-fold more prevalent than MYC/BCL2/BCL6 double-/triple-hit status, but conferred similar adverse prognostic risk.

TP53突变的患病率是MYC/BCL2/BCL6双重/三重突变状态的6倍，但预后风险相似。

Among patients with TP53-mutant disease, variant allele frequency (VAF) further stratified risk, with patients featuring VAF ≥ 75% (indicative of loss of heterozygosity) experiencing significantly inferior PFS/OS.

在TP53突变疾病的患者中，变异等位基因频率（VAF）进一步细分了风险，具有VAF ≥ 75%（表明杂合性丢失）的患者经历了显著较差的无进展生存期（PFS）和总生存期（OS）。

Downregulation of interferon signaling and lower macrophage content were identified in TP53-mutant samples derived from patients with poor outcomes or VAF ≥ 75%.

在 TP53 突变样本中，来自预后较差或变异等位基因频率（VAF）≥75%的患者的干扰素信号下调和巨噬细胞含量较低被识别出来。

TP53 mutations were adversely prognostic among patients with DLBCL assigned to specific LymphGen subtypes (EZB, MCD), malignant B-cell states (S1), and ecotypes (LE4, LE7, LE8), whereas outcomes were similar to wild-type disease within other molecular subtypes.

在被分配到特定 LymphGen 亚型（EZB、MCD）、恶性 B 细胞状态（S1）和生态型（LE4、LE7、LE8）的弥漫性大 B 细胞淋巴瘤（DLBCL）患者中，TP53 突变预后不良，而在其他分子亚型中，其结果与野生型疾病相似。

In re-examination of the Phoenix trial data, addition of ibrutinib to R-CHOP improved PFS in patients with TP53-mutant DLBCL and abrogated the deleterious impact of high VAF, irrespective of patients' age.

在重新审视凤凰试验数据时，将伊布替尼添加到R-CHOP中改善了TP53突变弥漫性大B细胞淋巴瘤患者的无进展生存期，并消除了高变异等位基因频率（VAF）的不利影响，无论患者的年龄如何。

Conclusions

The poor prognosis of TP53-mutant DLBCL is dependent on intrinsic features, such as VAF, and modulated by co-occurring genomic lesions or lymphoma cell-intrinsic or microenvironmental expression patterns.

TP53突变弥漫性大B细胞淋巴瘤的预后不良依赖于内在特征，如变异等位基因频率（VAF），并受到共发的基因组病变或淋巴瘤细胞内在或微环境表达模式的调节。