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Background <p>Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin’s lymphoma. The applicability of circulating tumor DNA (ctDNA) for predicting treatment response and prognosis in MCL remains underexplored.</p> Methods <p>This study included 34 MCL patients receiving first-line chemoimmunotherapy. We assessed the ability of plasma ctDNA to detect tumor-specific genetic alterations and explored its potential as a noninvasive biomarker for treatment response and prognosis in MCL.</p> Results <p>Commonly mutated genes in MCL included <i>CCND1</i> (93.5%), <i>ATM</i> (48.4%), <i>KMT2D</i> (25.8%), and <i>TP53</i> (25.8%). Subgroup analysis of tissue samples showed that <i>CDKN2A</i> mutations (<i>P</i> = 0.028), along with alterations in BCR and TCR signaling (<i>P</i> = 0.004) and the PI3K pathway (<i>P</i> = 0.008), were enriched in the blastoid subtype. <i>ATM</i> mutations (<i>P</i> = 0.041) were more prevalent in MIPI-low patients, while epigenetic chromatin remodeling pathway alterations (<i>P</i> = 0.028) were more common in MIPI-high patients. Plasma ctDNA demonstrated high sensitivity for detecting structural variants (96.6%), followed by mutations (71.3%) and copy number variants (30.0%). 75% of patients exhibited moderate-to-high concordance in detecting genomic variants between plasma and tissue samples. Pretreatment ctDNA levels exhibited high specificity in predicting clinical efficacy but had a suboptimal sensitivity of 68.2%. Higher ctDNA levels were significantly associated with shorter progression-free survival (PFS; <i>P</i> = 0.002) and overall survival (OS; <i>P</i> = 0.009). Additional ctDNA-based genetic features associated with shorter PFS included <i>TP53</i> (<i>P</i> = 0.002), <i>TRAF2</i> (<i>P</i> = 0.023), and <i>SMARCA4</i> (<i>P</i> = 0.023) mutations, while <i>TP53</i> (<i>P</i> = 0.006) and <i>TERT</i> (<i>P</i> = 0.031) mutations predicted shorter OS. Persistent positive ctDNA in post-treatment plasma samples indicated molecular relapse and poor prognosis, whereas undetectable ctDNA defined a subset of patients with favorable survival outcomes.</p> Conclusions <p>This study identified plasma ctDNA as a promising biomarker that noninvasively captures tumor-derived genetic variants associated with treatment response and survival outcomes in MCL, highlighting the clinical value of ctDNA for diagnosis, recurrence prediction, and surveillance monitoring.</p>

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Genomic signatures in plasma circulating tumor DNA reveal treatment response and prognostic insights in mantel cell lymphoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月3日

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  • Zhou Ouyang,
  • Ruolan Zeng,
  • Song Wang,
  • Xiaoying Wu,
  • Yajun Li,
  • Yizi He,
  • Caiqin Wang,
  • Chen Xia,
  • Qiuxiang Ou,
  • Hua Bao,
  • Wei Yang,
  • Ling Xiao,
  • Hui Zhou

摘要

Background

Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin’s lymphoma. The applicability of circulating tumor DNA (ctDNA) for predicting treatment response and prognosis in MCL remains underexplored.

Methods

This study included 34 MCL patients receiving first-line chemoimmunotherapy. We assessed the ability of plasma ctDNA to detect tumor-specific genetic alterations and explored its potential as a noninvasive biomarker for treatment response and prognosis in MCL.

Results

Commonly mutated genes in MCL included CCND1 (93.5%), ATM (48.4%), KMT2D (25.8%), and TP53 (25.8%). Subgroup analysis of tissue samples showed that CDKN2A mutations (P = 0.028), along with alterations in BCR and TCR signaling (P = 0.004) and the PI3K pathway (P = 0.008), were enriched in the blastoid subtype. ATM mutations (P = 0.041) were more prevalent in MIPI-low patients, while epigenetic chromatin remodeling pathway alterations (P = 0.028) were more common in MIPI-high patients. Plasma ctDNA demonstrated high sensitivity for detecting structural variants (96.6%), followed by mutations (71.3%) and copy number variants (30.0%). 75% of patients exhibited moderate-to-high concordance in detecting genomic variants between plasma and tissue samples. Pretreatment ctDNA levels exhibited high specificity in predicting clinical efficacy but had a suboptimal sensitivity of 68.2%. Higher ctDNA levels were significantly associated with shorter progression-free survival (PFS; P = 0.002) and overall survival (OS; P = 0.009). Additional ctDNA-based genetic features associated with shorter PFS included TP53 (P = 0.002), TRAF2 (P = 0.023), and SMARCA4 (P = 0.023) mutations, while TP53 (P = 0.006) and TERT (P = 0.031) mutations predicted shorter OS. Persistent positive ctDNA in post-treatment plasma samples indicated molecular relapse and poor prognosis, whereas undetectable ctDNA defined a subset of patients with favorable survival outcomes.

Conclusions

This study identified plasma ctDNA as a promising biomarker that noninvasively captures tumor-derived genetic variants associated with treatment response and survival outcomes in MCL, highlighting the clinical value of ctDNA for diagnosis, recurrence prediction, and surveillance monitoring.