高肿瘤突变负荷（TMB）是广泛研究的免疫检查点抑制剂的预测生物标志物之一，并已被证明与多种癌症类型的免疫治疗反应密切相关。然而，对于常规治疗失败而即将接受免疫治疗的患者，对于肿瘤取样进行TMB分析的时机尚无共识建议，不同疗法对TMB的影响也尚未明确。这项回顾性观察研究旨在调查治疗压力下 TMB 和基因组突变的异质性。我们回顾性地收集了 30 项已发表研究中发现的 15 种肿瘤类型（> 50 个样本/肿瘤）的 8051 个样本的可用基因组和治疗信息，并调查了不同队列治疗下 TMB 的分布和异质性。这项综合分析表明，抗癌治疗增加了 TMB。在未接受过治疗的 TMB 较低的肿瘤类型中，更常观察到 TMB 治疗的显着效果，包括乳腺癌、前列腺癌和儿科癌症。对于不同的癌症治疗，化疗往往与大多数癌症类型的 TMB 增加相关。与此同时，乳腺癌、前列腺癌、膀胱癌和神经胶质瘤的 TMB 高类别比例在化疗后显着增加。与初治肿瘤相比，化疗后肿瘤中的一些可作用基因（包括乳腺癌中的 ERS1 和 NF1）以及一些预后标志物（包括膀胱癌中的 TERT 和神经胶质瘤中的 IDH1）发生了显着变化。我们的研究揭示了 TMB 的异质性。不同癌症类型的治疗，并提供证据表明化疗与 TMB 以及 TMB 高类别分数的增加相关，这表明重新采样肿瘤组织以计算化疗后 TMB 可能是预测免疫治疗反应的更好选择，特别是对于最初 TMB 较低的肿瘤。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

High tumor mutational burden (TMB) is one of the widely researched predictive biomarkers of immune checkpoint inhibitors and has been shown to be closely related with response to immunotherapy in multiple cancer types. However, for patients who have failed conventional therapy and are about to undergo immunotherapy, there is no consensus recommendation on the timing of tumor sampling for TMB analysis, and the effects of different therapies on TMB have not been clarified. This retrospective observational study aimed to investigate the heterogeneity of TMB and genomic mutation under the treatment pressure.We retrospectively collected the available genomic and therapeutic information from 8051 samples across 15 tumor types (>50 samples/tumor) found in 30 published studies and investigated the distribution and heterogeneity of TMB under treatment across diverse cohorts.This integrated analysis has shown anticancer treatments increased TMB. Significant effects of treatment on TMB were more frequently observed in tumor types with lower treatment-naïve TMB, including breast, prostate, and pediatric cancers. For different cancer therapies, chemotherapy was prone to be correlated with an increased TMB in most cancer types. Meanwhile, the fraction of the TMB-high category of breast, prostate, and bladder cancers and glioma increased significantly after chemotherapy. Several actionable genes including ERS1 and NF1 in breast cancer, as well as some prognostic markers including TERT in bladder cancer and IDH1 in glioma, were significantly changed in post-chemotherapy tumors compared to treatment-naïve tumors.Our study reveals the heterogeneity of TMB under treatment across diverse cancer types and provides evidences that chemotherapy was associated with increases in TMB as well as the fraction of TMB-high category, suggesting that resampling tumor tissues for calculating post-chemotherapy TMB could be a better option for predicting the response to immunotherapy, especially for tumors with initially low TMB.Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.