SCI

9 September 2024

Tumour mutational burden: clinical utility, challenges and emerging improvements

（nature reviews clinical oncology, if=81.1）

  • Budczies J, Kazdal D, Menzel M, Beck S, Kluck K, Altbürger C, Schwab C, Allgäuer M, Ahadova A, Kloor M, Schirmacher P, Peters S, Krämer A, Christopoulos P, Stenzinger A

  • Correspondence: jan.budczies@med.uni-heidelberg.de

Tumour mutational burden (TMB), defined as the total number of somatic non-synonymous mutations present within the cancer genome, varies across and within cancer types. A first wave of retrospective and prospective research identified TMB as a predictive biomarker of response to immune-checkpoint inhibitors and culminated in the disease-agnostic approval of pembrolizumab for patients with TMB-high tumours based on data from the Keynote-158 trial. Although the applicability of outcomes from this trial to all cancer types and the optimal thresholds for TMB are yet to be ascertained, research into TMB is advancing along three principal avenues: enhancement of TMB assessments through rigorous quality control measures within the laboratory process, including the mitigation of confounding factors such as limited panel scope and low tumour purity; refinement of the traditional TMB framework through the incorporation of innovative concepts such as clonal, persistent or HLA-corrected TMB, tumour neoantigen load and mutational signatures; and integration of TMB with established and emerging biomarkers such as PD-L1 expression, microsatellite instability, immune gene expression profiles and the tumour immune contexture. Given its pivotal functions in both the pathogenesis of cancer and the ability of the immune system to recognize tumours, a profound comprehension of the foundational principles and the continued evolution of TMB are of paramount relevance for the field of oncology.

肿瘤突变负荷（TMB），定义为癌症基因组中存在的体细胞非同义突变总数，在癌症类型中各不相同。第一波回顾性和前瞻性研究将TMB确定为对免疫检查点抑制剂反应的预测性生物标志物，并最终根据Keynote-158试验的数据，批准了pembrolizumab用于TMB高肿瘤患者。尽管该试验结果对所有癌症类型的适用性和TMB的最佳阈值尚待确定，但对TMB的研究正在沿着三条主要途径推进：通过实验室过程中严格的质量控制措施，包括减轻混淆因素，如有限的小组范围和低肿瘤纯度，加强TMB评估；通过引入克隆、持续性或HLA校正的TMB、肿瘤新抗原载量和突变特征等创新概念，完善传统的TMB框架；以及TMB与已建立和新兴的生物标志物的整合，如PD-L1表达、微卫星不稳定性、免疫基因表达谱和肿瘤免疫背景。鉴于TMB在癌症发病机制和免疫系统识别肿瘤的能力中的关键功能，深入理解TMB的基本原理和持续进化对肿瘤学领域至关重要。


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