Humaira Noor

Background: Tumour mutation burden (TMB) is an emerging pan‐cancer biomarker with predictive value for immune checkpoint inhibitor (ICI) outcomes, yet evidence is inconsistent due to methodological variability and cut‐off thresholds. This systematic review and meta‐analysis evaluated the impact of TMB on overall survival (OS) and progression‐free survival (PFS) across solid tumours in ICI‐treated cohorts and its predictive relevance in non‐ICI‐treated cohorts. Methods: Following PRISMA 2020 guidelines, we searched PubMed, Scopus, ScienceDirect and Cochrane for studies published between 2010 and 2024 reporting hazard ratios (HRs) and 95% confidence intervals (CIs) for OS and PFS in high‐ versus low‐TMB cohorts. High and low TMB were defined by study‐specific cut‐offs, and ultra‐high TMB was defined as the top 20% of cohort‐specific values. Study quality was assessed with the Newcastle‐Ottawa Scale; heterogeneity with I ² ; publication bias with funnel plots/Egger's test; and robustness by leave‐one‐out analysis. Results: 5278 patients across 28 studies were analysed. High TMB, defined by cohort‐specific cut‐offs, was significantly associated with improved OS and PFS, particularly in non‐small cell lung cancer (OS: HR = 0.56), selected gastrointestinal cancers (OS: HR = 0.36), and advanced/recurrent tumours (OS: HR = 0.52). Benefits were greatest in ICI‐treated patients, especially with combined anti‐PD‐L1/PD‐1 and anti‐CTLA‐4 therapy (OS: HR = 0.47; PFS: HR = 0.50). Chemotherapy‐treated cohorts also showed better outcomes, but less consistently (OS: HR = 0.60; PFS: HR = 0.55). Ultra‐high TMB had better OS than the universal 10 mut/Mb cut‐off (HR = 0.44 vs. 0.58). Non‐beneficial associations were observed in glioma and penile squamous cell carcinoma, highlighting disease‐specific variability. Sequencing platforms and cut‐off definitions remained sources of heterogeneity. Conclusion: TMB demonstrates prognostic relevance and predictive utility in a histology‐ and treatment‐context‐dependent manner, with the most consistent associations in selected ICI‐treated tumours. Associations in non‐ICI‐treated cohorts were weaker and inconsistent, indicating putative predictive value. Standardising TMB assessment and refining relevant thresholds are essential for optimising its role in precision oncology. Trial Registration: PROSPERO Registration Number: CRD42024608809

Spatial distribution of AIMP1 and AIMP3 expression across tumor tissues in two representative GBM slides

Pan-cancer comparison of AIMP1/2/3 mRNA expression levels between tumor (TCGA) versus normal tissue (GTEx).

Prognostic AIMP1/2/3 CpG-sites in TCGA GBM and TCGA Astrocytoma

Spatial and cell type–specific expression of AIMP2 in GBM tumors. A, Spatial distribution of AIMP2 expression across tumor tissues in two representative GBM slides (i: slide 334_T and ii: slide 268_T) analyzed using a spatial transcriptomic dataset. The heatmaps display homogeneous expression of AIMP2 with varying intensity from low (purple) to high (yellow), indicating the absence of localized expression hotspots. B, Violin plots representing AIMP2 expression across GBM cellular subtypes. i,AIMP2 expression in key GBM subtypes, including MES-like, AC-like, oligodendrocyte progenitor cell (OPC)–like, and neural progenitor cell (NPC)–like cells from a concatenated single-cell RNA-seq cohort (Kruskal–Wallis P = 2.32e−02). ii,AIMP2 expression across malignant GBM subtypes from a spatial transcriptomic dataset. (Kruskal–Wallis P = 1.32e−03).

Bevacizumab treatment response is associated with specific AIMP CpG site methylation status in gliomas. A, Significant association between two CpG sites and astrocytoma (n = 22) pathologic response to bevacizumab treatment. A Student t test P value < 0.05 was considered significant. B, Forest plots depicting Cox proportional hazards model univariate (i) and multivariate (ii) analysis for the effects of AIMP1/2/3 CpG methylation status in GBM (n = 27) and astrocytoma (n = 24).

Results of Cox Proportional Hazards univariate analysis of AIMP CpG methylation with adjusted p-values

AIMPs are associated with tumor aggressiveness, recurrence, and prognosis. AIMP mRNA expression levels in (Ai) low-grade (II; n = 103) and high-grade (III and IV; n = 218) gliomas (P values 0.011, < 0.001, and 0.014 for AIMP1, AIMP2, and AIMP3, respectively), and (Aii) primary (n = 229) and recurrent gliomas (n = 62) in CGGA dataset (P values 0.058, P < 0.001, and P < 0.001 for AIMP1, AIMP2, and AIMP3, respectively). A Mann–Whitney test P value < 0.05 was considered statistically significant. B, Kaplan–Meier survival curves depicting prognostic effects of AIMP1/2/3 mRNA expressions in CGGA, TCGA, REMBRANDT, and Gravendeel cohorts of GBM. Red = high expression and green = low expression based on median cutoff; A log-rank P value < 0.05 is considered significant.

Correlation between specific AIMP1/2/3 CpG site methylation levels and their respective mRNA expression levels

Kaplan-Meier survival analysis on retrospective clinical trials of recurrent GBM (REGOMA and BELOB trials).