Pan-cancer analysis of heterogeneity of tumor mutational burden and genomic mutation under treatment pressure

Background: 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 clari fi ed. This retrospective observational study aimed to investigate the heterogeneity of TMB and genomic mutation under the treatment pressure. Patients and methods: 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. Results: This integrated analysis has shown anticancer treatments increased TMB. Signi fi cant effects of treatment on TMB were more frequently observed in tumor types with lower treatment-na & iuml;ve 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 signi fi cantly 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 signi fi cantly changed in post-chemotherapy tumors compared to treatment-na & iuml;ve tumors. Conclusion: 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.