|Title||Cancer-Specific Thresholds Adjust for Whole Exome Sequencing-based Tumor Mutational Burden Distribution.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Fernandez EM, Eng K, Beg S, Beltran H, Faltas BM, Mosquera JMiguel, Nanus DM, Pisapia DJ, Rao RA, Robinson BD, Rubin MA, Elemento O, Sboner A, Shah MA, Song W|
|Journal||JCO Precis Oncol|
Purpose: To understand the clinical context of tumor mutational burden (TMB) when comparing a pan-cancer threshold and a cancer-specific threshold.
Materials and Methods: Using whole exome sequencing (WES) data from primary tumors in The Cancer Genome Atlas (TCGA) (n=3,534) and advanced/metastatic tumors from Weill Cornell Medicine (WCM Advanced) (n=696), TMB status was determined using a pan-cancer and cancer-specific threshold. Survival curves, number of samples classified as TMB high, and predicted neoantigens were used to evaluate the differences between thresholds.
Results: The distribution of TMB varied dramatically between cancer types. A cancer-specific threshold was able to adjust for the different TMB distributions, while the pan-cancer threshold was often too stringent. The dynamic nature of the cancer-specific threshold resulted in more tumors being classified as TMB high compared to the static pan-cancer threshold. Additionally, no significant difference in survival outcomes was found with the cancer-specific threshold compared to the pan-cancer one. Further, the cancer-specific threshold maintains higher predicted neoantigen load for the TMB high samples compared to the TMB low samples, even when the threshold is lower than the pan-cancer threshold.
Conclusion: TMB is relative to the context of cancer type, metastatic state, and disease stage. Compared to a pan-cancer threshold, a cancer-specific threshold classifies more patients as TMB high while maintaining clinical outcomes that were not significantly different. Furthermore, the cancer-specific threshold identifies patients with a high number of predicted neoantigens. Due to the potential impact in cancer patient care, TMB status should be determined in a cancer-specific manner.
|Alternate Journal||JCO Precis Oncol|
|PubMed Central ID||PMC6716608|
|Grant List||R01 CA194547 / CA / NCI NIH HHS / United States |
U24 CA210989 / CA / NCI NIH HHS / United States