Designing gene panels for tumor mutational burden estimation: the need to shift from ‘correlation’ to ‘accuracy’

AbstractTumor mutational burden (TMB) assessment is at the forefront in precision medicine. The TMB could represent a biomarker for immune checkpoint inhibitors (ICIs) responses. Whole exome sequencing (WES) is the gold standard to derive the TMB; while targeted next-generation sequencing panels might be more feasible. However, mainstream panels use ‘correlation’ (R2) between panel- and WES-based TMB to validate TMB estimation, which could be vulnerable to be distorted by cases with relatively ultra-high TMB within each cancer type. The FDA-approved FoundationOne CDx (F1CDx) panel-based TMB estimation seemed reliable (R2 ≥ 0.75) in 24 out of 33 cancer types from the Cancer Genome Atlas, but most of them were overestimated by correlation as only seven cancer types had satisfactory accuracy (the proportion of cases correctly identified as TMB-high or TMB-low using panel-based TMB) above 90%. After removing case s with relatively ultra-high TMB within each cancer type, the correlation (R2) in 16 of these 24 cancer types declined dramatically ( Δ >  0.25) while all of their accuracy remained generally constant, indicating that accuracy is more robust than correlation. Similar results were also observed in other four panels. Further incorporating accuracy in panel design revealed that the minimal number of genes needed to achieve ≥ 90% acc uracy varied among cancer types and correlated negatively with their TMB levels (p = 0.001). In summary, currently ava...
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research