Panels and models for accurate prediction of tumor mutation burden in tumor samples

Abstract

Immune checkpoint blockade (ICB) is becoming standard-of-care in many types of human malignancies, but patient selection is still imperfect. Tumor mutation burden (TMB) is being evaluated as a biomarker for ICB in clinical trials, but most of the sequencing panels used to estimate it are inadequately designed. Here, we present a bioinformatics-based method to select panels and mathematical models for accurate TMB prediction. Our method is based on tumor-specific, forward-step selection of genes, generation of panels using a linear regression algorithm, and rigorous internal and external validation comparing predicted with experimental TMB. As a result, we propose cancer-specific panels for 14 malignancies which can offer reliable, clinically relevant estimates of TMBs. Our work facilitates a better prediction of TMB that can improve the selection of patients for ICB therapy.

Genetic Engineering of Dendritic Cells Using Partially Zwitterionic Dendrimer-Entrapped Gold Nanoparticles Boosts Efficient Tumor Immunotherapy

“…Instead, along with the aPD-L1 treatment, the increased effector T cell population leads to increased secretion of IFN-γ and other cytokines, whose receptors are overexpressed by tumor cells. This can positively influence and reactivate PD-L1 expression on the tumor cells. , In this way, the aPD-L1 treatment can lead to enhanced expression of tumor PD-L1 for sensitized ICB.…”

“…This can positively influence and reactivate PD-L1 expression on the tumor cells. 51,52 In this way, the aPD-L1 treatment can lead to enhanced expression of tumor PD-L1 for sensitized ICB.…”

Somatic mutation but not aneuploidy differentiates lung cancer in never-smokers and smokers

“…There was no significant difference in the FGA between both never-/light-and heavy smokers in our cohort (p>0.05) (Figure 4B, Methods). Analysis of the MSKCC [33][34][35][36] cohort showed that tumors from never-/light-smokers paradoxically had higher FGA than heavy smokers (p<0.0001) (Figure S5C). Consistently, FGA did not correlate with pack-years of cigarettes smoked in our cohort (Spearman's correlation r=-0.19, p=0.10) and showed a negative correlation in the Campbell cohort (Spearman's correlation r=-0.08, p=0.02) (Figure S5D).…”

The current state of molecular profiling in gastrointestinal malignancies

“…TMB, defined as the total number of exon mutations in a tissue sample [ 35 ], has emerged as an important biomarker associated with immunotherapy response in multiple tumor types [ 26 ]. TMB is a critical driver in the generation of immunogenic neopeptides presented on major histocompatibility complexes on the tumor cell surface [ 36 ].…”