Predicting response to immune checkpoint blockade in NSCLC with tumour-only RNA-seq

Markham, JF; Fellowes, AP; Green, T; Leal, JL; Legaie, R; Cullerne, D; Morris, T; John, T; Solomon, B; Fox, SB

Author(s): Markham, JF; Fellowes, AP; Green, T; Leal, JL; Legaie, R; Cullerne, D; Morris, T; John, T; Solomon, B; Fox, SB;
Details: Publication Year 2023-04,Volume 128,Issue #6,Page 1148-1154
Journal Title: British Journal of Cancer
Publication Type: Research article
Abstract: BACKGROUND: Targeted RNA sequencing (RNA-seq) from FFPE specimens is used clinically in cancer for its ability to estimate gene expression and to detect fusions. Using a cohort of NSCLC patients, we sought to determine whether targeted RNA-seq could be used to measure tumour mutational burden (TMB) and the expression of immune-cell-restricted genes from FFPE specimens and whether these could predict response to immune checkpoint blockade. METHODS: Using The Cancer Genome Atlas LUAD dataset, we developed a method for determining TMB from tumour-only RNA-seq and showed a correlation with DNA sequencing derived TMB calculated from tumour/normal sample pairs (Spearman correlation = 0.79, 95% CI [0.73, 0.83]. We applied this method to targeted sequencing data from our patient cohort and validated these results against TMB estimates obtained using an orthogonal assay (Spearman correlation = 0.49, 95% CI [0.24, 0.68]). RESULTS: We observed that the RNA measure of TMB was significantly higher in responders to immune blockade treatment (P = 0.028) and that it was predictive of response (AUC = 0.640 with 95% CI [0.493, 0.786]). By contrast, the expression of immune-cell-restricted genes was uncorrelated with patient outcome. CONCLUSION: TMB calculated from targeted RNA sequencing has a similar diagnostic ability to TMB generated from targeted DNA sequencing.
Publisher: Springer Nature
Keywords: Humans; *Lung Neoplasms/drug therapy; Immune Checkpoint Inhibitors/therapeutic use; RNA-Seq; Mutation; *Antineoplastic Agents, Immunological/therapeutic use; *Carcinoma, Non-Small-Cell Lung/drug therapy; Sequence Analysis, RNA; Rna; Biomarkers, Tumor/genetics
Department(s): Pathology; Laboratory Research
PubMed ID: 36572732
Publisher's Version: https://doi.org/10.1038/s41416-022-02105-w
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-08-03 07:58:18

Last Modified: 2023-08-03 08:01:33