The average copy number variation (CNVA) of chromosome fragments is a potential surrogate for tumor mutational burden in predicting responses to immunotherapy in non-small-cell lung cancer.

Abstract

ObjectivesThe tumor mutational burden (TMB) is closely related to immunotherapy outcome. However, the cost of TMB detection is extremely high, which limits its use in clinical practice. A new indicator of genomic instability, the average copy number variation (CNVA), calculates the changes of 0.5‐Mb chromosomal fragments and requires extremely low sequencing depth.MethodsIn this study, 50 samples (23 of which were from patients who received immunotherapy) were subjected to low‐depth (10X) chromosome sequencing on the MGI platform. CNVA was calculated by the formula avg (abs (copy number‐2)). In addition, CNVA and TMB were compared with regard to their ability to predict immune infiltration in 509 patients from TCGA.ResultsThe high‐CNVA group had higher expression levels of PD‐L1, CD39 and CD19 and a higher degree of infiltration of CD8+ T cells and CD3 + T cells. Among the 23 patients treated with immunotherapy, the average CNVA value of the stable disease/partial response group was higher than that of the progressive disease group (P < 0.05). Whole‐genome sequencing data of 509 patients from TCGA and RT‐PCR results of 22 frozen specimens showed that CNVA is more effective than TMB in indicating infiltration of CD8+ T cells and expression of PD‐L1, and CNVA also showed a specific positive correlation with TMB (r = 0.2728, P < 0.0001).ConclusionsCopy number variation can be a good indicator of immune infiltration and immunotherapy efficacy, and with its low cost, it is expected to become a substitute for TMB.