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

Objectives. The 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. Methods. In this study, 50 samples (23 of which were from patients who received immunotherapy) were subjected to lowdepth (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. Results. The 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). Conclusions. Copy 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.

Mutational and Transcriptional Characterization Establishes Prognostic Models for Resectable Lung Squamous Cell Carcinoma

“…It was observed that patients with high mutational burden generally exhibited low copy number changes, while patients with low mutational burden may have high copy number changes. 35 Some cancers exhibit low mutational burden but high copy number variation (CNV) and some cancers are contrary, 35 , 43 and those with high CNV changes generally exhibited worse prognosis. 44 Metastatic cancers generally exhibit higher CNV changes than those at earlier stages.…”

Association between plasma somatic copy number variations and response to immunotherapy in patients with programmed death-ligand 1-negative non-small cell lung cancer

“…Several recent studies indicated that chromosomal abnormalities might cause dysregulation of the immune microenvironment, and tumors with low CNV levels displayed more immune infiltration and a better response to ICI treatment. 29 , 30 Detailed analysis of two published clinical trials of melanoma patients treated with immunotherapy showed that the somatic CNV level was a stronger predictive marker of cytotoxic immune cell infiltration than TMB. 29 These findings suggest that plasma CNV score may become an effective and accurate biomarker for predicting resistance to immunotherapeutic agents in patients with lung cancer.…”

Chromatin Separation Regulators Predict the Prognosis and Immune Microenvironment Estimation in Lung Adenocarcinoma

“…What's more, we found a higher TMB score in cluster 1, which was positively associated with the 48 CSRs. A recent study has shown that the average copy number variation (CNVA) of chromosome fragments is a potential surrogate for tumor mutational burden in predicting responses to immunotherapy in NSCLC (Lei et al, 2021). Therefore, the increased genomic instability in tumors with dysregulated chromosome segregation alters mutational load and in turn impacts antitumoral immune responses, which further impacts the prognosis in LUAD.…”