Evolutionary characteristics and immunological divergence of lung and brain metastasis lesions in NSCLC.

Brain metastases are one of the main reasons for lung cancer-related deaths but lack prediction methods. Many patients with brain metastases do not benefit from immunotherapy. A comprehensive genomic analysis of matched primary tumors (PTs) and their brain metastasis (BM) lesions may provide new insight into the evolutionary and immune characteristics. To describe evolutionary features and immune characteristic differences, we analyzed whole-exome sequencing (WES) data for 28 paired PT and BM samples from 14 non-small cell lung cancer (NSCLC) patients. In addition, we used another 26 matched PT and BM samples as a validation cohort. We found that total mutational signatures were relatively consistent between paired primary and brain metastatic tumors. Nevertheless, the shared mutations of the two lesions were fewer than the mutations present in each of the lesions alone. In the process of brain metastasis, driver genes undergo evolutionary branches. Typical driver genes, including EGFR and TP53, appear relatively conserved throughout evolution; however, specific signals are enriched in brain metastasis lesions. We found several main characteristics of lung cancer brain metastases that were different from primary lung cancer, such as genomic instability, novel driver genes, tumor mutational burden (TMB), and brain metastasis lesion private neoantigens. In addition, the estimated timing of dissemination showed that brain metastases might occur early in lung cancer. Implications: Mechanistic insight from this study provides new insight into the biology of the metastatic brain process and a new beneficial approach for preventing and treating lung cancer brain metastases.