TP53 or CDKN2A/B covariation in ALK/RET/ROS1-rearranged NSCLC is associated with a high TMB, tumor immunosuppressive microenvironment and poor prognosis.

Abstract

ALK-rearranged lung adenocarcinomas with TP53 mutations have more unstable genomic features, poorer ALK-TKI efficacy and a worse prognosis than ALK-rearranged lung adenocarcinomas with wild-type TP53. Here, we examine the gene variations that co-occur with ALK/RET/ROS1 rearrangements in NSCLC and the corresponding tumor immune microenvironment, as well as their association with prognosis. A total of 155 patients with ALK/RET/ROS1 fusions were included retrospectively. Tumor genome mutation analysis was performed by next-generation sequencing. PD-L1 expression and tumor-infiltrating lymphocytes were assessed by multiplex immunohistochemistry. The correlations among gene covariation, the tumor immune microenvironment, and clinicopathological characteristics were analyzed. Among the 155 patients, concomitant TP53 mutation appeared most frequently (31%), followed by CDKN2A/B copy number loss (15%). The ALK/RET/ROS1 fusion and TP53 or CDKN2A/B covariation group had more males and patients with stage IV disease (p < 0.001, p = 0.0066). Patients with TP53 or CDKN2A/B co-occurrence had higher tumor mutation burdens and more neoantigens (p < 0.001, p = 0.0032). PD-L1 expression was higher in the tumor areas of the TP53 or CDKN2A/B co-occurring group (p = 0.00038). However, the levels of CD8+, CD8+PD1-, and CD8+PD-L1- TILs were lower in the tumor areas of this group (p = 0.043, p = 0.029, p = 0.025). In the TCGA NSCLC cohorts, the top 2 mutated genes were CDKN2A/B (24%) and TP53 (16%). The TP53 or CDKN2A/B co-occurring group had higher tumor mutation burdens and shorter OS (p < 0.001, p < 0.001). Patients with co-occurring TP53/CDKN2A/B variations and ALK/RET/ROS1 rearrangements are associated with high TMB, more neoantigens, an immunosuppressive microenvironment and a worse prognosis.