Abstract 3634: Copy number alterations in chromosome 19 genes associate with reduced immune infiltrate and adverse outcomes in lung cancer

Abstract

Abstract Deleterious mutations in STK11/LKB1, KEAP1, and SMARCA4 have been shown to be associated with adverse response to immunotherapy in several lung cancer cohorts. However, the biological and clinical implications of deletions of these genes, which all reside on chromosome 19p (chr19p), has not been extensively described. We sought to first characterize the association between immune infiltration and these copy number changes in chr19p. To do this, we analyzed mutation, copy number, and gene expression data from non-small cell lung cancer cohorts in the Cancer Genome Atlas (TCGA). Chr19p is frequently deleted across cancers in the TCGA dataset, with higher rates in lung adenocarcinoma. In both lung adenocarcinoma and squamous cell carcinoma, nearly half of TCGA tumors have deletion of chr19p including STK11, KEAP1, and SMARCA4, and these tumors are enriched for STK11 mutation. Immune infiltrate (estimated by methylation patterns) was not significantly associated with STK11 mutation but was significantly reduced in tumors with chr19 deletion when controlling for tumor type and overall copy number load. In addition, low-level deletion of any of these genes correlated with decreased expression of immune signaling pathways. Based on these findings, we next wanted to characterize the association between chr19p copy number and immunotherapy response. We previously reported that low-level deletion of STK11 correlated with an immunosuppressive, treatment-refractory phenotype in samples collected from non-small cell lung cancer (NSCLC) patients with resectable disease in a phase II study of neoadjuvant atezolizumab + chemotherapy. To confirm these findings in a larger cohort, we examined the AACR GENIE NSCLC biopharma collective (BPC) dataset. A subset of this cohort included patients treated with immunotherapy (atezolizumab, nivolumab, and/or pembrolizumab) and with copy number data available or GISTIC analysis of individual genes (n = 204). Here, deletion of any of these three genes correlated with worse overall survival, and this was statistically significant for STK11 deletion. Overall, our data suggests that a broader set of patients, defined by copy number changes in these genes, may experience this adverse immunobiology. Further study to elucidate the mechanistic implications of this association is warranted. Citation Format: Brian S. Henick, Yohanna Georgis, Benjamin O. Herzberg, Carla P. Concepcion-Crisol, Alison M. Taylor. Copy number alterations in chromosome 19 genes associate with reduced immune infiltrate and adverse outcomes in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3634.