152 Integrated Clinical Genomic Analysis Reveals Xenobiotic Metabolic Genes are Downregulated in Meningiomas of Current Smokers

Abstract

INTRODUCTION: Meningiomas are the most common primary intracranial tumor. We sought to identify clinical drivers of different molecular changes in meningioma. As such, clinical and genomic consequences of smoking in patients with meningiomas remain unexplored. METHODS: 88 tumor samples were analyzed. Whole exome sequencing (WES) was used to assess somatic mutation burden. RNA sequencing data was used to identify differentially expressed genes (DEG) and genes sets (GSEA). RESULTS: Fifty-seven patients had no history of smoking, thirty-one patients had history of ever smoking. Smokers were less likely to present with headache (p = 0.045) or have incidentally discovered meningiomas (p = 0.049). WES revealed no difference in canonical mutation burden. Smokers had increased mutation rate in KRTAP1-3, RECQL4, PTPRT, and PLB1 compared to never smokers (p < 0.05). Mutational signature from smokers showed disrupted DNA mismatch repair (cosine-similarity = .784). DEG analysis of current smokers as compared to past or never smokers revealed the xenobiotic metabolic genes UGT2A1 and UGT2A2 were both significantly downregulated in current smokers compared to past (Log2FC = -3.97, padj = 0.0347 and Log2FC = -4.18, padj = 0.0304) and never smokers (Log2FC = -3.86, padj = 0.0235 and Log2FC = -4.20, padj = 0.0149). GSEA analysis of current smokers showed downregulation of xenobiotic metabolism and enrichment for G2M checkpoint, E2F targets, and mitotic spindle compared to past and never smokers (FDR <25% each). CONCLUSIONS: There are limited differences in the clinical course of meningioma patients who smoke. There is no difference in burden of canonical mutations in meningiomas from patients who smoke, but differential mutation in several novel meningioma genes is identified. Mutational signatures in meningiomas from smokers show disrupted DNA mismatch repair. Meningiomas from current smokers demonstrate downregulation of xenobiotic metabolic enzymes UGT2A1 and UGT2A2, which are downregulated in other smoking related cancers. Taken together, our demonstrate novel alterations in meningioma molecular biology in response to systemic carcinogens.