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Integrated clinical genomic analysis reveals xenobiotic metabolic genes are downregulated in meningiomas of current smokers

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Abstract

Introduction

Meningiomas are the most common primary intracranial tumor. Recently, various genetic classification systems for meningioma have been described. 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 in this study. 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, twenty-two were past smokers, and nine were current smokers. The clinical data showed no major differences in natural history across smoking status. WES revealed absence of AKT1 mutation rate in current or past smokers compared to non-smokers (p = 0.046). Current smokers had increased mutation rate in NOTCH2 compared to past and never smokers (p < 0.05). Mutational signature from current and past smokers showed disrupted DNA mismatch repair (cosine-similarity = 0.759 and 0.783). DEG analysis 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).

Conclusion

In this study, we conducted a comparative analysis of meningioma patients based on their smoking history, examining both their clinical trajectories and molecular changes. Meningiomas from current smokers were more likely to harbor NOTCH2 mutations, and AKT1 mutations were absent in current or past smokers. Moreover, both current and past smokers exhibited a mutational signature associated with DNA mismatch repair. Meningiomas from current smokers demonstrate downregulation of xenobiotic metabolic enzymes UGT2A1 and UGT2A2, which are downregulated in other smoking related cancers. Furthermore, current smokers exhibited downregulation xenobiotic metabolic gene sets, as well as enrichment in gene sets related to mitotic spindle, E2F targets, and G2M checkpoint, which are hallmark pathways involved in cell division and DNA replication control. In aggregate, our results demonstrate novel alterations in meningioma molecular biology in response to systemic carcinogens.

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Data availability

All data is publicly available in the Gene Expression Omnibus (GEO) database (accession no. GSE136661).

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Funding

Parts of this study were funded by the Roderick D. Mac- Donald Fund, the Jan and Dan Duncan Neurologic Research Institute at Texas Children’s Hospital, and the Hamill Foundation. A.J.P. is supported by a K08 award by the National Institute of Neurological Disorders and Stroke (K08NS102474).

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Author notes

  1. A. Basit Khan, Rajan Patel, Malcolm F. McDonald have contributed equally.

Authors and Affiliations

  1. Department of Neurosurgery, Baylor College of Medicine, Houston, USA

    A. Basit Khan, Rajan Patel, Malcolm F. McDonald, Eric Goethe, Collin English, Ron Gadot, Arya Shetty, Shervin Hosseingholi Nouri, Akdes S. Harmanci, Tiemo J. Klisch & Akash J. Patel

  2. Medical Scientist Training Program, Baylor College of Medicine, Houston, USA

    Malcolm F. McDonald

  3. School of Biomedical Informatics, University of Texas Health Science Center Houston, Houston, USA

    Arif O. Harmanci

  4. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, USA

    Tiemo J. Klisch & Akash J. Patel

  5. Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, USA

    Akash J. Patel

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Contributions

ABK, RP, MFM, AOH, ASH, TJK, and AJP designed the research. ABK, RP, MFM, RG, EG, AS, CE, SHN, TJK, and AJP performed the research. ABK, RP, MFM, ASH, AOH, TJK, and AJP analyzed the data. ABK, RJ, MFM, RG, and AJP wrote the manuscript.

Corresponding author

Correspondence to Akash J. Patel.

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The authors declare no competing interests.

Informed consent

All patients provided written informed consent, and tumor tissues were collected under an IRB approved protocol at BCM.

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Supplementary Information

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Supplementary file1 (PDF 595 KB)

Fig. S1 Classification of mutation type in each sample. (a) Mutational summary of meningioma of current, past, and never smokers. (b) Transition and transversion analysis of meningioma of current, past, and never smokers. (c) Most frequently mutated genes in of meningioma of current, past, and never smokers.

Supplementary file2 (PDF 647 KB)

Fig. S2 (a) Heatmap of the 1000 most expressed genes with samples organized by unsupervised clustering. (b) PCA plot coded by MenG Group and smoking history.

Supplementary file3 (PDF 1291 KB)

Fig. S3 Within MenG Group GSEA analysis on the basis of smoking status.

Supplementary file4 (DOCX 18 KB)

Supplementary file5 (DOCX 27 KB)

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Khan, A.B., Patel, R., McDonald, M.F. et al. Integrated clinical genomic analysis reveals xenobiotic metabolic genes are downregulated in meningiomas of current smokers. J Neurooncol 163, 397–405 (2023). https://doi.org/10.1007/s11060-023-04359-7

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  • DOI: https://doi.org/10.1007/s11060-023-04359-7

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