The MIF promoter SNP rs755622 is associated with immune activation in glioblastoma
Tyler J. Alban, Matthew M. Grabowski, Balint Otvos, Defne Bayik, Wesley Wang, Ajay Zalavadia, Vlad Makarov, Katie Troike, Mary McGraw, Anja Rabljenovic, Adam Lauko, Chase Neumann, Gustavo Roversi, Kristin A. Waite, Gino Cioffi, Nirav Patil, Thuy T. Tran, Kathleen McCortney, Alicia Steffens, C. Marcela Diaz, J. Mark Brown, Kathleen M. Egan, Craig M. Horbinski, Jill S. Barnholtz-Sloan, Prajwal Rajappa, Michael A. Vogelbaum, Richard Bucala, Timothy A. Chan, Manmeet S. Ahluwalia, Justin D. Lathia
Tyler J. Alban, Matthew M. Grabowski, Balint Otvos, Defne Bayik, Wesley Wang, Ajay Zalavadia, Vlad Makarov, Katie Troike, Mary McGraw, Anja Rabljenovic, Adam Lauko, Chase Neumann, Gustavo Roversi, Kristin A. Waite, Gino Cioffi, Nirav Patil, Thuy T. Tran, Kathleen McCortney, Alicia Steffens, C. Marcela Diaz, J. Mark Brown, Kathleen M. Egan, Craig M. Horbinski, Jill S. Barnholtz-Sloan, Prajwal Rajappa, Michael A. Vogelbaum, Richard Bucala, Timothy A. Chan, Manmeet S. Ahluwalia, Justin D. Lathia
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Research Article Immunology Oncology

The MIF promoter SNP rs755622 is associated with immune activation in glioblastoma

Abstract

Intratumoral heterogeneity is a defining hallmark of glioblastoma, driving drug resistance and ultimately recurrence. Many somatic drivers of microenvironmental change have been shown to affect this heterogeneity and, ultimately, the treatment response. However, little is known about how germline mutations affect the tumoral microenvironment. Here, we find that the single-nucleotide polymorphism (SNP) rs755622 in the promoter of the cytokine macrophage migration inhibitory factor (MIF) is associated with increased leukocyte infiltration in glioblastoma. Furthermore, we identified an association between rs755622 and lactotransferrin expression, which could also be used as a biomarker for immune-infiltrated tumors. These findings demonstrate that a germline SNP in the promoter region of MIF may affect the immune microenvironment and further reveal a link between lactotransferrin and immune activation.

Authors

Tyler J. Alban, Matthew M. Grabowski, Balint Otvos, Defne Bayik, Wesley Wang, Ajay Zalavadia, Vlad Makarov, Katie Troike, Mary McGraw, Anja Rabljenovic, Adam Lauko, Chase Neumann, Gustavo Roversi, Kristin A. Waite, Gino Cioffi, Nirav Patil, Thuy T. Tran, Kathleen McCortney, Alicia Steffens, C. Marcela Diaz, J. Mark Brown, Kathleen M. Egan, Craig M. Horbinski, Jill S. Barnholtz-Sloan, Prajwal Rajappa, Michael A. Vogelbaum, Richard Bucala, Timothy A. Chan, Manmeet S. Ahluwalia, Justin D. Lathia

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Figure 1

Patients with the MIF SNP rs755622 have an increase in lactotransferrin (LTF) and immune microenvironment signaling.

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Patients with the MIF SNP rs755622 have an increase in lactotransferrin ...
(A) Expression of the MIF gene mRNA in TCGA_GBMLGG (n = 701) was compared among the histological subtypes astrocytoma, oligodendroglioma, oligoastrocytoma, and GBM using unpaired t test. (B) The MIF gene structure highlighting the -794 CATT repeat, which contains between 5 and 8 repeats, and the MIF SNP rs755622 at position -173. (C) Using GBM samples from (n = 17) patients with a G/G genotype and (n = 17) with a C/G genotype, differential expression analysis was performed using DESeq2 on raw counts and the genes with log fold-change > 1 and with P > –log10 (adjusted P value). (D) The 25 genes with the largest increases and decreases in gene expression by fold change are shown via heatmap (rs755622; red, CG; blue, GG; ID, colors indicate individual samples with column being a unique sample). Heatmap rows are clustered using hierarchical clustering; transcripts per million are scaled to rows for heatmap color scale. (E) GSEA was performed using Hallmark gene sets on the differentially expressed gene list comparing the C/G genotype to the G/G genotype sorted by log2 fold-change for gene-rank position. Normalized enrichment scores (NES) are shown in red/blue, with red enriched in C/G and blue enriched in G/G, while the size of the circle represents the –log10 P value as determined by GSEA.