Inherited variation in immune genes and pathways and glioblastoma risk.

in Carcinogenesis by Judith A Schwartzbaum, Yuanyuan Xiao, Yanhong Liu, Spyros Tsavachidis, Mitchel S Berger, Melissa L Bondy, Jeffrey S Chang, Susan M Chang, Paul A Decker, Bo Ding, Sarah J Hepworth, Richard S Houlston, Fay J Hosking, Robert B Jenkins, Matthew L Kosel, Lucie S McCoy, Patricia A McKinney, Kenneth Muir, Joe S Patoka, Michael Prados, Terri Rice, Lindsay B Robertson, Minouk J Schoemaker, Sanjay Shete, Anthony J Swerdlow, Joe L Wiemels, John K Wiencke, Ping Yang, Margaret R Wrensch

TLDR

  • This study analyzed genetic data from glioblastoma patients and controls to identify immune genes and pathways associated with the risk of developing glioblastoma, with findings highlighting the potential importance of the IL-2RA cytokine gene and the glioblastoma microenvironment.

Abstract

To determine whether inherited variations in immune function single-nucleotide polymorphisms (SNPs), genes or pathways affect glioblastoma risk, we analyzed data from recent genome-wide association studies in conjunction with predefined immune function genes and pathways. Gene and pathway analyses were conducted on two independent data sets using 6629 SNPs in 911 genes on 17 immune pathways from 525 glioblastoma cases and 602 controls from the University of California, San Francisco (UCSF) and a subset of 6029 SNPs in 893 genes from 531 cases and 1782 controls from MD Anderson (MDA). To further assess consistency of SNP-level associations, we also compared data from the UK (266 cases and 2482 controls) and the Mayo Clinic (114 cases and 111 controls). Although three correlated epidermal growth factor receptor (EGFR) SNPs were consistently associated with glioblastoma in all four data sets (Mantel-Haenzel P values = 1 × 10⁻⁵ to 4 × 10⁻³), independent replication is required as genome-wide significance was not attained. In gene-level analyses, eight immune function genes were significantly (minP < 0.05) associated with glioblastoma; the IL-2RA (CD25) cytokine gene had the smallest minP values in both UCSF (minP = 0.01) and MDA (minP = 0.001) data sets. The IL-2RA receptor is found on the surface of regulatory T cells potentially contributing to immunosuppression characteristic of the glioblastoma microenvironment. In pathway correlation analyses, cytokine signaling and adhesion-extravasation-migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets. Our findings represent the first systematic description of immune genes and pathways that characterize glioblastoma risk.

Overview

  • The study aimed to investigate whether inherited variations in immune function genes and pathways affect the risk of developing glioblastoma.
  • The researchers analyzed data from recent genome-wide association studies, immune function genes, and pathways in two independent data sets from the University of California, San Francisco (UCSF) and the MD Anderson (MDA).
  • The primary objective of the study was to identify immune genes and pathways that are associated with glioblastoma risk, with a focus on the IL-2RA cytokine gene and the glioblastoma microenvironment.

Comparative Analysis & Findings

  • The study found three correlated epidermal growth factor receptor (EGFR) SNPs that were consistently associated with glioblastoma in all four data sets, although genome-wide significance was not attained.
  • Eight immune function genes, including the IL-2RA cytokine gene, were significantly associated with glioblastoma risk, with the IL-2RA receptor being found on the surface of regulatory T cells potentially contributing to immunosuppression.
  • The cytokine signaling and adhesion-extravasation-migration pathways showed similar associations with glioblastoma risk in both MDA and UCSF data sets, with these findings representing the first systematic description of immune genes and pathways that characterize glioblastoma risk.

Implications and Future Directions

  • The study provides valuable insights into the role of immune genes and pathways in glioblastoma risk, highlighting the potential importance of the IL-2RA cytokine gene and the glioblastoma microenvironment.
  • Future studies should aim to independently replicate the findings, particularly the genome-wide association study results, to better understand the complex relationships between immune function and glioblastoma risk.
  • The identification of immune genes and pathways associated with glioblastoma risk may lead to the development of new therapeutic strategies, such as immune-modulating treatments, to improve patient outcomes.
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