Genetic predisposition to altered blood cell homeostasis is associated with glioma risk and survival

Glioma is a highly fatal brain tumor comprised of molecular subtypes with distinct clinical trajectories. Observational studies have suggested that variability in immune response may play a role in glioma etiology. However, their findings have been inconsistent and susceptible to reverse causation due to treatment effects and the immunosuppressive nature of glioma. We applied genetic variants associated (p<5×10−8) with blood cell traits to a meta-analysis of 3418 glioma cases and 8156 controls. Genetically predicted increase in the platelet to lymphocyte ratio (PLR) was associated with an increased risk of glioma (odds ratio (OR)=1.25, p=0.005), especially in IDH-mutant (IDHmut OR=1.38, p=0.007) and IDHmut 1p/19q non-codeleted (IDHmut-noncodel OR=1.53, p=0.004) tumors. However, reduced glioma risk was observed for higher counts of lymphocytes (IDHmut-noncodel OR=0.70, p=0.004) and neutrophils (IDHmut OR=0.69, p=0.019; IDHmut-noncodel OR=0.60, p=0.009), which may reflect genetic predisposition to enhanced immune-surveillance. In contrast to susceptibility, there was no association with survival in IDHmut-noncodel; however, in IDHmut 1p/19q co-deleted tumors, we observed higher mortality with increasing genetically predicted counts of lymphocytes (hazard ratio (HR)=1.65, 95% CI: 1.24-2.20), neutrophils (HR=1.49, 1.13-1.97), and eosinophils (HR=1.59, 1.18-2.14). Polygenic scores for blood cell traits were also associated with tumor immune microenvironment features, with heterogeneity by IDH status observed for 17 signatures related to interferon signaling, PD-1 expression, and T-cell/Cytotoxic responses. In summary, we identified novel, immune-mediated susceptibility mechanisms for glioma with potential disease management implications. SIGNIFICANCE This study suggests that genetic determinants of peripheral blood cell counts influence subtype-specific glioma susceptibility and mortality, with potential effects on the tumor immune microenvironment. These findings may have disease management implications. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement LK is supported by funding from the National Institutes of Health (NIH): R00CA246076. Work at University of California, San Francisco was supported by the NIH (grant numbers T32CA151022, R01CA52689, P50CA097257, R01CA126831, R01CA139020, R01AI128775, and R25CA112355), the National Brain Tumor Foundation, the Stanley D. Lewis and Virginia S. Lewis Endowed Chair in Brain Tumor Research, the Robert Magnin Newman Endowed Chair in Neuro-oncology, and by donations from families and friends of John Berardi, Helen Glaser, Elvera Olsen, Raymond E. Cooper, and William Martinusen. This publication was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI grant number UL1 RR024131. Work at Mayo was supported by NIH grants CA230712, P50 CA108961, and CA139020; the National Brain Tumor Society; the loglio Collective; the Mayo Clinic; and the Ting Tsung and Wei Fong Chao Foundation. Contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UCSF glioma cases include participants of the San Francisco Bay Area Adult Glioma Study (AGS). This study was approved by the UCSF Committee on Human Research. Use of Mayo Clinic glioma cases was approved by the Mayo Clinic Office for Human Research Protection. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Genotype data of control samples from the 1958 British Birth Cohort and UK Blood Service Control Group were made available from the Wellcome Trust Case Control Consortium (WTCCC) and downloaded from the European Genotype Archive under ascension numbers EGAD00000000021 and EGAD00000000023, respectively. Genotype data of glioma cases from The Cancer Genome Atlas (TCGA) were obtained from Database of Genotypes and Phenotypes (dbGaP) (phs000178). Genotype data of control samples from the Glioma International Case Control Study (GICC) are available from dbGaP under accession phs001319.v1.p1.