Glioma is a highly fatal and heterogeneous brain tumor with few known risk factors. Our study examines genetically predicted variability in blood cell indices in relation to glioma risk and survival in 3418 cases and 8156 controls. We find that increased platelet to lymphocyte ratio (PLR) confers an increased risk of glioma (odds ratio (OR) = 1.25, p = 0.005), especially tumors with isocitrate dehydrogenase (IDH) mutations (OR = 1.38, p = 0.007) and IDHmut 1p/19q intact (IDHmut-intact OR = 1.53, p = 0.004) tumors. Genetically inferred increased counts of lymphocytes (IDHmut-intact OR = 0.70, p = 0.004) and neutrophils (IDHmut OR = 0.69, p = 0.019; IDHmut-intact OR = 0.60, p = 0.009) show inverse associations with risk, which may reflect enhanced immune-surveillance. Considering survival, we observe higher mortality risk in patients with IDHmut 1p/19q with genetically predicted increased 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 are also differentially associated with 17 tumor immune microenvironment features in a subtype-specific manner, including signatures related to interferon signaling, PD-1 expression, and T-cell/Cytotoxic responses. Our findings highlight immune-mediated susceptibility mechanisms with potential disease management implications. Glioma is an aggressive brain tumor subtype with few known risk factors. Here, the authors utilise Mendelian Randomisation to investigate correlation of immune cell counts with subtype-specific risk and mortality in glioma patients.

The prognosis and survival of oligodendroglioma (oligo) patients vary. Although prior research has associated immune cell composition and patient age with survival, the impact of serum-based proteomic profiles on patient outcomes remains unclear. This study examines the association between serum proteomics and immune profiles from peripheral blood and patients’ survival outcomes. Patients are a subset of the UCSF Adult Glioma Study, with blood samples collected after surgery. The immune cell compositions of 110 oligo patients were characterized using an immunomethylomic deconvolution algorithm. Serum proteomic data were obtained through the Olink Target 96 Immuno-Oncology panel; cytokines with > 25% missingness were excluded from the analysis. A recursive partitioning analysis (RPA) was applied for identifying survival risk groups using 12 immune cell proportions, 82 cytokines, age, sex, grade at diagnosis, and dexamethasone at the time of blood draw. Of the 110 Oligo patients with a median age of diagnosis of 41 years, 65 (59%) were male, 28 (25%) had grade 3, and 30 (27%) had dexamethasone at the time of blood draw. Patients were partitioned into three survival groups: 40 patients with a high level of MMP7 (>=12.6) and ICOSLG (> 5.9) had a median survival of 17.9 years; 27 patients with a high level of MMP7 and low level of ICOSLG had the shortest median survival of 11.9 years, 43 patients with a low level of MMP7 had the longest median survival of 20.4 years (p < 0.0001). Our findings suggested that MMP7 and ICOSLG may help identify survival subgroups in oligo patients. MMP7 promotes tumor growth, whereas ICOSLG regulates immune activation. Further investigation on a validation set is warranted.

BACKGROUND:Glioma is the most common malignant primary brain tumor and is associated with significant morbidity and mortality. Modifiable risk factors remain unidentified. New advances in exposure assessment, genomic analyses, and statistical techniques permit more accurate evaluation of glioma risk associated with exogenous occupational or environmental exposures. METHODS:By using whole-exome sequencing data from matched germline and glioma tumor samples, the authors compared tumor mutational signatures for 17 persons with glioma and a documented occupational history of firefighting with those of 18 persons with glioma without an occupational history of firefighting. All 35 individuals were participants in the University of California, San Francisco Adult Glioma Study. RESULTS:There was a positive correlation among firefighters between the median number of sample variants attributable to single-base substitution signature 42, a single-base substitution mutational signature associated with haloalkane exposure (from the Catalogue of Somatic Mutational Signatures in Cancer) and firefighting years (p = .04; R2 = 0.29). Among nonfirefighters, the individuals with the highest number of median variants attributable to single-base substitution signature 42 also had occupations that possibly exposed them to haloalkanes, such as painting and being a mechanic. CONCLUSIONS:In summary, the authors identified gliomas that had mutational signatures associated with haloalkane exposure that were enriched in firefighters and other occupations.

Striking disparities in lung cancer exist, with Black/African American individuals disproportionately affected by lung cancer, yet the genetic architecture in African ancestry individuals is poorly understood. We aimed to address this by performing a comprehensive genetic association study of lung cancer, incorporating local ancestry, across 6,490 African ancestry individuals (2,390 individuals with lung cancer and 4,100 control subjects). We identified a single genome-wide significant (p < 5 × 10-8) locus, 15q25.1 (lead SNP rs17486278, OR [95% CI] = 1.34 [1.23-1.45], p = 4.52 × 10-12), that has consistently shown a strong association with lung cancer across populations. Additionally, we identified nine suggestive (p < 1 × 10-6) loci. Four of these loci (3p12.1, 8q22.2, 14q11.2, and 18q22.3) have no prior reported associations with lung cancer. We performed a multi-ancestry lung cancer meta-analysis using prior large-scale summary statistics from European and Asian ancestry populations, incorporating our African ancestry results. The meta-analysis identified 17 genome-wide significant loci, including an association with locus 4q35.2 (p = 1.22 × 10-8), a genomic region that has been previously linked to forced expiratory volume. Genome-wide SNP-based heritability for lung cancer was 16% among African ancestry individuals. Follow-up in silico functional analyses identified genetically regulated gene expression (GReX) of nine genes (AC012184.3, ADK, CCDC12, CHRNA3, EML4, PSMA4, SNRNP200, TMEM50A, and ZYG11A) associated with lung cancer risk and biological pathways relevant to cancer and lung function. Cumulatively, these findings further elucidate the genetic architecture of lung cancer in African ancestry individuals, confirming prior loci and revealing new loci.

BACKGROUND:Temozolomide (TMZ) treatment has demonstrated a variable impact on glioma prognosis. This study examines associations of survival with DNA repair gene germline polymorphisms among glioma patients who did and did not have TMZ treatment. Identifying genetic markers which sensitize tumor cells to TMZ could personalize therapy and improve outcomes. METHODS:We evaluated TMZ-related survival associations of pathogenic germline SNPs and genetically predicted transcript levels within 34 DNA repair genes among 1504 glioma patients from the University of California San Francisco Adult Glioma Study (UCSF AGS) and Mayo Clinic, whose diagnoses spanned pre- and post-TMZ eras within the major known glioma prognostic molecular subtypes. RESULTS:Among those who received TMZ, 5 SNPs were associated with overall survival, but not in those who did not receive TMZ. Only rs2308321-G, in MGMT, was associated with decreased survival (hazard ratio = 1.21, P = .019) for all glioma subtypes. Rs73191162-T (near UNG), rs13076508-C (near PARP3), rs7840433-A (near NEIL2), and rs3130618-A (near MSH5) were only associated with survival and TMZ treatment for certain subtypes, suggesting subtype-specific germline chemosensitization. Genetically predicted elevated expression of PNKP, compared to normal brain expression, was associated with markedly poor survival in TMZ-treated patients with isocitrate dehydrogenase (IDH)-mutant and 1p/19q non-codeleted gliomas (P = .015), with a median difference of over 70 months in overall survival times. Similarly, NEIL2 and TDG expressions were associated with altered TMZ-related survival only among certain subtypes. CONCLUSIONS:Functional germline alterations within DNA repair genes were associated with TMZ sensitivity, measured by overall survival among adults with glioma. These variants should be evaluated in prospective analyses and functional studies.

IDH-wildtype diffuse astrocytic gliomas with lower-grade histological features alongside specific genomic alterations (e.g., TERT promoter mutation, EGFR amplification, gain Chr7/loss Chr10) are presently diagnosed as glioblastoma, IDH-wildtype (GBM) under WHO 2021 criteria. Previous analyses categorized these into “early/evolving” or “surgically undersampled” GBMs. However, it remains unclear whether these tumors share identical clinical and prognostic features with histologic GBM. Data from IDH-wt molecular GBMs across six institutions were aggregated. Astrocytic IDH-wt tumors of any grade that lacked necrosis or microvascular proliferation on initial histopathology yet exhibited molecular alterations consistent with WHO 2021 GBM diagnosis, were included. Recursive partitioning analysis (RPA) was used to categorize patients into risk groups based on overall survival (OS). Among the 264 patients included, the median age was 60 years (IQR: 51-67), with 162 (61%) being male. Additionally, 210 (80%) were diagnosed since 2016, and 216 (82%) received chemoradiation plus adjuvant temozolomide (GBM-SOC). The median follow-up period was 3.9 years (95% CI: 3.4, 4.6). Identified univariate risk factors for worse survival included older age, biopsy-only status, EGFR amplification, absence of initial adjuvant treatment, low post-operative KPS, and tumor histologic grade of 3. RPA divided patients into four distinct survival groups (p<0.0001). The “best” risk group comprised lower grade (<=2) tumors (n=58, median OS (mOS): 40 months (95% CI: 33, NA)). The “second best” group included Grade 3 patients receiving GBM-SOC without steroids during initial RT (n=139, mOS: 25 months (95% CI: 22, 28)). The “second worst” group encompassed Grade 3 patients who were on steroids during initial RT while receiving GBM-SOC (n=38, mOS: 15 months (95% CI: 13, 20)). The “worst” group contained Grade 3 tumors that had not undergone SOC (n=29, mOS: 9 months (95% CI: 4, 26)). These data show that histologic features and treatment are strong indicators of patient outcomes.

Abstract BACKGROUND Non-invasive determination of IDH mutational status in patients with glioma could offer significant therapeutic opportunities. While IDH wildtype (WT) tumors typically show enhancement on MRI, IDH mutant (MUT) tumors often lack this enhancement. However, relying solely on anatomic radiology may lead to misclassification, and currently, tissue acquisition is the primary method for assessing IDH-status in gliomas. These limitations hamper the development of neoadjuvant or intraoperative therapeutic strategies based on IDH-status; thus, more minimally invasive methods to determine IDH-status are needed. In this study, we assessed peripheral immune cell proportions, which vary by glioma subtype, from pre-surgery peripheral blood samples as an alternative method of classifying the IDH-status in gliomas without enhancement. MATERIALS AND METHODS We employed a highly accurate large language model (GPT-4-Turbo-128k) with over 99% accuracy to read radiology notes and exclude patients with enhancing gliomas. Then, we identified 12 immune cell subtypes from whole blood using deconvolution algorithms based on DNA methylation data. These immune cell subtypes, along with patient age, were integrated into a machine learning model (random forest) to predict IDH-status (WT vs. MUT), leveraging conditional Generative Adversarial Networks to generate synthetic data and mitigate bias in the datasets. Two independent datasets were included for training and validating the model. RESULTS The random forest model had an AUC of 0.90 and accurately identified IDH-status in 81% of a training set of 287 gliomas (65 WT and 222 MUT at varied time points after diagnosis). In an independent validation data set of 99 gliomas (6 WT and 93 MUT) from pre-surgery blood samples, the AUC was 0.93, and accurately predicted IDH-status in 92% of cases with a sensitivity of 93% and specificity of 83%. CONCLUSIONS We predicted the IDH-status of non-enhancing gliomas using patients’ age and immunomethylomic data from pre-surgical peripheral blood samples. This minimally invasive approach is a promising step toward reducing risk and enabling earlier therapies based on IDH-status.

Abstract Prior epidemiological research shows a correlation between serum immunoglobulin E (IgE) levels and decreased risk of glioma. However, the relationship between IgE and the prognosis of glioma remains poorly understood. This study seeks to investigate how factors such as sex, tumor subtype, and IgE class influence the association of serum IgE levels with both glioma risk and survival outcomes. METHODS- In this investigation, we conducted a case-control study utilizing participants enrolled in the UCSF Adult Glioma Study from 1997 to 2010. We measured serum IgE levels for total, respiratory, and food allergy in adults diagnosed with glioma (n=1,696), and controls (n=1,135) matched based on age, sex, and race/ethnicity. Logistic regression, adjusted for patient demographics, was employed to evaluate the correlation between IgE levels and glioma risk. Multivariable Cox regression, adjusted for patient-specific and tumor-specific factors, was utilized to compare survival outcomes between the elevated and normal IgE groups. RESULTS- Increased levels of total IgE were linked to a decreased risk of both IDH wildtype (OR=0.65, 95% CI: 0.54-0.78) and IDH mutant glioma (OR=0.65, 95% CI: 0.50-0.85). In multivariable Cox regression analysis, heightened respiratory IgE levels were associated with enhanced survival among individuals with IDH wildtype glioma (HR=0.78, 95% CI: 0.67-0.91). Notably, this improved survival was more pronounced in females (HR=0.71, 95% CI: 0.53-0.96) compared to males (HR=0.80, 95% CI: 0.66-0.97), resulting in median survival improvements of 6.2 months (P<.001) and 1.6 months (P=0.003), respectively. CONCLUSION- Increased levels of serum IgE were associated with reduced risk of glioma overall, and improved prognosis for IDH wildtype glioma, which was particularly strong in females. These findings hint at potential sexual dimorphism in the antitumor activity of IgE-mediated immune responses, suggest an important role for IgE assessment in glioblastoma clinical trial design, and provide justification for investigations into IgE-based therapeutics.

Abstract Using data from The Cancer Genome Atlas (TCGA) and Glioma Longitudinal Analysis (GLASS), we identified specific environmentally related mutational signatures in glioma including a signature associated with haloalkane exposure (SBS42) from the Catalogue of Somatic Mutational Signatures (COSMIC). Haloalkanes are widely used commercially including in flame retardants and fire extinguishants and are an intriguing finding given an observed increased glioma risk in firefighters. To validate our findings, we use new study participants with data on occupation (not available in either TCGA/GLASS) from the University of California, San Francisco Adult Glioma Study (AGS) to compare mutational signatures in tumors from 17 persons with glioma and documented occupational exposure to firefighting with those of 18 matched glioma patients without history of firefighting. Using whole exome sequencing, we identified environmental exposure signatures in tumor tissue from firefighters as well as in non-firefighters who had other relevant occupational exposure (e.g. auto/truck mechanic work). In these data, glioma is largely associated with aging and mutational signatures relating to endogenous mutational processes that correlate with age, such as spontaneous or enzymatic deamination of 5-methylcytosine. However, some gliomas have detectable signatures associated with exogenous mutational processes, such as SBS42 haloalkanes. Thus, we confirm detection of haloalkane signatures in persons likely highly exposed, i.e. long-term firefighters. Identifying exogenous mutational processes in cancers are important as they may inform public health intervention strategy to reduce mutagenesis and prevent cancer inception. Identifying occupational correlates with SBS42, associated with occupational exposure to haloalkanes, will pinpoint occupational hazards that may be avoidable. This is especially important for glioma and other cancers where exogenous mutagenesis is not well established.

Abstract Background Variations in survival among patients with oligodendroglioma are unexplained by known prognostic factors. To assess the impact of peripheral immune profiles on prognosis, we applied immunomethylomics analyses—DNA methylation of archived whole blood samples, to characterize immune cells. Methods We compared the proportions of immune cells from patients with oligodendroglioma to other glioma subtypes and controls. We used recursive partitioning analysis (RPA) within the oligodendrogliomas to correlate with survival. Results Patients with oligodendrogliomas (141) were median age at diagnosis of 44 years; 57% male; 75% White; 60% prior chemotherapy; and 25% on dexamethasone at sample collection. Patients with oligodendrogliomas had immune profiles more similar to controls than other glioma subtypes, though with notably lower B-cells. RPA of patients with oligodendrogliomas delineated 2 survival groups based on an interaction between age and B-naïve cells. Patients with longer survival (median 24.2 years) were ≤42 years of age with higher B-naïve cells versus worse survival (median 16.9 years) who were ≤42 years of age with lower B-naïve cells or >42 years of age (P = .00032). Patients with worse survival also had lower CD4- and CD8-naïve T-cells. Similar immune profiles were observed in an independent cohort of oligodendroglioma patients prior to surgery. Conclusions Peripheral blood immune profiles in oligodendroglioma suggested that younger patients with lower B-naïve cells experienced shorter survival. Though our findings lack of validation cohort and use a heterogenous patient population, they suggest peripheral blood immune profiles may be prognostic for patients with glioma and warrant further investigation.

Abstract Purpose: While risk factors for lung cancer incidence are well established, our understanding of factors driving an increased risk of lung cancer among Black/African American populations remains incomplete. Methods: We assembled data from five U.S. lung cancer case-control studies matched on race, gender and age: the Southern Community Cohort Study, the Inflammation, Health, Ancestry and Lung Epidemiology study, the Northern California Lung Cancer Study, three Detroit area lung studies, and the NCI-Maryland Lung Cancer Study. Incident lung cancers were ascertained from state and regional cancer registries or National Death Index mortality records. Social, behavioral, and environmental factors were ascertained by in-person interviews or mailed-in questionnaires. Participant's residential addresses were geocoded and area-level area deprivation and environmental justice variables were linked at the census block. We evaluated interactions between known lung cancer risk factors and race using multilevel logistic regression analyses and novel tree-based approaches to identify potential factors contributing to racial disparities. Tree-based approaches included a conditional matched classification tree analysis designed to detect complex interactions, as well as a specialized partially recursively induced structured moderation (PRISM) analysis to study variation in disparity in lung cancer risk across levels of educational status. Results: Among 5,829 lung cancer cases and 10,671 controls (64% self-identified Black/African American and 36% White), the average age was 60 years, 50% were female, and 24% had less than a high school education. Conditional logistic regression models fit after imputation of missing data identified increased risk of lung cancer associated with personal history of cancer, family history of lung cancer, current smoking status, smoking duration, smoking pack-years, and higher neighborhood deprivation; whereas, reduced lung cancer risk was associated with higher education and increased BMI. Similar patterns were observed among Black/African Americans only, with the addition of secondhand smoke exposure. Assessment for interactions with race identified significant interactions between race and body mass index (BMI) (p-value < 0.0001), PM2.5 (p= 0.010) and gender (p=0.001) and lung cancer risk. A conditional matched classification tree analysis identified both increased and decreased risk subgroups defined by multi-way interactions of similar variables that were identified as significant main effects in the conditional logistic regression analysis. Smoking pack-years and BMI were identified as the most important determinants of heterogeneity of disparity in lung cancer risk across educational levels in our study population. Conclusions: The use of both traditional and novel tree-based based approaches provide approaches for identifying factors contributing to racial disparities. Future studies should assess the interplay of lung cancer risk factors to inform development of targeted interventions. Citation Format: Melinda C. Aldrich, Chen Zhao, Christine M Lusk, Lucie McCoy, James Jaworski, Michael Mumma, Catherine Pichardo, Michael Betti, John K Wiencke, Brid Ryan, Ann G Schwartz, Sunil Rao. A comparison of modeling approaches to assess the interplay of social, behavioral, and environmental factors on lung cancer racial disparities [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr PR001.

Background. Variations in survival among patients with oligodendroglioma are unexplained by known prognostic factors. To assess the impact of peripheral immune profiles on prognosis, we applied immunomethylomics analyses-DNA methylation of archived whole blood samples, to characterize immune cells. Methods. We compared the proportions of immune cells from patients with oligodendroglioma to other glioma subtypes and controls. We used recursive partitioning analysis (RPA) within the oligodendrogliomas to correlate with survival. Results. Patients with oligodendrogliomas (141) were median age at diagnosis of 44 years; 57% male; 75% White; 60% prior chemotherapy; and 25% on dexamethasone at sample collection. Patients with oligodendrogliomas had immune profiles more similar to controls than other glioma subtypes, though with notably lower B-cells. RPA of patients with oligodendrogliomas delineated 2 survival groups based on an interaction between age and B-naive cells. Patients with longer survival (median 24.2 years) were <= 42 years of age with higher B-naive cells versus worse survival (median 16.9 years) who were <= 42 years of age with lower B-naive cells or >42 years of age (P = .00032). Patients with worse survival also had lower CD4- and CD8-naive T-cells. Similar immune profiles were observed in an independent cohort of oligodendroglioma patients prior to surgery. Conclusions. Peripheral blood immune profiles in oligodendroglioma suggested that younger patients with lower B-naive cells experienced shorter survival. Though our findings lack of validation cohort and use a heterogenous patient population, they suggest peripheral blood immune profiles may be prognostic for patients with glioma and warrant further investigation.

Background Lifetime exposure to the varicella-zoster virus (VZV) has been consistently inversely associated with glioma risk, however, the relationship of VZV with survival in adults with glioma has not been investigated. In this study, we analyzed the survival of adults with glioma in relation to their antibody measurements to 4 common herpes viral infections, including VZV, measured post-diagnosis. Methods We analyzed IgG antibody measurements to VZV, cytomegalovirus (CMV), herpes simplex virus 1/2 (HSV), and Epstein-Barr virus (EBV) collected from 1378 adults with glioma diagnosed between 1991 and 2010. Blood was obtained a median of 3 months after surgery. Associations of patient IgG levels with overall survival were estimated using Cox models adjusted for age, sex, self-reported race, surgery type, dexamethasone usage at blood draw, and tumor grade. Models were stratified by recruitment series and meta-analyzed to account for time-dependent treatment effects. Results VZV antibody seropositivity was associated with improved survival outcomes in adults with glioma (Hazard ratio, HR = 0.70, 95% Confidence Interval 0.54-0.90, P = .006). Amongst cases who were seropositive for VZV antibodies, survival was significantly improved for those above the 25th percentile of continuous reactivity measurements versus those below (HR = 0.76, 0.66-0.88, P = .0003). Antibody seropositivity to EBV was separately associated with improved survival (HR = 0.71, 0.53-0.96, P = .028). Antibody positivity to 2 other common viruses (CMV, HSV) was not associated with altered survival. Conclusions Low levels of VZV or EBV antibodies are associated with poorer survival outcomes for adults with glioma. Differential immune response rather than viral exposure may explain these findings.

Supplementary Tables 1-9 from Circulating Levels of the Innate and Humoral Immune Regulators CD14 and CD23 Are Associated with Adult Glioma

PURPOSE:In patients with diffuse low-grade glioma (LGG), the extent of surgical tumor resection (EOR) has a controversial role, in part because a randomized clinical trial with different levels of EOR is not feasible.METHODS:In a 20-year retrospective cohort of 392 patients with IDH-mutant grade 2 glioma, we analyzed the combined effects of volumetric EOR and molecular and clinical factors on overall survival (OS) and progression-free survival by recursive partitioning analysis. The OS results were validated in two external cohorts (n = 365). Propensity score analysis of the combined cohorts (n = 757) was used to mimic a randomized clinical trial with varying levels of EOR.RESULTS:Recursive partitioning analysis identified three survival risk groups. Median OS was shortest in two subsets of patients with astrocytoma: those with postoperative tumor volume (TV) > 4.6 mL and those with preoperative TV > 43.1 mL and postoperative TV ≤ 4.6 mL. Intermediate OS was seen in patients with astrocytoma who had chemotherapy with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL in addition to oligodendroglioma patients with either preoperative TV > 43.1 mL and residual TV ≤ 4.6 mL or postoperative residual volume > 4.6 mL. Longest OS was seen in astrocytoma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL who received no chemotherapy and oligodendroglioma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL. EOR ≥ 75% improved survival outcomes, as shown by propensity score analysis.CONCLUSION:Across both subtypes of LGG, EOR beginning at 75% improves OS while beginning at 80% improves progression-free survival. Nonetheless, maximal resection with preservation of neurological function remains the treatment goal. Our findings have implications for surgical strategies for LGGs, particularly oligodendroglioma.

PDF file, 333KB, Figure 1a: Genome-wide Constitutive SNP Analysis with GBM Patient Overall Survival, Figure 1b: Association of Gene Expression in Tumors with Overall GBM Patient Survival.

Abstract Immune dysregulation is a known characteristic of glioma, however there is little known about the peripheral immune status of lower-grade (LrGG) glioma patients across the course of disease. Using immunomethylomic (deconvoluted blood DNA methylation) data from the UCSF Immune Profiles Study, we explore changes in patient peripheral blood immune cell profiles in newly diagnosed and recurrent LrGG patients. For patients receiving radiation (RT) and temozolomide (TMZ) (n = 75), blood is collected pre-RT/TMZ, post-RT/TMZ, before, during, and after adjuvant TMZ (if applicable). For patients followed only by MRI (n = 53) and those with other treatment plans (n = 67), blood is collected at MRIs, and if applicable, before radiation. For all patients, blood is also collected before new treatment intervention. For patients (LrGG IDH mutated) with paired pre- and post-surgery samples (n = 139), we observed a significant post-surgery increase in the count of memory B-cells (p = 1.7e-5), neutrophils (p = 0.0001), basophils (p = 8.7e-5), monocytes (p = 0.0001), and T-regulatory cells (p = 0.0001) along with a significant decrease in natural killer cells (p = 0.0003). Treatment was also associated with altered patient immune profiles. The use of dexamethasone was associated with an increased count of B-memory (p = 0.0001) and B-naïve cells (p = 0.0001), monocytes (p = 2.1e-5), and neutrophils (p = 3.7e-6) post-surgery. Patients receiving chemoradiation (n = 12) exhibited significant and temporally sustained decreases in B-memory (p < 0.0001), B-naïve (p = 0.005), CD4 naïve cells (p = 0.002), and in neutrophils (p = 0.001). Patient follow-up, data collection, and further analyses are ongoing. These results shed light on the dynamic and variable immune changes in LrGG patients and provide a guide for future prognostic and therapeutic studies.

Top SNP associations in the 9p21.3 region evaluated in Hispanic ALL patients from CCLS and validated in European-ancestry ALL patients from COG, with functional annotation.

Glioblastomas (GBM) are lethal central nervous system cancers associated with tumor and systemic immunosuppression. Heterogeneous monocyte myeloid-derived suppressor cells (M-MDSC) are implicated in the altered immune response in GBM, but M-MDSC ontogeny and definitive phenotypic markers are unknown. Using single-cell transcriptomics, we revealed heterogeneity in blood M-MDSC from GBM subjects and an enrichment in a transcriptional state reminiscent of neutrophil-like monocytes (NeuMo), a newly described pathway of monopoiesis in mice. Human NeuMo gene expression and Neu-like deconvolution fraction algorithms were created to quantitate the enrichment of this transcriptional state in GBM subjects. NeuMo populations were also observed in M-MDSCs from lung and head and neck cancer subjects. Dexamethasone (DEX) and prednisone exposures increased the usage of Neu-like states, which were inversely associated with tumor purity and survival in isocitrate dehydrogenase wildtype (IDH WT) gliomas. Anti-inflammatory ZC3HA12/Regnase-1 transcripts were highly correlated with NeuMo expression in tumors and in blood M-MDSC from GBM, lung, and head and neck cancer subjects. Additional novel transcripts of immune-modulating proteins were identified. Collectively, these findings provide a framework for understanding the heterogeneity of M-MDSCs in GBM as cells with different clonal histories and may reshape approaches to study and therapeutically target these cells.