Sexual dimorphism in glioma glycolysis underlies sex differences in survival

Abstract

<p class="first" id="d9126060e197">The molecular bases for sex differences in cancer remain undefined and how to incorporate them into risk stratification remains undetermined. Given sex differences in metabolism and the inverse correlation between fluorodeoxyglucose (FDG) uptake and survival, we hypothesized that glycolytic phenotyping would improve glioma subtyping. Using retrospectively acquired lower-grade glioma (LGG) transcriptome data from The Cancer Genome Atlas (TCGA), we discovered male-specific decreased survival resulting from glycolytic gene overexpression. Patients within this high-glycolytic group showed significant differences in the presence of key genomic alterations (i.e., 1p/19q codeletion, <i>CIC</i>, <i>EGFR</i>, <i>NF1</i>, <i>PTEN</i>, <i>FUBP1</i>, and <i>IDH</i> mutations) compared with the low-glycolytic group. Although glycolytic stratification defined poor prognostic males independent of grade, histology, <i>TP53</i>, and <i>ATRX</i> mutation status, we unexpectedly found that females with high-glycolytic gene expression and wild-type <i>IDH</i> survived longer than all other wild-type patients. Validation with an independent metabolomics dataset from grade 2 gliomas determined that glycolytic metabolites selectively stratified males and also uncovered a potential sexual dimorphism in pyruvate metabolism. These findings identify a potential synergy between patient sex, tumor metabolism, and genomic alterations in determining outcome for glioma patients. </p><p class="first" id="d9126060e228">Transcriptome and metabolome-based profiling of glycolysis in gliomas selectively stratifies males and is associated with differences in key genomic alterations. </p>