High-grade gliomas (HGGs) are highly aggressive primary brain tumors, with a 5-year survival rate below 10 percent. Recent genomic and epigenomic profiling studies have revealed key distinctions between adult HGG and pediatric HGG, suggesting they are biologically distinct diseases.
Reflecting these differences, the 2021 WHO Classification of Tumors of the Central Nervous System made major changes to the classification of HGGs, separating pediatric and adult tumors into distinct categories. However, this leaves a less clearly defined group in between: adolescents and young adults (AYA), whose tumors can fall between the biological profiles of pediatric and adult disease.
Now, researchers at the Icahn School of Medicine at Mount Sinai and collaborators have found that HGG biology varies across this developmental spectrum, with additional differences between male and female patients.
The team analyzed tumors from 112 patients aged 83 days to 40 years using proteogenomics, combining measurements of DNA, RNA, proteins, and post-translational modifications such as phosphorylation and glycosylation. The researchers integrated this data with clinical information and additional datasets from adult glioblastoma patients and more than 5,000 people with HGG.
The findings, published in Cell Reports Medicine, could help identify new therapeutic targets and prognostic markers while highlighting biological differences that may be important for future clinical trials.
A molecular shift around age 26
Rather than dividing patients into established clinical age groups, the researchers examined how molecular features changed continuously with age. This analysis revealed a distinct molecular shift around age 26. Adolescents aged 15–26 years and young adults aged 26–40 years showed different tumor profiles, survival outcomes, and signaling programs.
The researchers also compared tumors with normal brain tissue across the same age range. “Because age and sex shape normal brain development, we wanted to separate features of the cancer from those associated with a patient’s developmental stage,” said Pei Wang, Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, in the press release.
They found that oxidative phosphorylation showed age- and sex-related changes in the tumors that were not present in normal brain tissue. The findings suggest that at least some of the molecular differences seen across age groups arise from tumor biology rather than simply reflecting changes in the developing brain.
Potential targets emerge
The team then used computational analyses and laboratory experiments to identify signaling proteins that could potentially be targeted therapeutically. Several kinases emerged as candidate targets, including CDK8 (cyclin-dependent kinase 8), ATM (Ataxia-Telangiectasia Mutated), ATR (Ataxia telangiectasia and Rad3-related), and LCK (Lymphocyte-specific protein-tyrosine kinase).
The researchers tested these candidates in tumor-derived cell lines using gene editing and drug treatment. Blocking the kinases slowed cell growth, particularly in cells where those specific kinases are usually more active.
CDK8 was of particular interest because it is less well characterized in HGG than established targets such as ATM and ATR. The analysis also indicated that CDK8 suppresses oxidative phosphorylation, which was in turn associated with more favorable survival outcomes. This suggests that CDK8 and oxidative phosphorylation may be part of the tumor-specific molecular differences observed across age and sex.
However, the researchers emphasized that these findings are an early step toward establishing CDK8 as a therapeutic target. Further studies, including animal models, will be needed before the approach can be considered for clinical testing.
Sex-specific differences
The analysis also revealed differences between male and female patients, with sex-associated patterns emerging across tumor biology, survival, and the immune environment.
Around 27 percent of the proteins measured showed different age-related patterns between male and female patients. Notably, more survival-associated glycopeptides were identified in male patients than female patients, suggesting that protein glycosylation may capture prognostic information that differs by sex.
“In this study, glycosylation captured aspects of tumor biology missed in other molecular data,” said Nicole Tignor, assistant professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai and lead first author, in the press release. “It may be especially valuable for understanding differences between male and female patients in immune responses and, potentially, treatment response.”
The immune landscape also differed between the sexes. Higher levels of infiltrating T cells were associated with better outcomes in female patients, but not male patients. Conversely, a higher fraction of certain tumor-associated macrophages was associated with poorer outcomes in female patients.
A pattern involving PDCD1 (programmed cell death 1), the gene encoding the immune checkpoint protein PD-1, was also found specifically in male pediatric and AYA patients. Since PD-1 inhibitors are already being investigated in this population, the finding could provide a rationale for exploring whether treatment strategies should account for these biological differences.
Developmental context could improve patient stratification
The researchers caution that the study's relatively small sample size limits the conclusions that can be drawn, particularly when patients are divided into groups according to age, sex, and tumor characteristics. The team therefore developed an analytic approach that uses molecular trajectories learned in one group to help interpret survival patterns in another.
“Patient data are becoming increasingly rich, but they also reflect cancers arising at different ages and in different biological settings,” said Wang. “Analyzing tumors in their developmental context can help us make better use of these data and identify patterns that might otherwise be missed.”
Accounting for these developmental and sex-related differences could help researchers identify therapeutic targets and biomarkers that might otherwise be obscured when patients are treated as a single group.
However, larger datasets will be needed to determine which of the molecular patterns identified in the study are specific to HGG and which occur across other childhood cancers. Further work will also be needed to validate candidate targets such as CDK8 and understand the biological mechanisms underlying the differences observed between male and female patients.
