Association of plasma biomarkers with diagnostic molecular markers for potential diagnosis and prognosis of diffuse gliomas.

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2045 Background: Diffuse gliomas were recently reclassified based on the 2021 WHO Classification criteria. Several molecular changes which carry diagnostic and prognostic power have been added to the classification parameters, including IDH1 mutation and MGMT promotor methylation. To characterize these molecular changes, however, an invasive biopsy is required. Our goal was to examine the relationship between seven plasma biomarkers for diffuse glioma and the established molecular changes and delineate if these markers can be used as surrogates of these molecular changes. Methods: Seven candidate markers, namely glial fibrillary acidic protein (GFAP), neurofilament light (NEFL), matrix metalloproteinase 1, 3, 9 (MMP1, MMP3, MMP9), total Tau (tTau) and fatty acid binding protein 4 (FABP4) were evaluated by quantitative research-use-only electrochemiluminescence assays available from Meso Scale Discovery by comparing the protein concentration distribution with non-parametric Wilcoxon rank sum tests and multiple testing adjustment. The molecular markers tested were IDH1, MGMT promotor and ATRX. The discovery cohort consisted of 49 IDH1 mutant (39%) and 77 IDH1 wildtype (61%) gliomas. Among this retrospective cohort were 103 primary samples (collected at diagnosis) and 23 recurrent samples (collected at time of recurrence). The retrospective validation cohort consisted of 36 IDH1 mutant (22%) and 129 IDH1 wildtype (78%), with 64 primary samples and 76 recurrent samples. Results: Several of the proteomic markers showed significant associations with genetic markers at an adjusted significance level of P < 0.05. For IDH1 status, the strongest association was with NEFL, with IDH1 wildtype samples showing higher levels of the protein. For ATRX expression, high FABP4 was correlated with ATRX retention. As expected, survival analysis based on molecular markers yielded that IDH1 status was most predictive of survival both in primary tumors and recurrent tumors. MGMT promotor methylation was predictive of survival in primary cases but not recurrent cases. When combining the genetic markers with protein concentrations, we were able to see some improvement in survival prediction. Conclusions: We demonstrate that some plasma biomarkers, particularly NEFL and FABP4, show significant associations with key molecular changes in diffuse gliomas, including IDH1 status and ATRX retention/loss. Future research will determine whether these proteomic markers can serve as surrogates for molecular alterations and assist in potentially improved diagnosis and monitoring of diffuse gliomas.

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