Robust detection of oncometabolic aberrations by 1H-13C heteronuclear single quantum correlation in intact biological specimens

Magnetic resonance (MR) spectroscopy has potential to non-invasively detect metabolites of diagnostic significance for precision oncology. Yet, many metabolites have similar chemical shifts, yielding highly convoluted H-1 spectra of intact biological material and limiting diagnostic utility. Here, we show that hydrogen-carbon heteronuclear single quantum correlation (H-1-C-13 HSQC) offers dramatic improvements in sensitivity compared to one-dimensional (1D) C-13 NMR and significant signal deconvolution compared to 1D H-1 spectra in intact biological settings. Using a standard NMR spectroscope with a cryoprobe but without specialized signal enhancing features such as magic angle spinning, metabolite extractions or C-13-isotopic enrichment, we obtain well-resolved 2D H-1-C-13 HSQC spectra in live cancer cells, in ex vivo freshly dissected xenografted tumors and resected primary tumors. This method can identify tumors with specific oncometabolite alterations such as IDH mutations by 2-hydroxyglutarate and PGD-deleted tumors by gluconate. Results suggest potential of H-1-C-13 HSQC as a non-invasive diagnostic in precision oncology. Barekatain et al. demonstrate that hydrogen-carbon heteronuclear single quantum correlation (HSQC) spectra, obtained using a standard NMR spectroscope, can detect tumours with specific oncometabolite alterations including IDH1 mutant glioblastoma, suggesting the feasibility of this method as a diagnostic tool.