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

AbstractMagnetic 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 1H spectra of intact biological material and limiting diagnostic utility. Here, we show that hydrogen–carbon heteronuclear single quantum correlation (1H–13C HSQC) offers dramatic improvements in sensitivity compared to one-dimensional (1D) 13C NMR and significant signal deconvolution compared to 1D 1H 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 13C-isotopic enrichment, we obtain well-resolved 2D 1H–13C 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 1H–13C HSQC as a non-invasive diagnostic in precision oncology.

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Robust detection of oncometabolic aberrations by 1H-13C heteronuclear single quantum correlation in live cells and intact tumors ex-vivo

10.1101/2019.12.18.881177 ◽

2019 ◽

Author(s):

Yasaman Barekatain ◽

Victoria C Yan ◽

Kenisha Arthur ◽

Jeffrey J. Ackroyd ◽

Sunada Khadka ◽

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Keyword(s):

Quantum Correlation ◽

Ex Vivo ◽

Magic Angle Spinning ◽

Magic Angle ◽

Precision Oncology ◽

Single Quantum ◽

Primary Tumors ◽

Non Invasive ◽

Biological Studies ◽

Heteronuclear Single Quantum Correlation

AbstractExtensive efforts have been made to use non-invasive 1H magnetic resonance (MR) spectroscopy to quantify metabolites that are diagnostic of specific disease states. Within the realm of precision oncology, these efforts have largely centered on quantifying 2-hydroxyglutarate (2-HG) in tumors harboring isocitrate dehydrogenase 1 (IDH1) mutations. As many metabolites have similar chemical shifts, the resulting 1H spectra of intact biological material are highly convoluted, limiting the application of 1H MR to high abundance metabolites. Hydrogen-Carbon Heteronuclear single quantum correlation 1H-13C HSQC is routinely employed in organic synthesis to resolve complex spectra but has received limited attention for biological studies. Here, we show that 1H-13C HSQC offers a dramatic improvement in sensitivity compared to one-dimensional (1D) 13C NMR and dramatic signal deconvolution compared to 1D 1H spectra in an intact biological setting. Using a standard NMR spectroscope without specialized signal enhancements features such as magic angle spinning, metabolite extractions or 13C-isotopic enrichment, we obtain well-resolved 2D 1H-13C HSQC spectra in live cancer cells, in ex-vivo freshly dissected xenografted tumors and resected primary tumors. We demonstrate that this method can readily identify tumors with specific genetic-driven oncometabolite alterations such as IDH mutations with elevation of 2-HG as well as PGD-homozygously deleted tumors with elevation of gluconate. These data support the potential of 1H-13C HSQC as a non-invasive diagnostic tool for metabolic precision oncology.

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