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1H HR-MAS and Genomic Analysis of Human Tumor Biopsies Discriminate Between High and Low Grade Astrocytomas Valeria Righi A,B,C, Jose M

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1H HR-MAS and Genomic Analysis of Human Tumor Biopsies Discriminate Between High and Low Grade Astrocytomas Valeria Righi A,B,C, Jose M Research Article Received: 16 April 2008, Revised: 22 January 2009, Accepted: 22 January 2009, Published online in Wiley InterScience: 2009 (www.interscience.wiley.com) DOI:10.1002/nbm.1377 1H HR-MAS and genomic analysis of human tumor biopsies discriminate between high and low grade astrocytomas Valeria Righi a,b,c, Jose M. Rodad, Jose´ Pazd, Adele Muccib, Vitaliano Tugnolic, Gemma Rodriguez-Tarduchya, Laura Barriose, Luisa Schenettib, Sebastia´n Cerda´na* and Marı´a L. Garcı´a-Martı´na,y We investigate the profile of choline metabolites and the expression of the genes of the Kennedy pathway in biopsies of human gliomas (n ¼ 23) using 1H High Resolution Magic Angle Spinning (HR-MAS, 11.7 Tesla, 277 K, 4000 Hz) and individual genetic assays. 1H HR-MAS spectra allowed the resolution and relative quantification by the LCModel of the resonances from choline (Cho), phosphocholine (PC) and glycerophosphorylcholine (GPC), the three main components of the combined tCho peak observed in gliomas by in vivo 1H NMR spectroscopy. All glioma biopsies depicted a prominent tCho peak. However, the relative contributions of Cho, PC, and GPC to tCho were different for low and high grade gliomas. Whereas GPC is the main component in low grade gliomas, the high grade gliomas show a dominant contribution of PC. This circumstance allowed the discrimination of high and low grade gliomas by 1H HR-MAS, a result that could not be obtained using the tCho/Cr ratio commonly used by in vivo 1H NMR spectroscopy. The expression of the genes involved in choline metabolism has been investigated in the same biopsies. High grade gliomas depict an upregulation of the b gene of choline kinase and phospholipase C, as well as a downregulation of the cytidyltransferase B gene, the balance of these being consistent with the accumulation of PC. In the low grade gliomas, phospholipase A1 and lysophospholypase are upregulated and phospholipase D is downregulated, supporting the accumulation of GPC. The present findings offer a promising procedure that will potentially help to accurately grade glioma tumors using 1H HR-MAS, providing in addition the genetic background for the alterations of choline metabolism observed in high and low grade gliomas. Copyright ß 2009 John Wiley & Sons, Ltd. Keywords: choline metabolism; tumors; HR-MAS; gliomas; genomics * Correspondence to: S. Cerda´n, Instituto de Investigaciones Biome´dicas ‘Alberto Contract/grant sponsor: The Community of Madrid; contract/grant number: Sols’ CSIC/UAM, c/ Arturo Duperier 4, Madrid 28029, Spain. S-BIO/0179/2006. E-mail: [email protected] Contract/grant sponsor: The Integrated EU Project MEDITRANS; contract/ grant number: 026668. a V. Righi, G. Rodriguez-Tarduchy, S. Cerda´n, M. L. Garcı´a-Martı´n Contract/grant sponsor: The Institute of Health Charles III; contract/grant Instituto de Investigationes Biome´dicas ‘Alberto Sols’ CSIC/UAM, c/ Arturo number: PI051845. Duperier 4, E-28029 Madrid, Spain Contract/grant sponsor: Italian Government; contract/grant number: b V. Righi, A. Mucci, L. Schenetti IT0725H5F4. Dipartimento di Chimica, Universita` di Modena, via G. Campi 183, I-41100 Contract/grant sponsor: Accio´n Integrada Hispano-Italiana; contract/grant Modena, Italy number: HI2006–0101. c V. Righi, V. Tugnoli Abbreviations used: at, glycerol-3-phosphate acyltransferases (GPNAM); ck, Dipartimento di Biochimica ‘G.Moruzzi’, Universita` di Bologna, via Belmeloro choline kinase (CHKA, CHKB); ct, cytidylyl-transferase (PCYT1A, PCYT1B); CTL, 8/2, I- 40126 Bologna, Italy choline transporter (CTL1, CTL2); COSY, COrrelation SpectroscopY; CPMG, d J. M. Roda, J. Paz Carr–Purcell–Meiboom–Gill; Cr/PCr, phosphocreatine; GABA, g-amino butyric Servicio de Neurocirurgia, Hospital Universitario ‘La Paz’, Madrid, Spain acid; Glu, glutamate; Glx, glutamine plus glutamate; GPC, glycerophosphocho- line; GPE, glycerophosphorylethanolamine; HR-MAS, high-resolution magic e L. Barrios angle spinning; Lac, lactate; Lip, lipids; lpl, lysophospholipase (LYPLA1); Centro Te´cnico de Informa´tica CSIC, c/ Pinar 19, E-28006 Madrid, Spain Man, mannitol; Myo, myo-inositol; NAA, N-acetylaspartate; pap, phosphati- date phosphohydrolase (PPAP2A); PC, phosphocholine; PE, phosphoryletha- y Present address: RM Nuestra Sen˜ora del Rosario, c/ Principe de Vergara 53, nolamine; pla, phospholipase A (PLA2G6, PLA2G4A, PLA1A); plc, phospholipase Madrid 28012, Spain. C (PLCG1); pld, phospholipase D (PLD1, PLD2); ptc, phosphocholine cytidylyl- Contract/grant sponsor: The Spanish Ministry of Education and Science; transferase (CHPT1); Scy, scyllo-inositol; tCho, total choline; TOCSY, TOtal contract/grant numbers: SAF 2004–03197; NAN 2004–09125-C07–03. Correlation SpectroscopY. 1 NMR Biomed. (2009) Copyright ß 2009 John Wiley & Sons, Ltd. V. RIGHI ET AL. INTRODUCTION line content. The changes detected by 1H HR-MAS are consistent with the upregulation of the choline kinase b or phospholipase C Discrimination between high and low glioma grade remains a genes and the downregulation of the cytidyltransferase gene in vital diagnostic decision, determining the most effective high grade gliomas, or the upregulation of phospholipase A1 treatment and having an important impact on patient manage- detected in low grade gliomas. ment and outcome (1–4). In vivo 1H MR spectroscopic examinations are often used in clinical environments to assess tumor aggressiveness and help the MRI-based tumor diagnosis. A EXPERIMENTAL useful parameter in this sense is the total Choline (tCho) versus Tissue biopsies Creatine (Cr) ratio, which has previously been reported to be related to tumor grade (5–7). This diagnostic assigment has been Tumor specimens were provided by the Department of helped more recently through the implementation of a variety of Neurosurgery, University Hospital ‘La Paz’, Madrid, complying pattern recognition methodologies (8). The accuracy of these with all bioethical criteria of the ethics committee of the Hospital. methods is increasing progressively, but difficulties remain Tumor biopsies were obtained from the patients in the operating currently in the unambiguous classification of high and low room following intracranial surgery, immediately frozen in liquid 1 grade gliomas. This may be due to the fact that in vivo 1H NMR nitrogen and stored at À708C until H HR-MAS analysis. An spectroscopy approaches, as available in the clinic, are normally adjacent biopsy of the tumor was obtained for histopathological limited in sensitivity and resolution, resulting in relatively large classification. Tumor specimens from 23 patients were histologi- voxel volumes and insufficient precission in the spectral cally classified according to the revised WHO criteria. The samples assigments. In particular, the in vivo tCho peak, normally found included nine low-grade astrocytomas (WHO grade II), six to increase in high and low grade gliomas (9,10), contains anaplastic astrocytomas (WHO grade III) and eight glioblastoma contributions from a variety of choline containing metabolites multiforme (WHO grade IV) (16). Grades III and IV were grouped including mainly, free choline (Cho), phosphocholine (PC), and as ‘high grade’ gliomas, to favour a more robust clinical glycerophosphocholine (GPC). In spite of the crucial information classification between low and high grade gliomas. Normal that these metabolites could provide on the alterations of brain samples (n ¼ 3) were obtained from patients undergoing phospholipid metabolism underlying transformation and pro- partial lobectomy as indicated in the treatment of some gression of astrocytomas, their relative contribution to the epilepsies (17). combined Cho peak cannot be derived from the in vivo detected tCho resonance. Sample preparation for HR-MAS experiments High Resolution Magic Angle Spinning (HR-MAS) approaches have been recently proposed to investigate normal and diseased Before HR-MAS analysis, each sample (15–20 mg) was flushed tissues, thus overcoming some of the limitations of in vivo with D2O to remove the residual blood and water with the aim to spectroscopy (11,12). The HR-MAS approach uses small biopsies improve water suppression. The sample was introduced in an of the tumors, providing similar sensitivity and resolution to that HR-MAS zirconium rotor (4 mm OD) fitted with a 50 ml cylindrical previously obtained from the high resolution 1H NMR analyses of insert to increase sample homogeneity and then transferred into tumor extracts. However, few studies to date have investigated the MAS probe, cooled to 4 8C. The HR-MAS spectra were the metabolism of choline derivatives in human gliomas using acquired from a 11.7 Tesla MHz Bruker AVANCE Spectrometer this methodology (13,14). operating at 500.13 MHz, at 48C and 4 kHz spinning rate. 1D Genomic approaches in tumors are currently envisioned to CPMG spectra were acquired using a water-suppressed spin-echo provide complementary information to the metabolic pattern CPMG sequence with 5 s water presaturation during relaxation obtained by HR-MAS, revealing the genomic ‘finger print’ of the delay, 1 ms echo time (t) and 144 ms total spin–spin relaxation tumor (15). In this respect, DNA microchips provide comprehen- delay (2nt), 32 786 data points and 128 scans (18). The 2D sive information on complete genome expression but the 1H-COSY spectra were acquired using a gradient pulse sequence analysis of the 57 000 genes dataset normally investigated is with 1 s water-presaturation during the relaxation delay, 4096 complex, and much of the information obtained is unrelated to data
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