Serum metabolome analysis by 1H-NMR reveals differences between chronic lymphocytic leukaemia molecular subgroups

Abstract

Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease exhibiting variable clinical course and survival rates. Mutational status of the immunoglobulin heavy chain variable regions (IGHVs) of CLL cells offers useful prognostic information for high-risk patients, but time and economical costs originally prevented it from being routinely used in a clinical setting. Instead, alternative markers of IGHV status, such as zeta-associated protein (ZAP70) or messenger RNA levels are often used. We report a 1 H-NMR-based metabolomics approach to examine serum metabolic profiles of early stage, untreated CLL patients (Binet stage A) classified on the basis of IGHV mutational status or ZAP70. Metabolic profiles of CLL patients (n ¼ 29) exhibited higher concentrations of pyruvate and glutamate and decreased concentrations of isoleucine compared with controls (n ¼ 9). Differences in metabolic profiles between unmutated (UM-IGHV; n ¼ 10) and mutated IGHV (M-IGHV; n ¼ 19) patients were determined using partial least square discriminatory analysis (PLS-DA; R 2 ¼ 0.74, Q 2 ¼ 0.36). The UM-IGHV patients had elevated levels of cholesterol, lactate, uridine and fumarate, and decreased levels of pyridoxine, glycerol, 3-hydroxybutyrate and methionine concentrations. The PLS-DA models derived from ZAP70 classifications showed comparatively poor goodness-of-fit values, suggesting that IGHV mutational status correlates better with diseaserelated metabolic profiles. Our results highlight the usefulness of 1 H-NMR-based metabolomics as a potential non-invasive prognostic tool for identifying CLL disease-state biomarkers.

Metabolic Signatures of Lung Cancer in Biofluids: NMR-Based Metabonomics of Blood Plasma

“…In regard to age, it was found to have a much smaller influence on the plasma composition than the disease, in line with the results reported by others for different cancer types, such as leukemia 47 or esophageal cancer. 25 However, possible bias arising from the disparate age distributions in controls (ages 22À60) and cancer subjects (ages 30À85) could not be ruled out, since the discrimination between these classes was found to be worse for a subgroup of subjects with more closely matched ages.…”

Multiple Myeloma Patients Have a Specific Serum Metabolomic Profile That Changes after Achieving Complete Remission

“…Spectra were automatically phased and baseline corrected, chemical shift referenced internally to the methyl group signal of alanine at 1.47 ppm using TOPSPIN 3.0 (Bruker Biospin) and analyzed with Analysis of MIXtures (AMIX; Bruker) for metabolites assignment. Metabolites of interest were identified using Amix v 3.9.7 in combination with the Bruker NMR Metabolic Profiling Database BBIOREFCODE 2.0.0 database (Bruker Biospin), as well as other existing public databases and literature reports (7,15,16).…”

“…High-resolution 1 H-NMR spectroscopy provides quantitative analysis of metabolite concentrations and reproducible information with minimal sample handling. Particularly in the cancer setting, metabolomics has been applied to develop novel early diagnostic biomarkers in renal cancer (3,4), colorectal cancer (5), pancreatic cancer (6), leukemia (7), ovarian cancer (8,9) and oral cancer (10). More recently, this approach has also been used to provide predictive biomarkers associated with prognosis, response to treatment and toxicity (11,12).…”

Metabolomic NMR Fingerprinting to Identify and Predict Survival of Patients with Metastatic Colorectal Cancer

“…Metabolomics is a post-genomic research field concerned with the study of metabolic profiles in biologic samples such as isolated cells (4), tissues (5) or body fluids (6)(7)(8)(9)(10). In recent years, metabolomic studies have provided a significant contribution to the detailed understanding of the biochemical network and pathways in oncology (11), highlighting the potential of metabolomic analyses of blood samples for the detection of cancers, including epithelial ovarian (12), leukemia (13), oral (14), breast (15,16), prostate (11), liver (17) as well as colorectal cancer (CRC; refs. [18][19][20][21][22][23][24][25].…”