Remodeling of central metabolism in invasive breast cancer compared to normal breast tissue – a GC-TOFMS based metabolomics study

Abstract

BackgroundChanges in energy metabolism of the cells are common to many kinds of tumors and are considered a hallmark of cancer. Gas chromatography followed by time-of-flight mass spectrometry (GC-TOFMS) is a well-suited technique to investigate the small molecules in the central metabolic pathways. However, the metabolic changes between invasive carcinoma and normal breast tissues were not investigated in a large cohort of breast cancer samples so far.ResultsA cohort of 271 breast cancer and 98 normal tissue samples was investigated using GC-TOFMS-based metabolomics. A total number of 468 metabolite peaks could be detected; out of these 368 (79%) were significantly changed between cancer and normal tissues (p<0.05 in training and validation set). Furthermore, 13 tumor and 7 normal tissue markers were identified that separated cancer from normal tissues with a sensitivity and a specificity of >80%. Two-metabolite classifiers, constructed as ratios of the tumor and normal tissues markers, separated cancer from normal tissues with high sensitivity and specificity. Specifically, the cytidine-5-monophosphate / pentadecanoic acid metabolic ratio was the most significant discriminator between cancer and normal tissues and allowed detection of cancer with a sensitivity of 94.8% and a specificity of 93.9%.ConclusionsFor the first time, a comprehensive metabolic map of breast cancer was constructed by GC-TOF analysis of a large cohort of breast cancer and normal tissues. Furthermore, our results demonstrate that spectrometry-based approaches have the potential to contribute to the analysis of biopsies or clinical tissue samples complementary to histopathology.

Glutamate enrichment as new diagnostic opportunity in breast cancer

“…The pattern of dysregulation observed here, including upregulation of amino acids, up-regulation of purin and pyrimidine metabolism, down-regulation of glucose, sucrose and free fatty acids, is similar to the deregulation pattern that we found between breast cancer and normal breast tissues before. 24 The findings are compatible with a possible depletion of sugars and free fatty acids as a consequence of higher glucose consumption by glycolysis and higher fatty acid usage for synthesis of cell membranes.…”

“…24 The metabolomics data were normalized by scaling with the mean intensity of the 162 detected metabolites with known chemical structure. Glutamate was quantified at m/z 5 246u, glutamine was quantified at m/z 5 156u.…”

Application of omic technologies in cancer research

“…46 Budczies et al analysed the metabolic profiles of different breast cancer stages and discovered an altered metabolite ratio of cytidine-5-monophosphate/pentadecanoic acid, which could show a strong discriminatory ability between breast cancer and healthy tissue. 47 A further study by the same group revealed that beta-alanine could distinguish between ER+ and ER-breast cancer. 48 The most commonly applied 'omics approaches and the latest methods/technologies used in each of these are summarised below and in Table 1.…”

Microfluidic sampling system for tissue analytics

“…Figure 11 presents only PC and PE lipids that indicate biomarkers for breast cancer. 7,8 The normal and tumour samples have also been tested with a standard extraction method with a homogenized mixture. This has been done in a previous work with the same samples.…”

“…3 An amount of different phospholipids has been studied as biomarkers for ovarian 4 and breast cancers. 5 The role of metabolites and lipids such as Phosphatidylcholines (PCs) and Phosphoethanolamines (PEs) as breast cancer biomarkers has been investigated by Eliyahu et al, 6 Hilvo et al, 7 and Butczies et al 8 Separation of breast cancer tissues from normal breast tissues was demonstrated to be feasible with high sensitivity and specificity. The same PC and PE biomarkers were also detected from urine samples by Kim et al 9 They succeeded to measure PC and PE lipids with nanoflow liquid chromatography tandem mass spectrometry.…”