Clinically meaningful molecular subtypes for classification of breast cancers have been established, however, initiation and progression of these subtypes remain poorly understood. The recent development of desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) facilitates the convergence of analytical chemistry and traditional pathology, allowing chemical profiling with minimal tissue pretreatment in frozen samples. Here, we characterized the chemical composition of molecular subtypes of breast cancer with DESI-MSI. Regions of interest were identified, including invasive breast cancer (IBC), ductal carcinoma in situ (DCIS), and adjacent benign tissue (ABT), and metabolomic profiles at 200 mm elaborated using Biomap software and the Lasso method. Top ions identified in IBC regions included polyunsaturated fatty acids, deprotonated glycerophospholipids, and sphingolipids. Highly saturated lipids, as well as antioxidant molecules [taurine (m/z 124.0068), uric acid (m/z 167.0210), ascorbic acid (m/z 175.0241), and glutathione (m/z 306.0765)], were able to distinguish IBC from ABT. Moreover, luminal B and triple-negative subtypes showed more complex lipid profiles compared with luminal A and HER2 subtypes. DCIS and IBC were distinguished on the basis of cell signaling and apoptosis-related ions [fatty acids (341.2100 and 382.3736 m/z) and glycerophospholipids (PE (P-16:0/22:6, m/z 746.5099, and PS (38:3), m/z 812.5440)]. In summary, DESI-MSI identified distinct lipid composition between DCIS and IBC and across molecular subtypes of breast cancer, with potential implications for breast cancer pathogenesis.Significance: These findings present the first in situ metabolomic findings of the four molecular subtypes of breast cancer, DCIS, and normal tissue, and add to the understanding of their pathogenesis.
<div>Abstract<p>Clinically meaningful molecular subtypes for classification of breast cancers have been established, however, initiation and progression of these subtypes remain poorly understood. The recent development of desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) facilitates the convergence of analytical chemistry and traditional pathology, allowing chemical profiling with minimal tissue pretreatment in frozen samples. Here, we characterized the chemical composition of molecular subtypes of breast cancer with DESI-MSI. Regions of interest were identified, including invasive breast cancer (IBC), ductal carcinoma <i>in situ</i> (DCIS), and adjacent benign tissue (ABT), and metabolomic profiles at 200 μm elaborated using Biomap software and the Lasso method. Top ions identified in IBC regions included polyunsaturated fatty acids, deprotonated glycerophospholipids, and sphingolipids. Highly saturated lipids, as well as antioxidant molecules [taurine (m/z 124.0068), uric acid (m/z 167.0210), ascorbic acid (m/z 175.0241), and glutathione (m/z 306.0765)], were able to distinguish IBC from ABT. Moreover, luminal B and triple-negative subtypes showed more complex lipid profiles compared with luminal A and HER2 subtypes. DCIS and IBC were distinguished on the basis of cell signaling and apoptosis-related ions [fatty acids (341.2100 and 382.3736 m/z) and glycerophospholipids (PE (P-16:0/22:6, m/z 746.5099, and PS (38:3), m/z 812.5440)]. In summary, DESI-MSI identified distinct lipid composition between DCIS and IBC and across molecular subtypes of breast cancer, with potential implications for breast cancer pathogenesis.</p>Significance:<p>These findings present the first <i>in situ</i> metabolomic findings of the four molecular subtypes of breast cancer, DCIS, and normal tissue, and add to the understanding of their pathogenesis.</p></div>
<p>Samples classifications, ions identified based on visual inspection and statistical analysis, different representative molecular images and mass spectra for each tumor type and tandem mass spectrometry data for metabolite identification.</p>
<p>Samples classifications, ions identified based on visual inspection and statistical analysis, different representative molecular images and mass spectra for each tumor type and tandem mass spectrometry data for metabolite identification.</p>
<div>Abstract<p>Clinically meaningful molecular subtypes for classification of breast cancers have been established, however, initiation and progression of these subtypes remain poorly understood. The recent development of desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) facilitates the convergence of analytical chemistry and traditional pathology, allowing chemical profiling with minimal tissue pretreatment in frozen samples. Here, we characterized the chemical composition of molecular subtypes of breast cancer with DESI-MSI. Regions of interest were identified, including invasive breast cancer (IBC), ductal carcinoma <i>in situ</i> (DCIS), and adjacent benign tissue (ABT), and metabolomic profiles at 200 μm elaborated using Biomap software and the Lasso method. Top ions identified in IBC regions included polyunsaturated fatty acids, deprotonated glycerophospholipids, and sphingolipids. Highly saturated lipids, as well as antioxidant molecules [taurine (m/z 124.0068), uric acid (m/z 167.0210), ascorbic acid (m/z 175.0241), and glutathione (m/z 306.0765)], were able to distinguish IBC from ABT. Moreover, luminal B and triple-negative subtypes showed more complex lipid profiles compared with luminal A and HER2 subtypes. DCIS and IBC were distinguished on the basis of cell signaling and apoptosis-related ions [fatty acids (341.2100 and 382.3736 m/z) and glycerophospholipids (PE (P-16:0/22:6, m/z 746.5099, and PS (38:3), m/z 812.5440)]. In summary, DESI-MSI identified distinct lipid composition between DCIS and IBC and across molecular subtypes of breast cancer, with potential implications for breast cancer pathogenesis.</p>Significance:<p>These findings present the first <i>in situ</i> metabolomic findings of the four molecular subtypes of breast cancer, DCIS, and normal tissue, and add to the understanding of their pathogenesis.</p></div>
INTRODUCTION Lipid profiling as a source for biomarkers identification is an evolving field with some enthusiastic results in cancer. Alterations on lipid metabolism have been increasingly recognized as a hallmark of cancer cells and may help to understand breast cancer carcinogenesis. Analytical chemistry and Pathology have been recently combined in the development of chemical microscopy using in situ mass spectrometry (MS) and may help to decipher breast cancer molecular initiation and progression. OBJECTIVE We aimed to use in situ Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) to investigate lipid profiles across invasive breast cancer (IBC) molecular subtypes and related normal parenchyma (NBP) and ductal carcinoma in situ (DCIS). METHODS: We selected frozen samples from 9 IBC with various ER/PR/HER2 status (ER 0 to 100%, PR 0 to 90%, HER2 0 and 3+, Ki67 10 to 70%). Unstained slides obtained from frozen tissue at 10μm were submitted to DESI-MS analysis with no pretreatment and spatial resolution of 100μm. Molecular profiles (mass to charge [m/z] ratio versus signal intensity) were generated in triplicate directly from tissues to detect changes from areas of interest: IBC (and adjacent normal breast parenchyma and DCIS whenever present) regions were identified by a breast pathologist on HE-stained sequential slides. Experiment was conducted in full-scan mode and m/z range of 100-1200. DESI mass spectra were obtained using a Thermo ScientificTM Q ExactiveTM Hybrid Quadrupole Orbitrap Mass Spectrometer in the positive ion mode. The Biomap software was used to visualize the images and to export the spectrums to metaboanalyst, where the data were statiscally analyzed. RESULTS: The images obtained by lipid profiling presented a direct correlation with HE stained slides, with some ions m/z clearly overlaying areas of normal parenchyma, DCIS and invasive breast cancer. The unsupervised hierarchical clustering analysis showed all technical triplicates remained grouped. All NBP but one clustered together. Triple negative IBC and its related NBP formed a distinct cluster from all other ER+ samples. The ER+/HER2 + tumor segregated from other ER+/HER2- tumors. DCIS and IBC from ER+/PR+/HER2- tumor clustered together. The Ions with m/z 186.9 and m/z 303.2 were consistently related to NBP and IBC respectively. CONCLUSIONS: Chemical microscopy using DESI-MS is a powerful tool to identify specific lipid profiles across molecular subtypes of IBC and can contribute to understand breast cancer carcinogenesis. Citation Format: Victor P. Andrade, Adriana L. Santoro, Sabrina T. Moretti, Nicolas V. Schwab, Marcos N. Eberlin. In situ mass spectrometry using desorption electrospray ionization mass spectrometry (DESI-MS) can detect specific lipid profiles across breast cancer molecular subtypes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3981.
k wCol , apresentou elevada consistência interna, com bom poder de correlação (R 2 = 0, 97) e predição (Q 2 = 0,86) para a partição destas moléculas.
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