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J Biomol Tech. 2010 September; 21(3 Suppl): S33.
PMCID: PMC2918067

Classification of HER2 Receptor Status in Breast Cancer Tissues by MALDI Imaging Mass Spectrometry

S. Rauser,1 C. Marquardt,1 B. Balluff,1,2 C. Albers,3 E. Belau,3 R. Hartmer,3 K. Specht,4 M.P. Ebert,2 M. Schmitt,5 M. Aubele,1 H. Höfler,1,4 and A. Walch1
1Institute of Pathology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany;
2Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany;
3Bruker Daltonik GmbH, Bremen, Germany;
4Institute of Pathology, Technische Universität München, Munich, Germany;
5Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany



Clinical laboratory testing for HER2 status in newly diagnosed, primary breast cancer tissues is critically important for therapeutic decision making. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a powerful tool for investigating proteins through the direct and morphology-driven analysis of tissue sections. Unlike immunohistochemistry (IHC), MALDI-IMS enables the acquisition of complex protein expression profiles without any labeling. We hypothesized that MALDI-IMS may determine HER2 status directly from breast cancer tissues. Breast cancer tissues (n=48) predefined for HER2 status by IHC and fluorescence-in-situ-hybridization (FISH) were subjected to MALDI-IMS and protein profiles were obtained through direct analysis of tissue sections. Protein identification was performed by tissue micro-extraction and fractionation followed by top-down tandem mass spectrometry on a spherical ion trap with ETD. A discovery and an independent validation set were used to predict HER2 status by applying proteomic classification algorithms. We found that specific protein/peptide expression changes strongly correlated with the HER2 over expression (m/z 4740, 8404, 8419, 8455, 8570, 8607, 8626). Among these, we identified m/z 8404 as Cysteine-rich intestinal protein 1 (CRIP1). Of particular note, the proteomic signature was able to accurately define HER2-positive from HER2-negative tissues achieving high values for sensitivity of 83%, for specificity of 92% and an overall accuracy of 89% (95% CI: 65% to 99%). Our results underscore the potential of MALDI-IMS proteomic algorithms for morphology-driven tissue diagnostics such as HER2 testing and show that MALDI-IMS can reveal biologically significant molecular details from tissues which are not limited to traditional high-abundance proteins. CRIP1 is a cytosolic protein that is potentially useful for serum based diagnostics of HER2 if tissue leakage can be demonstrated.

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