Cardiolipins Are Biomarkers of Mitochondria-Rich Thyroid Oncocytic Tumors

Zhang, Jialing; Yu, Wendong; Ryu, Seung Woo; Lin, Jianguo; Buentello, Gerardo; Tibshirani, Robert; Suliburk, James W.; Eberlin, Lívia S.

doi:10.1158/0008-5472.can-16-1545

Cited by 67 publications

(77 citation statements)

References 39 publications

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“…The mass spectra obtained in the negative ion mode for each tissue type presented a rich variety of molecular ions commonly observed from human tissues by DESI-MSI (18), with high relative abundances of metabolites, FA, and complex lipids. For example, the mass spectra obtained for PTC tissue sections presented lipid species previously identified as diagnostic markers by DESI-MSI (27), including a variety of doubly charged CL and other GL such as PI(38:4) ( m/z 885.550), PI(36:4) ( m/z 857.518), PE(38:4) ( m/z 766.539), and PE (36:2) ( m/z 742.539) (table S2). A distinct mass spectral profile was obtained for the normal thyroid tissue sections, presenting high relative abundances of iodine ( m/z 126.904), glutamine ( m/z 145.050), ascorbic acid ( m/z 175.024), C 36 H 78 O 9 N 3 I (tentatively assigned; m/z 822.472), and PI(38:4) ( m/z 885.551) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system

et al. 2017

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Conventional methods for histopathologic tissue diagnosis are labor- and time-intensive and can delay decision-making during diagnostic and therapeutic procedures. We report the development of an automated and biocompatible handheld mass spectrometry device for rapid and nondestructive diagnosis of human cancer tissues. The device, named MasSpec Pen, enables controlled and automated delivery of a discrete water droplet to a tissue surface for efficient extraction of biomolecules. We used the MasSpec Pen for ex vivo molecular analysis of 20 human cancer thin tissue sections and 253 human patient tissue samples including normal and cancerous tissues from breast, lung, thyroid, and ovary. The mass spectra obtained presented rich molecular profiles characterized by a variety of potential cancer biomarkers identified as metabolites, lipids, and proteins. Statistical classifiers built from the histologically validated molecular database allowed cancer prediction with high sensitivity (96.4%), specificity (96.2%), and overall accuracy (96.3%), as well as prediction of benign and malignant thyroid tumors and different histologic subtypes of lung cancer. Notably, our classifier allowed accurate diagnosis of cancer in marginal tumor regions presenting mixed histologic composition. Last, we demonstrate that the MasSpec Pen is suited for in vivo cancer diagnosis during surgery performed in tumor-bearing mouse models, without causing any observable tissue harm or stress to the animal. Our results provide evidence that the MasSpec Pen could potentially be used as a clinical and intraoperative technology for ex vivo and in vivo cancer diagnosis.

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Section: Resultsmentioning

confidence: 99%

Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system

et al. 2017

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“…Furthermore, the molecular model built by the Lasso to discriminate between HGSC and healthy tissue (Supplemental Table 3) pinpointed additional GP markers such as CL. Positive weights were assigned to CL 72:8 and CL 72:7 to characterize HGSC, suggesting a role for these lipids in tumor growth and proliferation (32). In the positive ion mode, several PC species were selected as predictive markers.…”

Section: Resultsmentioning

confidence: 99%

“…In our study, several PG and PI species were identified as predictive markers for tumor aggressiveness, with increased relative abundance in HGSC samples. CLs, which are complex GP species present almost exclusively in the inner mitochondrial membrane, were also observed in increased relative abundances in HGSC tissue when compared to normal tissue (32). Moreover, increased relative abundances of ubiquinone, a component of the mitochondrial respiratory chain, was also found to be characteristic of serous ovarian tumors (37).…”

Section: Discussionmentioning

confidence: 99%

Metabolic Markers and Statistical Prediction of Serous Ovarian Cancer Aggressiveness by Ambient Ionization Mass Spectrometry Imaging

et al. 2017

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Ovarian high-grade serous carcinoma (HGSC) results in the highest mortality among gynecological cancers, developing rapidly and aggressively. Dissimilarly, serous borderline ovarian tumors (BOT) can progress into low-grade serous carcinomas and have relatively indolent clinical behavior. The underlying biological differences between HGSC and BOT call for accurate diagnostic methodologies and tailored treatment options, and identification of molecular markers of aggressiveness could provide valuable biochemical insights and improve disease management. Here we used desorption electrospray ionization (DESI) mass spectrometry (MS) to image and chemically characterize the metabolic profiles of HGSC, BOT, and normal ovarian tissue samples. DESI-MS imaging enabled clear visualization of fine papillary branches in serous BOT and allowed for characterization of spatial features of tumor heterogeneity such as adjacent necrosis and stroma in HGSC. Predictive markers of cancer aggressiveness were identified, including various free fatty acids, metabolites, and complex lipids such as ceramides, glycerophosphoglycerols, cardiolipins, and glycerophosphocholines. Classification models built from a total of 89,826 individual pixels, acquired in positive and negative ion modes from 78 different tissue samples, enabled diagnosis and prediction of HGSC and all tumor samples in comparison to normal tissues, with overall agreements of 96.4% and 96.2%, respectively. HGSC and BOT discrimination was achieved with an overall accuracy of 93.0%. Interestingly, our classification model allowed identification of three BOT samples presenting unusual histologic features that could be associated with the development of low-grade carcinomas. Our results suggest DESI-MS as a powerful approach for rapid serous ovarian cancer diagnosis based on altered metabolic signatures.

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“…Gerbig et al systematically segregated colorectal adenocarcinoma tissue area from healthy intestine mucosa and smooth muscle tissue using DESI‐MSI with the aid of PCA/LDA statistical tool, as illustrated in Figure A . Oncocytic thyroid tumours and non‐oncocytic thyroid tumours were investigated in 45 tissue specimens using DESI‐MSI along with significance analysis of microarrays (SAM) statistical tool . Cardiolipins were identified as critical biomarkers for thyroid cancer with higher SAM contrast values for monolysocardiolipins [MLCL (54:5)], oxidized CL (18:2/18:2/18:2/9:1(OOH)), CL (18:2/18:2/18:2/18:1), CL (20:4/18:2/18:2/18:1) and CL + PC (108:9) in oncocytic tumor tissue than in non‐oncocytic tumor tissue and normal tissue.…”

Section: Recent Applications In Ambient Ms Imagingmentioning

confidence: 99%

“…95 Oncocytic thyroid tumours and non-oncocytic thyroid tumours were investigated in 45 tissue specimens using DESI-MSI along with significance analysis of microarrays (SAM) statistical tool. 96 accurate identification of meningioma tissue margins. 98 Psychiatric disorders such as schizophrenia, 99 Parkinson's and Alzheimer's were also studied by ambient MS to characterize and map critical metabolites pertaining to these neurological diseases.…”

Section: Other Rare Cancers and Diseased State Tissuesmentioning

confidence: 99%

Review and perspectives on the applications of mass spectrometry imaging under ambient conditions

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Bagga

Prova

et al. 2018

Rapid Comm Mass Spectrometry

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Ambient mass spectrometry (AMS)-based techniques are performed under ambient conditions in which the ionization and desorption occur in the open environment allowing the direct analysis of molecules with minimal or no sample preparation. A selected group of AMS techniques demonstrate imaging capabilities that can provide information about the localization of molecules on complex sample surfaces such as biological tissues. 2D, 3D, and multimodal imaging have unlocked an array of applications to systematically address complex problems in many areas of research such as drug monitoring, natural products, forensics, and cancer diagnostics. In the present review, we summarize recent advances in the field with respect to the implementation of new ambient ionization techniques and current applications in the last 5 years. In more detail, we mainly focus on imaging applications in topics related to animal whole bodies and tissues, single cells, cancer diagnostics and biomarkers, microbial cultures and co-cultures, plant and natural product metabolomics, and forensic applications. Finally, we discuss new areas of research, future perspectives, and the overall direction that the field may take in the years to come.

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Cardiolipins Are Biomarkers of Mitochondria-Rich Thyroid Oncocytic Tumors

Cited by 67 publications

References 39 publications

Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system

Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system

Metabolic Markers and Statistical Prediction of Serous Ovarian Cancer Aggressiveness by Ambient Ionization Mass Spectrometry Imaging

Review and perspectives on the applications of mass spectrometry imaging under ambient conditions

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