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Quantitative Proteomics Analysis of Sporadic Medullary Thyroid Cancer Reveals FN1 as a Potential Novel Candidate Prognostic Biomarker.

ABSTRACT: BACKGROUND:Sporadic medullary thyroid cancer (MTC) is a rare neuroendocrine tumor. Currently, although the diagnosis of sporadic MTC is relatively simple, the need to discover novel candidate prognostic biomarkers for sporadic MTC and investigate the underlying mechanism involved in this rare disease is urgent. MATERIALS AND METHODS:We employed tandem mass tag-based liquid chromatography-mass spectrometry to identify and analyze differentially expressed proteins (DEPs) in sporadic MTC. Western blotting was used to validate the DEPs. Immunohistochemistry was performed to investigate FN1 and RPS6KA3 in an independent set of sporadic MTC tissues. Immunohistochemical data were analyzed by different statistical methods. RESULTS:Three hundred eighty-eight DEPs were identified in mass spectrometry, mainly involved in the extracellular matrix, cytoskeletal remodeling, or oxidoreductase activity. Among them, THBS1, MMP9, FN1, RPS6KA3, SYT1, and carcinoembryonic antigen were successfully validated by Western blot. In addition, FN1 and RPS6KA3, enriched in extracellular matrix (ECM) remodeling and the mitogen-activated protein kinase (MAPK) signaling pathway, respectively, were investigated in an independent set of sporadic MTC tissues. Receiver-operator characteristic curve analysis showed that FN1 and RPS6KA3 can be used for discriminating sporadic MTC tumorous tissues from paired normal thyroid tissues, and the clinical biomarker calcitonin was positively correlated with FN1 and RPS6KA3 in tumorous tissues. Furthermore, the immunohistochemical scores of FN1 in tumorous tissue showed an inverse relationship with tumor classification, lymph node classification, and American Joint Committee on Cancer stage. Through univariate and multivariate analysis for progression-free survival, we also found that low FN1 expression in tumorous tissues was an independent worse prognostic factor for progression-free survival. CONCLUSION:We identified that the pathophysiology of sporadic MTC involve numerous pathways, including the synaptic vesicle pathway, the MAPK signaling pathway, and the ECM remodeling pathway. Furthermore, our study also identified FN1 as novel prognostic biomarkers related to the pathophysiologic changes in sporadic MTC. IMPLICATIONS FOR PRACTICE:Proteomic dissection and prognostic biomarkers are scarce in sporadic medullary thyroid cancer (MTC). This article reports the use of proteomics technology to comprehensively investigate the molecular mechanisms of sporadic MTC, which resulted in the identification of FN1 as a novel candidate prognostic biomarker.

SUBMITTER: Zhan S

PROVIDER: S-EPMC6292558 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Quantitative Proteomics Analysis of Sporadic Medullary Thyroid Cancer Reveals FN1 as a Potential Novel Candidate Prognostic Biomarker.

Zhan Shaohua S Li Jinming J Wang Tianxiao T Ge Wei W

The oncologist 20180508 12

<h4>Background</h4>Sporadic medullary thyroid cancer (MTC) is a rare neuroendocrine tumor. Currently, although the diagnosis of sporadic MTC is relatively simple, the need to discover novel candidate prognostic biomarkers for sporadic MTC and investigate the underlying mechanism involved in this rare disease is urgent.<h4>Materials and methods</h4>We employed tandem mass tag-based liquid chromatography-mass spectrometry to identify and analyze differentially expressed proteins (DEPs) in sporadic ...[more]

PMID: 29739896

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Project description:BackgroundPancreatic cancer is a heterogenous disease with a poor prognosis. This study aimed to discover and validate prognostic tissue biomarkers in pancreatic cancer using a mass spectrometry (MS) based proteomics approach.MethodsGlobal protein sequencing of fresh frozen pancreatic cancer and healthy pancreas tissue samples was conducted by MS to discover potential protein biomarkers. Selected candidate proteins were further verified by targeted proteomics using parallel reaction monitoring (PRM). The expression of biomarker candidates was validated by immunohistochemistry in a large tissue microarray (TMA) cohort of 141 patients with resectable pancreatic cancer. Kaplan-Meier and Cox proportional hazard modelling was used to investigate the prognostic utility of candidate protein markers.FindingsIn the initial MS-discovery phase, 165 proteins were identified as potential biomarkers. In the subsequent MS-verification phase, a panel of 45 candidate proteins was verified by the development of a PRM assay. Brain acid soluble protein 1 (BASP1) was identified as a new biomarker candidate for pancreatic cancer possessing largely unknown biological and clinical functions and was selected for further analysis. Importantly, bioinformatic analysis indicated that BASP1 interacts with Wilms tumour protein (WT1) in pancreatic cancer. TMA-based immunohistochemistry analysis showed that BASP1 was an independent predictor of prolonged survival (HR 0.468, 95% CI 0.257-0.852, p = .013) and predicted favourable response to adjuvant chemotherapy, whereas WT1 indicated a worsened survival (HR 1.636, 95% CI 1.083-2.473, p = .019) and resistance to chemotherapy. Interaction analysis showed that patients with negative BASP1 and high WT1 expression had the poorest outcome (HR 3.536, 95% CI 1.336-9.362, p = .011).InterpretationWe here describe an MS-based proteomics platform for developing biomarkers for pancreatic cancer. Bioinformatic analysis and clinical data from our study suggest that BASP1 and its putative interaction partner WT1 can be used as biomarkers for predicting outcomes in pancreatic cancer patients.

Project description:BackgroundThe cyclin-dependent-kinase inhibitors (CDKN)/retinoblastoma (RB1) pathway has been implicated as having a role in medullary thyroid carcinoma (MTC) tumorigenesis. CDKN2C loss has been associated with RET-mediated MTC in humans but with minimal phenotypic correlation provided. The objective of this study was to evaluate the association between tumor RET mutation status, CDKN2C loss, and aggressiveness of MTC in a cohort of patients with sporadic disease.MethodsTumors from patients with sporadic MTC treated at a single institution were evaluated for somatic RETM918T mutation and CDKN2C copy number loss. These variables were compared to patient demographics, pathology detail, clinical course, and disease-specific and overall survival.ResultsSixty-two MTC cases with an initial surgery date ranging from 1983 to 2009 met the inclusion criteria, of whom 36 (58%) were male. The median age at initial surgery was 53 years (range 22-81 years). The median tumor size was 30 mm (range 6-145 mm) with 29 (57%) possessing extrathyroidal extension. Nodal and/or distant metastasis at presentation was found in 47/60 (78%) and 12/61 (20%) patients, respectively. Median follow-up time was 10.5 years (range 1.1-27.8 years) for the censored observations. The presence of CDKN2C loss was associated with worse M stage and overall AJCC stage. Median overall survival of patients with versus without CDKN2C loss was 4.14 [confidence interval (CI) 1.93-NA] versus 18.27 [CI 17.24-NA] years (p < 0.0001). Median overall survival of patients with a combined somatic RETM918T mutation and CDKN2C loss versus no somatic RETM918T mutation and CDKN2C loss versus somatic RETM918T mutation and CDKN2C 2N versus no somatic RETM918T mutation and CDKN2C 2N was 2.38 [CI 1.67-NA] years versus 10.81 [CI 2.46-NA] versus 17.24 [CI 9.82-NA] versus not reached [CI 13.46-NA] years (p < 0.0001).ConclusionsThe detection of somatic CDKN2C loss is associated with the presence of distant metastasis at presentation as well decreased overall survival, a relationship enhanced by concomitant RETM918T mutation. Further defining the genes involved in the progression of metastatic MTC will be an important step toward identifying pathways of disease progression and new therapeutic targets.

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Quantitative Proteomics Analysis of Sporadic Medullary Thyroid Cancer Reveals FN1 as a Potential Novel Candidate Prognostic Biomarker.

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Quantitative Proteomics Analysis of Sporadic Medullary Thyroid Cancer Reveals FN1 as a Potential Novel Candidate Prognostic Biomarker.

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