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Targeted proteomics for multiplexed verification of markers of colorectal tumorigenesis


Uzozie, Anuli Christiana; Selevsek, Nathalie; Wahlander, Asa; Nanni, Paolo; Grossmann, Jonas; Weber, Achim; Buffoli, Federico; Marra, Giancarlo (2017). Targeted proteomics for multiplexed verification of markers of colorectal tumorigenesis. Molecular & Cellular Proteomics:1-48.

Abstract

Targeted proteomic methods can accelerate the verification of multiple tumor marker candidates in large series of patient samples. We utilized the targeted approach known as selected / multiple reaction monitoring (SRM/MRM) to verify potential protein markers of colorectal adenoma identified by our group in previous transcriptomic and quantitative shotgun proteomic studies of a large cohort of precancerous colorectal lesions. We developed SRM assays to reproducibly detect and quantify 25 (62.5%) of the 40 selected proteins in an independent series of precancerous and cancerous tissue samples (19 adenoma/normal mucosa pairs; 17 adenocarcinoma/normal mucosa pairs). Twenty-three proteins were significantly upregulated (n=17) or downregulated (n=6) in adenomas and/or adenocarcinomas, as compared with normal mucosa (linear fold changes ≥ ±1.3, adjusted P value <0.05). Most changes were observed in both tumor types (upregulation of ANP32A, ANXA3, SORD, LDHA, LCN2, NCL, S100A11, SERPINB5, CDV3, OLFM4, and REG4; downregulation of ARF6 and PGM5), and a five-protein biomarker signature distinguished neoplastic tissue from normal mucosa with a maximum area under the receiver operating curve greater than 0.83. Other changes were specific for adenomas (PPA1 and PPA2 upregulation; KCTD12 downregulation) or adenocarcinoma (ANP32B, G6PD, RCN1, and SET upregulation; downregulated AKR1B1, APEX1, and PPA1). Some changes significantly correlated with a few patient- or tumor-related phenotypes. Twenty-two (96%) of the 23 proteins have a potential to be released from the tumors into the bloodstream, and their detectability in plasma has been previously reported. The proteins identified in this study expand the pool of investment-worthy biomarker candidates that can be used to develop a standardized pre-colonoscopy blood test for the early detection of colorectal tumors.

Abstract

Targeted proteomic methods can accelerate the verification of multiple tumor marker candidates in large series of patient samples. We utilized the targeted approach known as selected / multiple reaction monitoring (SRM/MRM) to verify potential protein markers of colorectal adenoma identified by our group in previous transcriptomic and quantitative shotgun proteomic studies of a large cohort of precancerous colorectal lesions. We developed SRM assays to reproducibly detect and quantify 25 (62.5%) of the 40 selected proteins in an independent series of precancerous and cancerous tissue samples (19 adenoma/normal mucosa pairs; 17 adenocarcinoma/normal mucosa pairs). Twenty-three proteins were significantly upregulated (n=17) or downregulated (n=6) in adenomas and/or adenocarcinomas, as compared with normal mucosa (linear fold changes ≥ ±1.3, adjusted P value <0.05). Most changes were observed in both tumor types (upregulation of ANP32A, ANXA3, SORD, LDHA, LCN2, NCL, S100A11, SERPINB5, CDV3, OLFM4, and REG4; downregulation of ARF6 and PGM5), and a five-protein biomarker signature distinguished neoplastic tissue from normal mucosa with a maximum area under the receiver operating curve greater than 0.83. Other changes were specific for adenomas (PPA1 and PPA2 upregulation; KCTD12 downregulation) or adenocarcinoma (ANP32B, G6PD, RCN1, and SET upregulation; downregulated AKR1B1, APEX1, and PPA1). Some changes significantly correlated with a few patient- or tumor-related phenotypes. Twenty-two (96%) of the 23 proteins have a potential to be released from the tumors into the bloodstream, and their detectability in plasma has been previously reported. The proteins identified in this study expand the pool of investment-worthy biomarker candidates that can be used to develop a standardized pre-colonoscopy blood test for the early detection of colorectal tumors.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:4 January 2017
Deposited On:12 Jan 2017 09:29
Last Modified:06 Aug 2017 01:17
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:1535-9476
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1074/mcp.M116.062273
PubMed ID:28062797

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