Proteomic Signatures of Diffuse and Intestinal Subtypes of Gastric Cancer.

Smrita Singh,Jyoti Sharma,Neha S Joshi,Champaka Gopal,Anil K Madugundu,Akhilesh Pandey,Gajanan Sathe,Mohd Younis Bhat

doi:10.3390/cancers13235930

Abstract

Gastric cancer is a leading cause of death from cancer globally. Gastric cancer is classified into intestinal, diffuse and indeterminate subtypes based on histology according to the Laurén classification. The intestinal and diffuse subtypes, although different in histology, demographics and outcomes, are still treated in the same fashion. This study was designed to discover proteomic signatures of diffuse and intestinal subtypes. Mass spectrometry-based proteomics using tandem mass tags (TMT)-based multiplexed analysis was used to identify proteins in tumor tissues from patients with diffuse or intestinal gastric cancer with adjacent normal tissue control. A total of 7448 or 4846 proteins were identified from intestinal or diffuse subtype, respectively. This quantitative mass spectrometric analysis defined a proteomic signature of differential expression across the two subtypes, which included gremlin1 (GREM1), bcl-2-associated athanogene 2 (BAG2), olfactomedin 4 (OLFM4), thyroid hormone receptor interacting protein 6 (TRIP6) and melanoma-associated antigen 9 (MAGE-A9) proteins. Although GREM1, BAG2, OLFM4, TRIP6 and MAGE-A9 have all been previously implicated in tumor progression and metastasis, they have not been linked to intestinal or diffuse subtypes of gastric cancer. Using immunohistochemical labelling of a tissue microarray comprising of 124 cases of gastric cancer, we validated the proteomic signature obtained by mass spectrometry in the discovery cohort. Our findings should help investigate the pathogenesis of these gastric cancer subtypes and potentially lead to strategies for early diagnosis and treatment.

Highlights

Protein was extracted from the tumor and adjacent normal tissues and subjected to in-solution digestion using trypsin
The peptides from each sample were labeled with tandem mass tags (TMT) 10-plex labels and pooled
Mass spectrometry-based proteomic profiling of diffuse and intestinal subtypes of gastric cancer was performed with the aim of identifying differences between the two subtypes at a proteomic level

Summary

Introduction

Gastric cancer is a major cause of death worldwide, in Southeast Asia. Surgical resection with adjuvant chemotherapy is the preferred treatment for early gastric creativecommons.org/licenses/by/ 4.0/). Recurrence occurs in up to 30–40% of patients within 5 years. Gastric cancer is a clinically heterogeneous disease with diverse histology, morphology and molecular pathogenesis. The Lauren classification and the World Health Organization (WHO) classification are the two most commonly used histologic classifications. The Lauren system classifies gastric cancer into intestinal, diffuse and indeterminate types [1], while the 2010 WHO system classifies gastric adenocarcinoma into papillary, tubular, mucinous, poorly cohesive (including signet ring cell carcinoma and other variants) and mixed adenocarcinomas [2]

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