Proteomic Signatures of Diffuse and Intestinal Subtypes of Gastric Cancer

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.

Comprehensive transcriptomic profiling and mutational landscape of primary gastric linitis plastica

“…Intestinal-type is the most common in GC, followed by diffuse-type and indeterminate-type [3]. Numerous studies have confirmed that intestinal-type GC is associated with intestinal metaplasia and helicobacter pylori infection in gastric mucosa, while diffuse-type GC mostly occurs in young female patients, which may indicate distinct tumor development pathways for intestinal-type and diffuse-type GC [6][7][8]. World Health Organization (WHO) classification includes not only gastric adenocarcinomas, but also all other types of gastric tumors with a low frequency.…”

Proteomic alterations in extracellular vesicles induced by oncogenic PIK3CA mutations

“…Liquid chromatography tandem mass spectrometry (LC‐MS/MS) : LC‐MS/MS parameters for analysis of TMT‐labeled peptides have been published previously by our group [32, 33] and were modified for the current study as follows. Twelve bRPLC fractions were analyzed on an Orbitrap Fusion Lumos mass spectrometer (Thermo Fisher Scientific).…”

Gastric Cancer: A Comprehensive Literature Review

“…Included in these subtypes are the intestinal and diffuse varieties. Comprehending these fundamental mechanisms is of the utmost importance in furthering our understanding of gastric cancer and formulating efficacious approaches to its detection, prevention, and management [ 15 ].…”