Cross-testing of major molecular markers indicates distinct pathways of tumorigenesis in gastric adenocarcinomas and synchronous gastrointestinal stromal tumors

Abstract

Small subtype of the gastrointestinal stromal tumor (micro-GIST, MG) is usually asymptomatic and is frequently found incidentally in association with gastric adenocarcinoma (GAC). The background of this coincidence is still an open question. This study comprehensively characterized nine MGs and GACs present in the same surgical specimen by cross-testing the markers of the major pathogenetic pathways of both tumor types. All of the MGs were immunohistochemically positive for CD117/KIT, CD34, and DOG1. DOG1 was also detected in four GACs. Four MGs carried mutations in c-KIT (exons 9, 11, and 13) and two cases in PDGFRα (exon 18). None of the GACs carried activating mutations in c-KIT or PDGFRα. MMR immunopanel identified one GAC as microsatellite unstable tumor. No EBV-positive tumor was found. According to the TCGA molecular classification, one GAC was categorized in the MSI subgroup, three GACs in the genomically stable subgroup, and the rest into the chromosomal instability subgroup. Although a common carcinogenic effect cannot be ruled out, our data suggest a distinct molecular background in the evolvement of the synchronous MGs and GACs. The presence of a MG in gastric resection specimens may be indicative of the development of synchronous malignant tumors in or outside the stomach.

Gastric schwannoma coexisting with tubular adenoma of the gallbladder: a rare combination

“…There also may be an association between gastrointestinal mesenchymal tumors and adenomas of the digestive tract, such as in similar epidemiology, potential carcinogens, or shared or crossed pathogenetic molecular pathways. 1 , 8 , 12 These issues require further validation and investigation in clinical practice.…”

Tensin2 Is a Novel Diagnostic Marker in GIST, Associated with Gastric Location and Non-Metastatic Tumors

“…KIT and DOG1 are used as highly sensitive diagnostic markers for GIST, but they are expressed also in other mesenchymal tumors relevant for GIST differential diagnosis, such as synovial sarcomas, leiomyomas, leiomyosarcomas, angiosarcomas, Ewing sarcomas, malignant peripheral nerve sheath tumors, and schwannomas [28]. However, gastric adenocarcinomas do not provide a differential diagnostic problem, as they are most usually negative for KIT, DOG1, and CD34, while GISTs are usually positive for at least one of these markers [29]. In the present study, we found that 89% of gastric GISTs have intermediate to strong TNS2 expression, while 90% of non-GIST sarcomas examined were completely negative for TNS2 expression.…”

The characteristics and clinical relevance of tumor fusion burden in non-EBV (+) gastric cancer with MSS

“…GC cases from the TCGA cohort were divided into different molecular subtypes based on major pathogenic pathways (EBV-positive, MSI, GS, and CIN tumors). The simplified dichotomy algorithm was used to analyze EBV (+) status as described previously [ 31 ]. Based on the simplified dichotomy algorithm, an approximated reproduction of the TCGA classification was achieved by an algorithm that started with the analysis of the EBV positivity and then investigated the MSI status.…”