Differential Expression of CADM1 in Gastrointestinal Stromal Tumors of Different Sites and with Different Gene Abnormalities.

Koji Isozaki,Toshirou Nishida,Neinei Kimura,Takako Kihara,Jiayin Yuan,Yuka Hashikura,Mizuka Ohkouchi,Seiichi Hirota,Tsuyoshi Takahashi,Akihiko Ito

doi:10.3389/pore.2021.602008

Abstract

Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the human gastrointestinal tract, differentiating toward the interstitial cell of Cajal (ICC), arises predominantly in the stomach and small intestine. Small intestinal GISTs appear to have worse prognosis than gastric GISTs. In a pilot study of a cDNA expression chip using several GISTs, we found that Cell Adhesion Molecule 1 (CADM1), which could contribute to tumor growth and infiltration, is expressed more strongly in small intestinal GISTs than gastric GISTs. In the present study, we examined CADM1 expression in GISTs of different sites and with different gene abnormalities using a large number of gastric and small intestinal GISTs. First, immunoblotting confirmed significantly higher CADM1 expression in small intestinal GISTs with exon 11 c-kit mutation than gastric GISTs with exon 11 c-kit mutation. Real-time PCR also revealed that small intestinal GISTs with exon 11 c-kit mutation showed significantly higher CADM1 mRNA than gastric GISTs with exon 11 c-kit mutation. Although most small intestinal GISTs showed high CADM1 mRNA expression regardless of gene abnormality types, different CADM1 expression was detected between gastric GISTs with c-kit mutation and those with PDGFRA mutation. Immunohistochemistry showed that many small intestinal GISTs were CADM1-positive but most gastric GISTs CADM1-negative or -indefinite. In the normal gastric and small intestinal walls, immunoreactivity of CADM1 was detected only in nerves, but neither in gastric ICCs nor small intestinal ICCs, indicating that the high CADM1expression in small intestinal GISTs might be acquired during tumorigenesis. Different CADM1 expression between gastric and small intestinal GISTs might be related to different prognoses between them. Further functional experiments are needed to elucidate the role of CADM1 on GIST biology, and there is a possibility that targeting therapy against CADM1 has a preventive effect for tumor spreading in small intestinal GISTs.

Highlights

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal tract, differentiating toward the interstitial cell of Cajal (ICC) [1]
In a pilot study of a cDNA expression chip using several GISTs, we found that Cell Adhesion Molecule 1 (CADM1), which could contribute to tumor growth and infiltration, is expressed more strongly in small intestinal GISTs than gastric GISTs
We noticed that CADM1 might be highly expressed by small intestinal GISTs compared to gastric GISTs by cDNA expression chip using a small number of gastric and small intestinal GISTs

Summary

Introduction

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal tract, differentiating toward the interstitial cell of Cajal (ICC) [1]. Sporadic GISTs usually harbor gain-of-function mutations in either c-kit (80–85%) or PDGFRA (5–10%) [2]. Most of the c-kit mutations in GISTs are present at exon 11, but a minority at exon 8, 9, 13 or 17 [3]. Most GISTs with exon 9 c-kit mutations are located in the small intestine [4]. Most GISTs with PDGFRA mutations occur in the stomach. 10% of GISTs, defined as c-kit/PDGFRA wild-type (WT) GISTs [5], which carry wild-type sequences in all hot spots of c-kit and PDGFRA, represent some groups with distinct molecular characteristics, including defects in SDH complex [6], mutations of NF1 [7], or mutations of BRAF [8]

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Conclusion