DOG1: A novel Gastrointestinal Stromal Tumor (GIST) Biomarker

DOG1 is an antibody against a GIST-specific (gastrointestinal stromal tumor) gene, encoding for the hypothetical protein FLJ10261, dubbed “Discovered On GIST 1” (DOG1). The function of this protein is unknown but has an expected size of 114 Kb with 960 amino acids, and has 8 transmembrane regions suggesting that it may be an ion channel. The DOG1 protein shows no homology at the DNA or amino acid level with KIT. DOG1 antibody labels the epithelium of the following organs; breast, prostate, salivary gland, liver, stomach, testis, pancreas, and gallbladder.

The differential diagnosis of mesenchymal tumors of the gastrointestinal tract is quite wide including the following tumors; GIST, leiomyosarcoma, leiomyoma, Schwannoma, Neurofibroma, malignant peripheral nerve sheath tumor, desmoid fibromatosis, solitary fibrous tumor, ganglioneuroma, paraganglioma, synovial sarcoma, undifferentiated sarcoma, and metastatic lesions such as spindle cell melanoma. There is considerable morphologic overlap amongst these tumors. DOG1 is overexpressed in most gastrointestinal stromal tumors (GISTs), and is rarely expressed in other soft tissue tumors. The staining pattern is membranous and/or cytoplasmic in location. Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract, and are thought to originate from the interstitial cells of Cajal or its precursors. Molecular pathological studies have shown that most GISTs express KIT, a type III receptor tyrosine kinase, and have gain-of-function mutation of the KIT gene or the platelet-derived growth factor receptor alpha (PDGFRA) gene. These mutations are considered fundamental to development of most GISTs. Approximately 85% of GISTs harbor activating mutations in the KIT or PDGFRA gene. Inhibition of KIT and PDGFRA by tyrosine kinase inhibitors such as imatinib mesylate has revolutionized the treatment of GISTs and thus requires precision in diagnosis such that patients may benefit from these newly introduced drugs. Accurate diagnosis of GIST relies heavily on KIT immunoreactivity. Approximately 85% to 95% of GISTs are positive for KIT (CD117) by immunohistochemistry. However, about 5% to 15% of GISTs lack KIT expression, and are problematic in the diagnosis of GIST. DOG1 has been recently identified as a gene (aka TMEM16) in the CCD1-EMS1 locus on human chromosome 11q13. A Study by Liegl B, et al. demonstrated that DOG1 was expressed in 94.4% of GISTs and 10/28 (36%) of KIT-negative tumors, including PDGFRA mutants that fail to express KIT antigen. In another study by Espinosa et al., only 9% of PDGFRA-mutant GIST (3/32) were positive for KIT, whereas DOG1 was positive in the majority (23/29; 78%). Moreover, a third of the PDGFRA-mutant GIST that were DOG1+ and KIT – harbored mutations predicted to be imatinib sensitive. As stated, the lack of KIT staining in these cases might otherwise consign them to a non-GIST diagnosis, potentially denying patients the opportunity to be treated with imatinib. With the additional benefit of detecting 36% of KIT-negative GISTs, DOG1 is an additional sensitive marker in the diagnosis of GISTs, including unusual subtypes. DOG1 is also a potential target in the treatment of GIST, although studies on this topic remain to be seen.