The Novel Marker, DOG1, Is Expressed Ubiquitously in Gastrointestinal Stromal Tumors Irrespective of KIT or PDGFRA Mutation Status

West, Robert B.; Corless, Christopher L.; Chen, Xin; Rubin, Brian P.; Subramanian, Subbaya; Montgomery, Kelli; Zhu, Shirley; Ball, Catherine A.; Nielsen, Torsten O.; Patel, Rajiv M.; Goldblum, John R.; Brown, Patrick O.; Heinrich, Michael C.; Rijn, Matt van de

doi:10.1016/s0002-9440(10)63279-8

Cited by 593 publications

(514 citation statements)

References 23 publications

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“…TMEM16A was detected distinctly in the cytoplasm of neoplastic cells of HNSCC tumours, and diffusely in the basal layer of the epithelium of N tissue (uvula). These antibodies stained GIST samples strongly and homogeneously (data not shown), in agreement with a recent report (West et al, 2004).…”

Section: Pcr-dd and Validation By Reverse Northern Hybridizationsupporting

confidence: 92%

“…They were also analysed by Northern blots to establish the size of the transcripts, and antibodies were developed to analyse expression at the protein level by immunohistochemistry (IHC). TMEM16A (Transmembrane protein 16A), a putative receptor (Katoh, 2003), has been given various names FLJ10261 (Katoh, 2003), TAOS2 (Tumour Amplified and Overexpressed Sequence 1) (Huang et al, 2002), ORAOV2 (ORAl cancer OVerexpressed 2) (Strausberg et al, 2002) and DOG-1 (Discovered On GIST-1) (West et al, 2004)). The three candidates were isolated from bands that were more intense in tumour lanes on the DD gels (Figure 3, upper panels).…”

Section: Pcr-dd and Validation By Reverse Northern Hybridizationmentioning

confidence: 99%

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Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display

Millon²,

et al. 2005

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Head and neck squamous cell carcinoma (HNSCC) is common worldwide and is associated with a poor rate of survival. Identification of new markers and therapeutic targets, and understanding the complex transformation process, will require a comprehensive description of genome expression, that can only be achieved by combining different methodologies. We report here the HNSCC transcriptome that was determined by exhaustive differential display (DD) analysis coupled with validation by different methods on the same patient samples. The resulting 820 nonredundant sequences were analysed by high throughput bioinformatics analysis. Human proteins were identified for 73% (596) of the DD sequences. A large proportion (>50%) of the remaining unassigned sequences match ESTs (expressed sequence tags) from human tumours. For the functionally annotated proteins, there is significant enrichment for relevant biological processes, including cell motility, protein biosynthesis, stress and immune responses, cell death, cell cycle, cell proliferation and/or maintenance and transport. Three of the novel proteins (TMEM16A, PHLDB2 and ARH-GAP21) were analysed further to show that they have the potential to be developed as therapeutic targets.

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Section: Pcr-dd and Validation By Reverse Northern Hybridizationsupporting

confidence: 92%

Section: Pcr-dd and Validation By Reverse Northern Hybridizationmentioning

confidence: 99%

Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display

Millon²,

et al. 2005

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“…This adds to the expanding group of markers for soft tissue tumors identified through molecular genetic methods. For example, gene expression analysis has previously identified ANO1 (anoctamin 1, calcium activated chloride channel; also known as DOG1) as a specific marker of gastrointestinal stromal tumor, [24][25][26][27] TLE1 (transducin-like enhancer of split 1) for synovial sarcoma, 27,28 and MUC4 (mucin 4, cell surface associated) for low-grade fibromyxoid sarcoma. 29,30 Nuclear expression of STAT6 is found in nearly all cases of SFT and is very limited in other soft tissue neoplasms.…”

Section: Discussionmentioning

confidence: 99%

Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics

et al. 2014

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Solitary fibrous tumor (SFT) is composed of spindled to ovoid cells in a patternless architecture with prominent stromal collagen and hemangiopericytoma-like vessels. Some tumors show hypercellularity, nuclear atypia, and significant mitotic activity; the latter feature in particular often portends an aggressive clinical course. SFT can sometimes be difficult to distinguish from other benign mesenchymal tumors and sarcomas. The most characteristic (albeit nonspecific) immunohistochemical finding in SFT is CD34 expression. A NAB2-STAT6 gene fusion, resulting in a chimeric protein in which a repressor domain of NGFI-A binding protein 2 (EGR1 binding protein 2) (NAB2) is replaced with a carboxy-terminal transactivation domain from signal transducer and activator of transcription 6, interleukin-4 induced (STAT6), was recently identified as a consistent finding in SFT. However, as these genes are located in close proximity on 12q13, this fusion can only rarely be detected by conventional chromosomal banding or fluorescence in situ hybridization analysis. Nuclear expression of the carboxy terminal part of STAT6 is a consistent finding in SFT of the meninges (so-called 'meningeal hemangiopericytoma'). We investigated STAT6 expression by immunohistochemistry in SFTs and other soft tissue tumors arising outside the central nervous system to validate the diagnostic utility of this novel marker. Whole-tissue sections of 231 tumors were evaluated, including 60 cases of SFT as well as other benign and malignant mesenchymal neoplasms and sarcomatoid mesotheliomas. Fifty-nine of 60 SFT cases (98%) showed nuclear expression of STAT6, which was usually diffuse and intense. All other tumor types were negative for STAT6, except for three dedifferentiated liposarcomas and one deep fibrous histiocytoma, which showed weak staining. In conclusion, STAT6 is a highly sensitive and almost perfectly specific immunohistochemical marker for SFT and can be helpful to distinguish this tumor type from histologic mimics.

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“…7,8 The staining may be membranous, diffusely cytoplasmic, or concentrated in a dot-like perinuclear pattern. The addition of DOG1 (ANO1) as another GIST marker has made the diagnosis quite routine, 9 as DOG1 and CD117 each stain 495% of GISTs and, between them, serve to mark essentially all cases. These antigens are only rarely expressed in other mesenchymal tumors.…”

Section: Clinical and Pathological Featuresmentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

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The Novel Marker, DOG1, Is Expressed Ubiquitously in Gastrointestinal Stromal Tumors Irrespective of KIT or PDGFRA Mutation Status

Cited by 593 publications

References 23 publications

Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display

Head and neck squamous cell carcinoma transcriptome analysis by comprehensive validated differential display

Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics

Gastrointestinal stromal tumors: what do we know now?

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