DOG1 in the Diagnosis of GIST
About 'Discovered on GIST-1'
Obligatory—This is not medical advice
We talk frequently about the ambiguity associated with some diagnoses of sarcoma. A common refrain is that sarcoma diagnosis is ‘a visual sport,’ implying that there is a high degree of subjective interpretation. While such resources as the WHO classification of Tumours1 can be useful, it is important to understand that there is a nuance to the practice that cannot entirely be captured in words. This allows for significant variability, and, the general recommendation that tissue be reviewed at a high volume center. There are a few instances, however, in which a marker clearly points towards a diagnosis, and the readiest example within sarcoma is ‘Discovered on GIST 1’ (DOG1) antigen for gastrointestinal stromal tumors (GISTs). There are some limitations to explore, as well. Let’s talk about what it is and how it applies to patients.
What is DOG1?
As with much regarding the history of GIST, elaborate study of DOG1 began in the late 90s and early 2000s.2 Following genetic determination of the existence of this protein in GIST, it was further found to be present on 136 of 139 known GISTs that were tested (97.8% sensitivity). Only 4 of 438 non-GIST tumors stained positive for this marker (99% specific). Within a few years, the nature of the function of DOG1 was better defined.
DOG1 is also known as Anoctamin-1 (ANO1) and is a calcium-activated chloride channel.34 As can be seen, these are membrane spanning proteins that allow for transportation of various electrolytes into and out of a cell. This type of protein is crucial in regulating the excitability of types of smooth muscle cells and neurons. ANO1, or DOG1, is expressed on the Interstitial Cells of Cajal (ICC), which are believed to be the precursor cells that become GIST. These cells generate electrical activity, and, as what I am sure is an oversimplification, act as the ‘pacemaker’ of the GI tract. This is done through multiple complex mechanisms.5
As one might expect, given the function of this channel, this protein is present on other types of similar tissue as well. As a result, it has been seen in rare renal cell carcinoma subtypes, salivary tissue, and others. 6
How does it help us with diagnosis?
As we discussed, while DOG1 is present on other types of tissues or cancers, it is nonetheless very sensitive and specific for GIST. Given it is expressed on ~99% of GISTs regardless of KIT or PDGFRA mutation status, it can be helpful in cases where uncertainty remains. It may be used to shift the probability of a diagnosis towards GIST when correlated with clinical, pathologic, and anatomic features. See the table below.
Within this realm, if there continues to be diagnostic ambiguity, genetic sequencing to evaluate for the presence of KIT or PDGFRA mutations can likewise be helpful.
Some patients may also ask if there is a role for this protein in treatment for GIST. In other discussions about GIST, I have alluded to the fact that Tyrosine Kinase Inhibitors are ultimately only as useful as the balance of their efficacy and toxicity. I would imagine this also to be true of a medication targeted at DOG1. At the time of this writing, there are no FDA approved therapies specifically aimed at DOG1. Various groups have speculated that it could be used as a target for an antibody-drug conjugate protein.7 Nonetheless, given the role of this protein in the normal function of the gut and other parts of the body, there would serious concerns for toxicity and any treatment would need to pass through appropriate assessment with clinical trials.
Conclusions
DOG1 is a calcium-activated chloride channel. DOG1 is believed to help regulate excitability, and therefore action, of cells, such as the Interstitial Cells of Cajal. DOG1 is commonly used in diagnosis of patients with gastrointestinal stromal tumors as it has a high sensitivity and specificity. Nonetheless, DOG1 may be expressed on other types of cancers, and therefore consideration of anatomic, pathologic, and clinical criteria should also be incorporated for diagnosis. If there continues to be uncertainty, genetic testing may assist in ascertaining the etiology of a tumor.
https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/Soft-Tissue-And-Bone-Tumours-2020
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1618538/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480199/
https://pubmed.ncbi.nlm.nih.gov/9662380/
https://pubmed.ncbi.nlm.nih.gov/26678977