As we look back on the history of medicine, one clear advancement that we have made is in the area of disease diagnosis. In the past, the diagnosis of disease was frequently conflated with its symptoms; without modern technology, they were often considered one and the same. For example, it was common in the past for a patient to be diagnosed with “dropsy,” a term that means edema today. In modern medicine, that term has become archaic because we recognize that edema is a symptom—most commonly due to congestive heart failure—and not a diagnosis in itself. 

For a while, doctors had to rely on their 5 senses to come up with a set of differentials. As medicine moves forward, the diagnosis of disease is increasingly done in the lab. We rightfully recognize that diagnosis on a molecular level is not only more accurate, but also yields information that might impact treatment decisions without a significant increase in cost.

Gastrointestinal stromal tumors (GISTs) are a rare group of gastrointestinal cancers originating from the interstitial cells of Cajal. Researchers conducted a review of current clinical practices for diagnosing GIST from a molecular perspective and published their study in Cancers. Their review provides a valuable snapshot of where we are today in terms of the molecular diagnosis of cancers such as GISTs. 

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As early as 1998, GISTs have been linked to c-KIT mutations and KIT (CD117) mutations. Since then, researchers have also identified PDGFRA (platelet-derived growth factor receptor alpha) mutations, SDH (succinate dehydrogenase) alterations, and other mutations expressed in GISTs. Protein markers, such as DOG1 (discovered on GIST 1) and PKCθ (protein kinase C θ), were also linked to GIST, allowing clinicians to diagnose CD117-negative GISTs. Today, the “gold standard” in GIST diagnosis is the use of molecular analysis (KIT/PDGFRA) and an immunohistochemical (IHC) panel (CD117/DOG1). It is the hope of researchers everywhere that molecular research on GIST will allow us to develop drugs in the future for patients who are resistant to treatment. 

DOG1 Biomarker

Scientists have discovered that the CD117 biomarker is expressed in GISTs; however, it is also expressed in other cancers, such as melanomas and adenoid cystic carcinomas. Therefore, scientists sought to identify other specific biomarkers that can be linked more conclusively to GIST. 

A breakthrough took place in 2004, when a novel gene, DOG1, was discovered. Its role in the pathology of GIST was unclear until 2013, when it was revealed that it played a crucial role in modulating insulin-like growth factor (IGF)/insulin-like growth factor receptor (IGFR) signaling in the tumor microenvironment and excluded KIT-dependent pathways. Hence, DOG1 is a sensitive and specific biomarker for GIST, regardless of CD117 expression. 

Further studies show that DOG1 has a similar sensitivity and specificity to GIST as CD117, and the combination of both biomarkers in an IHC panel accounts for over 98% of GISTs in clinical practice. 

PKCθ Biomarker

In the event that a GIST does not express CD117 or DOG1 (about 1% to 2% of cases), it becomes exceedingly difficult to diagnose, even if the GIST has KIT/PDGFR mutations. Therefore, scientists have sought to identify proteins that might strengthen the molecular diagnosis of GIST. 

Studies have found that PKCθ is overexpressed in GIST, making it a useful IHC marker, with or without KIT expression. The one clear limitation of PKCθ is that it has a lower sensitivity in KIT-negative GISTs than in KIT-positive ones, limiting its usefulness in diagnosis. However, it is valuable in providing supporting evidence in the molecular diagnosis of GIST. 

KIT Mutations 

KIT mutations are incredibly valuable in the molecular diagnosis of GISTs because approximately 80% of GISTs possess them. Researchers have identified the KIT gene as the primary factor in GIST tumorigenesis. 

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One important point that should be highlighted is that secondary KIT mutations are observed at a high frequency in imatinib-resistant GISTs, a matter of huge clinical significance. It seems that KIT mutations in different regions can affect how a patient responds to targeted therapies. For example, the authors of the study stated that “imatinib works better in tumors with mutations in exon 11 mutations than those with exon 9 mutations.” A better understanding of KIT mutations can potentially lead to concrete solutions in treatment-resistant GISTs. 

PDGFRA Mutations

GISTs that lack a KIT mutation are known as KIT wild-type (KIT-WT) GISTs. This occurs in approximately 15% to 20% of cases. Further research has uncovered that 35% of KIT-WT GISTs have PDGFRA mutations. In fact, KIT and PDGFRA are mutually exclusive oncogenic mechanisms in GIST, although they both have similar mechanisms of pathogenesis and disease progression. Like KIT mutations, PDGFRA mutations in different exons can result in different sensitivity/insensitivity to chemotherapy medications such as imatinib and sunitinib. 


Around 10% to 15% of GISTs do not have a KIT or PDGFRA mutation, and they are collectively known as KIT/PDGFRA-WT GISTs. However, they can be identified through an alternative mechanism, as the majority of them lack SDH alteration and have a loss of succinate dehydrogenase complex iron-sulfur subunit B (SDHB) expression. 

From Molecular Analysis to New Treatments 

The most compelling case for spending time and money to deepen our knowledge of the molecular foundations of rare cancers like GIST is that it allows scientists to develop better drugs to combat the disease and improve patient survival rates. This study ends on a spectacular invitation to cast our vision into the future: “The development of an effective treatment for GISTs resistant to imatinib/sunitinib/regorafenib and KIT/PDGFRA-WT GISTs will be a challenge in the near future. Monoclonal antibodies against KIT/PDGFRA might be the future of treatment in GISTs.”


Wu CE, Tzen CY, Wang SY, Yeh CN. Clinical diagnosis of gastrointestinal stromal tumor (GIST): from the molecular genetic point of view. Cancers (Basel). 2019;11(5):679. doi:10.3390/cancers11050679

Kaltwasser J. Boosting molecular testing in patients with GIST would have minimal cost impact, study finds. Managed Healthcare Executive. July 6, 2021. Accessed September 24, 2021.