“This case suggests that oncogenic KIT signaling may remain the dominant driver of GIST behavior despite the presence of a germline SDHC mutation and highlights the importance of integrated molecular interpretation in GIST management.”
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. Although many GISTs can be effectively treated with targeted therapies, their response to treatment depends largely on the specific genetic alterations driving tumor growth. Advances in molecular testing have transformed the management of these tumors, allowing clinicians to tailor treatment based on each patient’s genetic profile.
A case report published in Volume 17 of Oncotarget, titled “Small bowel GIST harboring concurrent KIT exon 9 duplication and SDHC mutation: A case report,” describes an exceptionally rare case involving a patient whose tumor carried two genetic alterations that are traditionally considered mutually exclusive.
Understanding the Genetics of GIST
Most GISTs develop because of activating mutations in either the KIT or PDGFRA genes. These mutations continuously stimulate growth signals within tumor cells, making them highly responsive to targeted drugs known as tyrosine kinase inhibitors, particularly imatinib.
A smaller group of GISTs lack these mutations and instead develop through abnormalities involving the succinate dehydrogenase (SDH) complex. These SDH-deficient tumors tend to occur in younger patients, most often arise in the stomach, and generally respond poorly to imatinib.
Because these two molecular pathways are thought to represent distinct mechanisms of tumor development, tumors containing both alterations are considered extremely uncommon. This case adds to growing evidence that rare exceptions to this long-standing assumption can occur.
An Unusual Genetic Profile
The patient was a 68-year-old man who sought medical attention after experiencing several weeks of worsening abdominal pain, bloating, and constipation. Imaging revealed a large mass arising from the small intestine.
A biopsy confirmed that the tumor was a spindle-cell GIST. Comprehensive next-generation sequencing identified two notable genetic findings:
- A KIT exon 9 A502_Y503 duplication, a mutation known to drive many small bowel GISTs and predict responsiveness to higher-dose imatinib.
- A germline SDHC p.R50C mutation, an inherited alteration associated with hereditary syndromes involving GISTs and certain neuroendocrine tumors.
Finding both mutations in the same patient was highly unusual because KIT-driven and SDH-deficient GISTs have traditionally been regarded as separate molecular subtypes. Genetic counseling subsequently confirmed that the SDHC mutation was inherited rather than acquired within the tumor itself.
Targeted Therapy Produced a Strong Response
Because the tumor carried a KIT exon 9 mutation, the multidisciplinary care team recommended treatment with imatinib before surgery to shrink the tumor and improve the chances of complete removal.
The patient initially received standard-dose imatinib, followed by dose escalation to 800 mg daily, consistent with current recommendations for KIT exon 9-mutant GISTs.
After three months of treatment, imaging demonstrated a clear partial response. The tumor decreased in size, and positron emission tomography (PET) scans showed a marked reduction in metabolic activity, indicating that the cancer had become substantially less active.
Following six months of targeted therapy, surgeons successfully removed the tumor. Pathologic examination revealed extensive treatment-related necrosis with negative surgical margins, and follow-up imaging five months after surgery showed no evidence of disease recurrence.
Why the SDHC Mutation Did Not Appear to Drive the Tumor
One of the most intriguing aspects of the case was that the inherited SDHC mutation did not produce the biological features typically seen in SDH-deficient GISTs.
Normally, tumors caused by SDH deficiency lose expression of SDHB, a protein commonly used by pathologists as a marker of dysfunction within the SDH complex. In this patient’s tumor, however, SDHB expression remained intact despite the presence of the inherited SDHC mutation.
The researchers suggest that this occurred because only one copy of the SDHC gene was altered. Development of true SDH-deficient GIST generally requires loss of function in both gene copies, whereas activating KIT mutations can drive tumor growth even when only one allele is affected.
Taken together, the preserved SDHB expression, the tumor’s location in the small intestine, and its robust response to high-dose imatinib all supported the conclusion that the KIT mutation—not the SDHC mutation—was the dominant driver of the cancer.
Why This Case Matters
As next-generation sequencing becomes increasingly common in cancer care, clinicians are identifying more tumors that harbor multiple potentially important genetic alterations.
This report highlights an important principle of precision oncology: not every detected mutation necessarily drives tumor behavior or determines treatment response. Instead, molecular findings must be interpreted alongside pathology, imaging, clinical presentation, and treatment outcomes.
The case also demonstrates the value of comprehensive genomic testing. Although the inherited SDHC mutation did not appear to influence treatment of this GIST, identifying it allowed the patient to receive genetic counseling because germline SDHC mutations have been associated with hereditary conditions that increase the risk of other tumors, including paragangliomas and pheochromocytomas.
Looking Ahead
The authors conclude that this rare case expands current understanding of GIST biology by showing that a tumor harboring both a KIT exon 9 duplication and a germline SDHC mutation can still behave like a classic KIT-driven GIST and respond well to high-dose imatinib. While additional cases will be needed to determine how often these uncommon genetic combinations occur, the findings underscore the importance of integrating molecular testing with clinical and pathological evaluation when selecting targeted therapies.
As precision medicine continues to evolve, studies such as this illustrate that understanding which genetic alteration truly drives a tumor may be just as important as identifying every mutation it carries.
Click here to read the full case report published in Oncotarget.
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