A new case report was published in Volume 17 of Oncotarget, titled “Small bowel GIST harbouring concurrent KIT exon 9 duplication and SDHC mutation: A case report.”

The study was led by first author Cameron B. Speyer from the UCLA David Geffen School of Medicine, and corresponding author Joseph G. Crompton, who holds appointments at both the  UCLA David Geffen School of Medicine and the Jonsson Comprehensive Cancer Centre.

In this report, the authors describe a rare and clinically informative case of a small bowel gastrointestinal stromal tumour (GIST) harbouring two genetic alterations that are typically considered mutually exclusive.

GISTs are most commonly driven by activating mutations in the KIT or PDGFRA genes, which confer sensitivity to targeted therapies such as imatinib.

In contrast, tumours associated with succinate dehydrogenase (SDH) deficiency represent a distinct subgroup that is generally resistant to these treatments.

The patient, a 68-year-old man, presented with progressive abdominal pain, bloating, and constipation.

Imaging studies revealed a large heterogeneous mass in the lower abdomen measuring up to 18 cm.

A biopsy confirmed a spindle cell neoplasm consistent with GIST, with immunohistochemical staining positive for CD117 and DOG1.

Genomic analysis identified both a KIT exon 9 duplication (A502_Y503) and a germline SDHC mutation (p.

R50C)—a highly unusual combination.

Despite the presence of the SDHC mutation, which is typically associated with resistance to therapy, the patient demonstrated a strong response to high-dose imatinib.

After six months of neoadjuvant treatment, imaging showed a marked reduction in tumour size and metabolic activity, enabling successful surgical resection.

“This case suggests that oncogenic KIT signalling may remain the dominant driver of GIST behaviour despite the presence of a germline SDHC mutation and highlights the importance of integrated molecular interpretation in GIST management.”

Pathologic examination of the resected tumour revealed significant treatment response, including extensive necrosis and reduced tumour viability.

Notably, immunohistochemistry demonstrated retained SDHB expression, indicating preserved SDH complex function despite the identified germline mutation.

The case highlights an important clinical insight: not all detected genetic alterations contribute equally to tumour behaviour.

While SDH-deficient GISTs are typically resistant to imatinib, this tumour behaved in a manner consistent with KIT-driven disease, underscoring the importance of interpreting molecular findings within their clinical and pathological context.

Overall, this report emphasises the need for integrated molecular analysis in cancer diagnosis and treatment.

As next-generation sequencing becomes more widely used, clinicians may encounter tumours with multiple coexisting mutations.

Determining the dominant oncogenic driver is essential for selecting the most effective therapy and improving patient outcomes.

Source: Impact Journals LLC