D898_E901 RET deletion is a rare gene mutation associated with medullary thyroid carcinoma (MTC) that appears to be oncogenic potential; patients with MTC associated with this mutation could be more responsive to treatment with tyrosine kinase inhibitors, according to a recently published case report in Precision Oncology.
The pathogenesis of MTC is closely related to mutations in the RET protooncogene, with over 90% of these mutations as missense substitutions, of which M918T and C634R are the most common ones, the authors noted.
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Research concerning rarer mutations, such as the D898_E901 RET deletion, is scarce. Therefore, the relevance and clinical significance of these types of mutations present in 10% to 15% of patients is unknown, they added.
The case involved a 35-year-old male with sporadic MTC with several lymph node metastases. The disease was detected through self-exploration of lymph nodes, as the patients had no constitutional symptoms at the moment of diagnosis; calcitonin and carcinoembryonic antigen (CEA) levels were elevated at the moment of diagnosis.
Initially, the patient underwent 2-step neck surgery, and genetic testing of tumor tissue revealed a D898_E901 RET deletion. A month after the surgery, bilateral tumor remnants were found together with neck and mediastinal lymph node metastasis. The patient underwent systemic therapy with vandetanib. However, a control CT performed 2 months later revealed the progression of the disease, systemic therapy was suspended, and the patient received radiotherapy to the neck and mediastinum.
After 2 years of follow-up, control CT scans revealed progression in the form of neck lymph node metastases and liver metastases. After beginning systemic therapy with selpercatinib, the patient experienced significant improvement, evidenced by a reduction in the sum of tumor diameters and a reduction of calcitonin and CEA levels.
However, a year later disease progressed with a 60% increase in tumor diameter; despite systemic therapy with cabozantinib for 4 months, the disease continued to progress, and the patient died 6 months later.
The authors aimed to functionally analyze the oncogenic potential of the D898_E901 RET deletion by expressing RET Δ898-901–mutant protein in HEK 293T cells revealing enhancement in phosphorylation on canonical RET autophosphorylation sites. The injection of D898_E901 RET cells in immunosuppressed mice led to tumor growth.
D898_E901 RET were exposed to cabozantinib and selpercatinib, showing that both could inhibit cell proliferation, with the latter being approximately 5-fold more effective than the former. These results suggest that the patient’s tumor response to cabozantinib could be attributed to a RET-independent mechanism.
“In conclusion, we demonstrated that the D898_E901 RET deletion in MTC is a gain-of-function mutation that confers a clinical aggressive behavior to MTC and responds to tyrosine kinase inhibitors,” the authors concluded.
Reference
Porcelli T, Moccia M, De Stefano MA, et al. D898_E901ret deletion is oncogenic, responds to selpercatinib, and treatment resistance can arise via ret-independent mechanisms. JCO Precisi Oncol. Published online August 3, 2023. doi:10.1200/po.23.00052
