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Adrenocortical carcinoma and succinate dehydrogenase gene mutations: an observational case series
Tobias Else1, Antonio Marcondes Lerario1, Jessica Everett2
1Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Objective:
Germline loss-of-function mutations in succinate dehydrogenase (SDHx) genes results in rare tumor syndromes that include pheochromocytoma, paraganglioma, and others. Here we report a case series of patients with adrenocortical carcinoma (ACC) that harbor SDHx mutations.
Patients And Results:
We report four unrelated patients with ACC and SDHx mutations. All cases presented with Cushing syndrome and large adrenal masses that were confirmed to be ACC on pathology. All four ACC specimens were found to have truncating mutations in either SDHC or SDHA, while cases 1, 2 and 3 also had the mutations confirmed in the germline: Case 1: SDHC c.397C > T, pR133X; Case 2: SDHC c.43C > T, p.R15X; Case 3: SDHA c.91C > T, p.R31X; Case 4: SDHA c.1258C > T, p.Q420X. Notably, Case 1 had a father and daughter who both harbored the same SDHC germline mutation, and the father had a paraganglioma and renal cell carcinoma. A combination of next generation sequencing, and/or immunohistochemistry, and/or mass spectroscopy was used to determine whether there was loss of heterozygosity and/or loss of SDH protein expression or function within the ACC. Potential evidence of loss of heterozygosity was observed only in Case 2.
Conclusions:
We observed truncating mutations in SDHA or SDHC in the ACC and/or germline of four unrelated patients. Given how statistically improbable the concurrence of ACC and pathogenic germline SDHx mutations is expected to be, these observations raise the question whether ACC may be a rare manifestation of SDHx mutation syndromes. Further studies are needed to investigate the possible role of SDH deficiency in ACC pathogenesis.
Insights
Succinate dehydrogenase (SDHx) mutations are linked to rare tumors. This study found SDHx mutations in four patients with adrenocortical carcinoma (ACC), suggesting ACC may be a rare manifestation of SDHx-related tumor syndromes.
Area of Science:
- Endocrinology
- Oncology
- Genetics
Background:
- Germline loss-of-function mutations in succinate dehydrogenase (SDHx) genes are associated with rare tumor syndromes like pheochromocytoma and paraganglioma.
- Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex.
Observation:
- This case series reports on four unrelated patients diagnosed with ACC who were found to harbor SDHx mutations.
- All patients presented with Cushing syndrome and large adrenal masses confirmed as ACC.
- Mutations were identified in SDHC or SDHA genes in the ACC specimens, with germline confirmation in three cases.
Findings:
- Truncating mutations in SDHA or SDHC were observed in the ACC and/or germline of four unrelated patients.
- Case 1 demonstrated familial inheritance of an SDHC mutation, with the affected father also having paraganglioma and renal cell carcinoma.
- Evidence of loss of heterozygosity was noted in one ACC case, suggesting a potential role in tumorigenesis.
Implications:
- The concurrence of ACC and pathogenic germline SDHx mutations is statistically improbable, suggesting a potential link.
- These findings raise the possibility that ACC may represent a rare clinical manifestation of SDHx mutation syndromes.
- Further research is warranted to elucidate the role of SDH deficiency in the pathogenesis of ACC.
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