Succinate dehydrogenase (SDH)-deficient pancreatic neuroendocrine tumor expands the SDH-related tumor spectrum

Nicolasine D. Niemeijer, Thomas G. Papathomas, Esther Korpershoek, Ronald R. De Krijger, Lindsey Oudijk, Hans Morreau, Jean Pierre Bayley, Frederik J. Hes, Jeroen C. Jansen, Winand N.M. Dinjens, Eleonora P.M. Corssmit

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

64 Citaten (Scopus)

Samenvatting

Context: Mutations in genes encoding the subunits of succinate dehydrogenase (SDH) can lead to pheochromocytoma/paraganglioma formation. However, SDH mutations have also been linked to nonparaganglionic tumors. Objective: The objective was to investigate which nonparaganglionic tumors belong to the SDHassociated tumor spectrum. Design: This was a retrospective cohort study. Setting: The setting was a tertiary referral center. Patients: Patients included all consecutive SDHA/SDHB/SDHC and SDHD mutation carriers followed at the Department of Endocrinology of the Leiden University Medical Center who were affected by non-pheochromocytoma/paraganglioma solid tumors. Main Outcome Measures: Main outcome measures were SDHA/SDHB immunohistochemistry, mutation analysis, and loss of heterozygosity analysis of the involved SDH-encoding genes. Results: Twenty-five of 35 tumors (from 26 patients) showed positive staining on SDHB and SDHA immunohistochemistry. Eight tumors showed negative staining for SDHB and positive staining for SDHA: a pancreatic neuroendocrine tumor, a macroprolactinoma, two gastric gastrointestinal stromal tumors, an abdominal ganglioneuroma, and three renal cell carcinomas. With the exception of the abdominal ganglioneuroma, loss of heterozygosity was detected in all tumors. A prolactinoma in a patient with a germline SDHA mutation was the only tumor immunonegative for both SDHA and SDHB. Sanger sequencing of this tumor revealed a somatic mutation (p.D38V) as a likely second hit leading to biallelic inactivation of SDHA. One tumor (breast cancer) showed heterogeneous SDHB staining, positive SDHA staining, and retention of heterozygosity. Conclusions: This study strengthens the etiological association of SDH genes with pituitary neoplasia, renal tumorigenesis, and gastric gastrointestinal stromal tumors. Furthermore, our results indicate that pancreatic neuroendocrine tumor also falls within the SDH-related tumor spectrum.

Originele taal-2Engels
Pagina's (van-tot)E1386-E1393
TijdschriftJournal of Clinical Endocrinology and Metabolism
Volume100
Nummer van het tijdschrift10
DOI's
StatusGepubliceerd - 1 okt. 2015
Extern gepubliceerdJa

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