Frequent germ-line succinate dehydrogenase subunit D gene mutations in patients with apparently sporadic parasympathetic paraganglioma.
OBJECTIVE
Recently, familial paraganglioma (PGL) was shown to be caused bymutations in the gene encoding succinate dehydrogenase subunit D (SDHD). However, the prevalence of SDHD mutations in apparently sporadic PGL is unknown. We studied the frequency and spectrum of germ-line and somatic SDHD mutations in patients with parasympathetic PGL. EXPERIMENTAL DESIGH: We studied 57 unselected patients who developed parasympathetic PGLs (n = 105 tumors) and who were treated between 1987 and 1999 at the Erasmus MC (Rotterdam, the Netherlands). Thirty-eight (67%) of these patients (n = 51 tumors) lacked a family history of parasympathetic PGL. We used conformation-dependent gel electrophoresis and sequence determination analysis of germ-line and tumor DNA to identify SDHD mutations. We compared the clinical and molecular characteristics of sporadic and hereditary PGLs.


RESULTS
Three different SDHD germ-line mutations were identified in 32 of the 57 (56%) patients. These included 19 of 19 (100%) patients with familial PGL and also 13 of 38 (34%) patients with apparently sporadic PGL. All three mutations were characterized as missense mutations (D92Y, L95P, and L139P) in highly conserved regions of the SDHD gene and were not observed in 200 control alleles. No somatic mutations were found.


CONCLUSIONS
Germ-line mutations of the SDHD gene are present in a significant number of patients with apparently sporadic parasympathetic PGL. Somatic SDHD mutations do not play a significant role in the sporadic form of this tumor. Genetic testing for SDHD germ-line mutations should be considered for every patient presenting with this tumor, even if a personal or family history of PGL is absent, to allow appropriate clinical management.
Dannenberg
Hilde
H
Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, 1738 Rotterdam, the Netherlands.
Dinjens
Winand N M
WN
Abbou
Mustaffa
M
Van Urk
Hero
H
Pauw
Bernard K H
BK
Mouwen
Diane
D
Mooi
Wolter J
WJ
de Krijger
Ronald R
RR
D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000032:analysis; D042963:Electron Transport Complex II; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics*; D009423:Nervous System Neoplasms / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics*; D010236:Paraganglioma, Extra-Adrenal / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D012189:Retrospective Studies; D013385:Succinate Dehydrogenase / Q000235:genetics*
D017931:DNA Primers; D004273:DNA, Neoplasm; D009097:Multienzyme Complexes; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase