Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD.
Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and extraadrenal pheochromocytomas, head and neck paragangliomas (HNPGL), and other tumor types. We report tumor risks in 358 patients with SDHB (n=295) and SDHD (n=63) mutations. Risks of HNPGL and pheochromocytoma in SDHB mutation carriers were 29% and 52%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) were higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) were identified. No clear genotype-phenotype correlations were detected for SDHB mutations. However, SDHD mutations predicted to result in loss of expression or a truncated or unstable protein were associated with a significantly increased risk of pheochromocytoma compared to missense mutations that were not predicted to impair protein stability (most such cases had the common p.Pro81Leu mutation). Analysis of the largest cohort of SDHB/D mutation carriers has enhanced estimates of penetrance and tumor risk and supports in silicon protein structure prediction analysis for functional assessment of mutations. The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma risks suggests differing mechanisms of tumorigenesis in SDH-associated HNPGL and pheochromocytoma.
Ricketts
Christopher J
CJ
Cancer Research UK Renal Molecular Oncology Group, Department of Medical and Molecular Genetics, University of Birmingham, Institute of Biomedical Research, Birmingham, United Kingdom.
Forman
Julia R
JR
Rattenberry
Eleanor
E
Bradshaw
Nicola
N
Lalloo
Fiona
F
Izatt
Louise
L
Cole
Trevor R
TR
Armstrong
Ruth
R
Kumar
V K Ajith
VK
Morrison
Patrick J
PJ
Atkinson
A Brew
AB
Douglas
Fiona
F
Ball
Steve G
SG
Cook
Jackie
J
Srirangalingam
Umasuthan
U
Killick
Pip
P
Kirby
Gail
G
Aylwin
Simon
S
Woodward
Emma R
ER
Evans
D Gareth R
DG
Hodgson
Shirley V
SV
Murday
Vicky
V
Chew
Shern L
SL
Connell
John M
JM
Blundell
Tom L
TL
Macdonald
Fiona
F
Maher
Eamonn R
ER
D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010235:Paraganglioma / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000235:genetics*; D055815:Young Adult
C491545:SDHD protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase