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. Hum Mutat 31:41–51, 2010. © 2009 Wiley‐Liss, Inc.

[1]  L. Aaltonen,et al.  Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. , 2004, American journal of human genetics.

[2]  W. Linehan,et al.  High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. , 2006, The Journal of clinical endocrinology and metabolism.

[3]  Peter Devilee,et al.  Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma , 2006, BMC Medical Genetics.

[4]  E. Maher,et al.  Genotype–phenotype correlations in von Hippel‐Lindau disease , 2004, Human mutation.

[5]  W. Kaelin,et al.  Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. , 2005, Cancer cell.

[6]  C. Eng,et al.  Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. , 2004, JAMA.

[7]  G. Stamp,et al.  Expression of HIF-1α, HIF-2α (EPAS1), and Their Target Genes in Paraganglioma and Pheochromocytoma with VHL and SDH Mutations , 2006 .

[8]  A. Vénisse,et al.  The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. , 2009, The Journal of clinical endocrinology and metabolism.

[9]  T. Blundell,et al.  Distinguishing structural and functional restraints in evolution in order to identify interaction sites. , 2004, Journal of molecular biology.

[10]  Ulrich Müller,et al.  Mutations in SDHC cause autosomal dominant paraganglioma, type 3 , 2000, Nature Genetics.

[11]  B. Devlin,et al.  Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. , 2000, Science.

[12]  Catherine L. Worth,et al.  Structural bioinformatics mutation analysis reveals genotype–phenotype correlations in von Hippel‐Lindau disease and suggests molecular mechanisms of tumorigenesis , 2009, Proteins.

[13]  S. Richard,et al.  Genetic testing in pheochromocytoma or functional paraganglioma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  D. Marsh,et al.  Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas , 2003, Oncogene.

[15]  J. López-Barneo,et al.  The Mitochondrial SDHD Gene Is Required for Early Embryogenesis, and Its Partial Deficiency Results in Persistent Carotid Body Glomus Cell Activation with Full Responsiveness to Hypoxia , 2004, Molecular and Cellular Biology.

[16]  J R Griffiths,et al.  Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. , 2005, Human molecular genetics.

[17]  K. Sotlar,et al.  Active succinate dehydrogenase (SDH) and lack of SDHD mutations in sporadic paragangliomas. , 2005, Anticancer research.

[18]  K. Byth,et al.  Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. , 2006, The Journal of clinical endocrinology and metabolism.

[19]  M. Lerman,et al.  Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. , 1994, Human molecular genetics.

[20]  K. Pacak,et al.  Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. , 2007, The Journal of clinical endocrinology and metabolism.

[21]  D. Evans,et al.  Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility , 2003, Clinical endocrinology.

[22]  P. Rustin,et al.  The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. , 2001, American journal of human genetics.

[23]  C. Ricketts,et al.  Germline SDHB mutations and familial renal cell carcinoma. , 2008, Journal of the National Cancer Institute.

[24]  E. Maher,et al.  SDHB-associated renal oncocytoma suggests a broadening of the renal phenotype in hereditary paragangliomatosis , 2009, Familial Cancer.

[25]  P. Rustin,et al.  Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. , 2003, Cancer research.

[26]  B. Baysal,et al.  Clinical and molecular progress in hereditary paraganglioma , 2008, Journal of Medical Genetics.

[27]  P. Devilee,et al.  Nearly all hereditary paragangliomas in The Netherlands are caused by two founder mutations in the SDHD gene , 2001, Genes, chromosomes & cancer.

[28]  Charis Eng,et al.  Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. , 2008, American journal of human genetics.

[29]  P. Caron,et al.  Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. , 2008, The Journal of clinical endocrinology and metabolism.

[30]  C. Eng,et al.  The pressure rises: update on the genetics of phaeochromocytoma. , 2002, Human molecular genetics.

[31]  C. Eng,et al.  Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. , 2000, Cancer research.

[32]  D. Marsh,et al.  K40E: a novel succinate dehydrogenase (SDH)B mutation causing familial phaeochromocytoma and paraganglioma , 2004, Clinical endocrinology.

[33]  B. Martínez-Delgado,et al.  Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: A possible hot spot? , 2006, Genes, chromosomes & cancer.

[34]  D. Evans,et al.  Germline SDHD mutation in familial phaeochromocytoma , 2001, The Lancet.

[35]  B. Sykes,et al.  Ubiquinone-binding Site Mutations in the Saccharomyces cerevisiae Succinate Dehydrogenase Generate Superoxide and Lead to the Accumulation of Succinate* , 2007, Journal of Biological Chemistry.

[36]  A. Webster,et al.  An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: evidence for modifier effects. , 1998, American journal of human genetics.

[37]  David G. Watson,et al.  Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. , 2005, Cancer cell.

[38]  L. Serrano,et al.  High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in northern Spain: mitochondrial succinate dehydrogenase structure-function relationships and clinical-pathological correlations. , 2007, The Journal of clinical endocrinology and metabolism.

[39]  Sungsam Gong,et al.  A Structural Bioinformatics Approach to the Analysis of nonsynonymous Single nucleotide polymorphisms (nsSNPS) and their Relation to Disease , 2007, J. Bioinform. Comput. Biol..

[40]  Z. Rao,et al.  Crystal Structure of Mitochondrial Respiratory Membrane Protein Complex II , 2005, Cell.

[41]  F. Mantero,et al.  Paraganglioma Syndrome , 2006 .

[42]  C. Eng,et al.  Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. , 2005, JAMA.

[43]  A. Drucker,et al.  A case of familial paraganglioma syndrome type 4 caused by a mutation in the SDHB gene , 2006, Nature Clinical Practice Endocrinology &Metabolism.

[44]  C. Eng,et al.  Large germline deletions of mitochondrial complex II subunits SDHB and SDHD in hereditary paraganglioma. , 2004, The Journal of clinical endocrinology and metabolism.

[45]  A. Grossman,et al.  Familial paraganglioma: a novel presentation of a case and response to therapy with radiolabelled MIBG. , 2004, Hormones.

[46]  W. Kaelin,et al.  Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. , 1999, Science.

[47]  E S Husebye,et al.  Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. , 2001, American journal of human genetics.

[48]  W. Rubinstein,et al.  Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas , 2002, Journal of medical genetics.

[49]  R. Houlston,et al.  Identification of cyclin D1 and other novel targets for the von Hippel-Lindau tumor suppressor gene by expression array analysis and investigation of cyclin D1 genotype as a modifier in von Hippel-Lindau disease. , 2002, Cancer research.

[50]  Thomas Bourgeron,et al.  Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency , 1995, Nature Genetics.

[51]  C. Eng,et al.  Molecular characterisation of a common SDHB deletion in paraganglioma patients , 2007, Journal of Medical Genetics.

[52]  J. Mora,et al.  Pediatric paraganglioma: An early manifestation of an adult disease secondary to germline mutations , 2006, Pediatric blood & cancer.

[53]  G. Arnaldi,et al.  Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. , 2009, The Journal of clinical endocrinology and metabolism.

[54]  W. Young,et al.  Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene. , 2002, The Journal of clinical endocrinology and metabolism.

[55]  E. Maher,et al.  Succinate dehydrogenase subunit B (SDHB) gene deletion associated with a composite paraganglioma/neuroblastoma , 2008, Journal of Medical Genetics.

[56]  E. Baudin,et al.  Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. , 2007, The Journal of clinical endocrinology and metabolism.

[57]  David F. Burke,et al.  Andante: reducing side-chain rotamer search space during comparative modeling using environment-specific substitution probabilities , 2007, Bioinform..

[58]  C. Aston,et al.  Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect , 2003, Human Genetics.

[59]  P. Schofield,et al.  The prevalence of SDHB, SDHC, and SDHD mutations in patients with head and neck paraganglioma and association of mutations with clinical features , 2004, Journal of Medical Genetics.

[60]  T L Blundell,et al.  Prediction of the stability of protein mutants based on structural environment-dependent amino acid substitution and propensity tables. , 1997, Protein engineering.

[61]  J. Ellison,et al.  Clinical and molecular genetics of patients with the Carney–Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD , 2008, European Journal of Human Genetics.

[62]  P. Schofield,et al.  Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss , 2001, Genes, chromosomes & cancer.

[63]  M. Mannelli,et al.  Genetic screening for pheochromocytoma: should SDHC gene analysis be included? , 2007, Journal of Medical Genetics.