Genetic Mutation Screening in an Italian Cohort of Nonsyndromic Pheochromocytoma/Paraganglioma Patients

Abstract:  To assess the prevalence of genetic mutations in nonsyndromic pheochromocytoma/paraganglioma (PHEO/PGL) patients we have performed a systematic search for mutations in the succinate dehydrogenase (SDH) B, C, and D subunits, von Hippel–Lindau (VHL), and RET genes by direct bidirectional sequencing. Patients were selected from the medical records of hypertension centers. After exclusion of syndromic patients, 45 patients with familial (F+, n= 3) and sporadic (F−, n= 42) cases of isolated PHEO/PGL were considered. They included 35 patients with PHEO, 7 with PGL, and 3 with head/neck PGL (hnPGL). Three patients with PHEO (2F−, 1F+) presented VHL mutations (P86A, G93C, and R167W), six with PGL (4F−, 2F+) were positive for SDH or VHL mutations (SDHB R230G in two patients, SDHB S8F, R46Q, R90Q, and VHL P81L in one subject each), and one with hnPGL carried the SDHD 348–351delGACT mutation. We have also detected missense (SDHB S163P, SDHD H50R and G12S), synonymous (SDHB A6A, SDHD S68S), and intronic mutations that have been considered nonpathological polymorphic variants. No mutation was found in SDHC or RET genes. Our data indicate that germline mutations of VHL and SDH subunits are not infrequent in familial as well as in sporadic cases of nonsyndromic PHEO/PGL (overall, 12 of 45 probands, 22%). Accordingly, screening for such mutations seems to be justified. However, a more precise characterization of the functional relevance of any observed sequence variant and of other genetic and environmental determinants of neoplastic transformation is essential in order to plan appropriate protocols for family screening and follow‐up.

[1]  Peter Devilee,et al.  The SDH mutation database: an online resource for succinate dehydrogenase sequence variants involved in pheochromocytoma, paraganglioma and mitochondrial complex II deficiency , 2005, BMC Medical Genetics.

[2]  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.

[3]  R. Ferrell,et al.  An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma , 2004, Journal of Medical Genetics.

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

[5]  M. Fraga,et al.  Genetic and epigenetic profile of sporadic pheochromocytomas , 2004, Journal of Medical Genetics.

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

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

[8]  J. Benítez,et al.  G12S and H50R variations are polymorphisms in the SDHD gene , 2003, Genes, chromosomes & cancer.

[9]  E. Leteurtre,et al.  Hereditary phaeochromocytomas and paragangliomas: a study of five susceptibility genes , 2003, Journal of medical genetics.

[10]  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.

[11]  P. Rustin,et al.  Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. , 2002, The Journal of clinical endocrinology and metabolism.

[12]  J. Benítez,et al.  SDHB mutation analysis in familial and sporadic phaeochromocytoma identifies a novel mutation , 2002, Journal of medical genetics.

[13]  J. Strauchen Germ-line mutations in nonsyndromic pheochromocytoma. , 2002, The New England journal of medicine.

[14]  B. Baysal Hereditary paraganglioma targets diverse paraganglia , 2002, Journal of medical genetics.

[15]  J. Benítez,et al.  Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma , 2002, European Journal of Human Genetics.

[16]  C. Larsson,et al.  Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas , 2002, Genes, chromosomes & cancer.

[17]  S. Nakamura,et al.  Detection of circulating cancer cells with von hippel-lindau gene mutation in peripheral blood of patients with renal cell carcinoma. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  H. Bonjer,et al.  Germline mutations in the vhl gene in patients presenting with phaeochromocytomas , 1998, International journal of cancer.

[19]  H. Brauch,et al.  Sporadic pheochromocytomas are rarely associated with germline mutations in the vhl tumor suppressor gene or the ret protooncogene. , 1997, The Journal of clinical endocrinology and metabolism.

[20]  X. Jeunemaître,et al.  Genetic alterations of the RET proto-oncogene in familial and sporadic pheochromocytomas. , 1997, Hormone research.

[21]  R. Hofstra,et al.  Extensive mutation scanning of RET in sporadic medullary thyroid carcinoma and of RET and VHL in sporadic pheochromocytoma reveals involvement of these genes in only a minority of cases. , 1996, The Journal of clinical endocrinology and metabolism.

[22]  K. Nakao,et al.  The RET proto-oncogene in sporadic pheochromocytomas. , 1996, Internal medicine.

[23]  S. Chew,et al.  Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas. , 1995, Journal of medical genetics.

[24]  J. Corvol,et al.  The RET protooncogene in sporadic pheochromocytomas: frequent MEN 2-like mutations and new molecular defects. , 1995, The Journal of clinical endocrinology and metabolism.

[25]  S. Thibodeau,et al.  Mutations in the RET protooncogene in sporadic pheochromocytomas. , 1995, The Journal of clinical endocrinology and metabolism.

[26]  W. Linehan,et al.  Germline mutations in the von Hippel–Lindau disease tumor suppressor gene: Correlations with phenotype , 1995, Human mutation.

[27]  C. Larsson,et al.  Somatic and MEN 2A de novo mutations identified in the RET proto-oncogene by screening of sporadic MTC:s. , 1994, Human molecular genetics.

[28]  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.

[29]  P. Maaswinkel-Mooy,et al.  GENOMIC IMPRINTING IN HEREDITARY GLOMUS TUMOURS: EVIDENCE FOR NEW GENETIC THEORY , 1989, The Lancet.

[30]  M. Gillman,et al.  Familial carotid body tumors: Case report and epidemiologic review , 1980, Cancer.