Mutations Seen Among Patients with Pheochromocytoma and Paraganglioma at a Referral Center From India

Abstract Determining the mutational status of susceptibility genes including RET, VHL, SDHx (SDHB, SDHC, SDHD) among patients with pheochromocytoma/paraganglioma (PCC/PGL) is gaining importance. These genes have not been systematically characterized among patients with PCC/PGL from India. The aim of the work was to screen the most frequently mutated genes among patients with PCC/PGL to determine the frequency and spectrum of mutations seen in this region. Fifty patients with PCC/PGL treated at our tertiary care hospital between January 2010 and June 2012 were screened for mutations in susceptibility genes using an algorithmic approach. Thirty-two percent (16/50) of patients were found to be positive for mutations including mutations among RET (n=4), VHL (n=6), SDHB (n=3), and SDHD (n=3) genes. None of these patients were positive for SDHC mutations. A significant association was found between young patients with bilateral tumors and VHL mutations (p=0.002). Two of the 3 patients with extra-adrenal SDHB associated tumors, had unique mutations, viz., c.436delT (exon 5) and c.788_857del (exon 8), one of which was malignant. High frequency of mutations seen among patients in this study emphasizes the need to consider mutational analysis among Indian patients with PCC/PGL.

[1]  A. Ebenazer,et al.  Usefulness of Succinate dehydrogenase B (SDHB) immunohistochemistry in guiding mutational screening among patients with pheochromocytoma‐paraganglioma syndromes , 2014, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[2]  S.H. Choi,et al.  Germline mutations and genotype–phenotype correlations in patients with apparently sporadic pheochromocytoma/paraganglioma in Korea , 2014, Clinical genetics.

[3]  W. Foulkes,et al.  Pheochromocytoma and paraganglioma syndromes: genetics and management update. , 2013, Current oncology.

[4]  S. Marx.  Multiplicity of hormone-secreting tumors: common themes about cause, expression, and management. , 2013, The Journal of clinical endocrinology and metabolism.

[5]  A. Vicha,et al.  Genetics of pheochromocytoma and paraganglioma syndromes: new advances and future treatment options , 2013, Current opinion in endocrinology, diabetes, and obesity.

[6]  M. Korbonits,et al.  A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. , 2013, The Journal of clinical endocrinology and metabolism.

[7]  G. C,et al.  p.Arg82Leu von Hippel-Lindau (VHL) Gene Mutation among Three Members of a Family with Familial Bilateral Pheochromocytoma in India: Molecular Analysis and In Silico Characterization , 2013, PloS one.

[8]  D. Fraker,et al.  Inherited Mutations in Pheochromocytoma and Paraganglioma: Why All Patients Should Be Offered Genetic Testing , 2013, Annals of Surgical Oncology.

[9]  A. Ebenazer,et al.  Detection of large deletions in the VHL gene using a Real-Time PCR with SYBR Green , 2013, Familial Cancer.

[10]  N. Thomas,et al.  Pheochromocytomas of the vesical and paravesical region , 2012 .

[11]  A. Vénisse,et al.  A Decade (2001–2010) of Genetic Testing for Pheochromocytoma and Paraganglioma , 2012, Hormone and Metabolic Research.

[12]  X. Jeunemaître,et al.  Presymptomatic Genetic Testing in Minors at Risk of Paraganglioma and Pheochromocytoma: Our Experience of Oncogenetic Multidisciplinary Consultation , 2012, Hormone and Metabolic Research.

[13]  M. Urioste,et al.  MAX Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma , 2012, Clinical Cancer Research.

[14]  S. Agarwal,et al.  Familial carotid body tumors in patients with SDHD mutations: a case series. , 2012, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[15]  C. Vocke,et al.  Genetic Screening for von Hippel-Lindau Gene Mutations in Non-syndromic Pheochromocytoma: Low Prevalence and False-positives or Misdiagnosis Indicate a Need for Caution , 2012, Hormone and Metabolic Research.

[16]  H. Affres,et al.  TMEM127 screening in a large cohort of patients with pheochromocytoma and/or paraganglioma. , 2012, The Journal of clinical endocrinology and metabolism.

[17]  O. Nilsson,et al.  Prevalence of Germline Mutations in Patients with Pheochromocytoma or Abdominal Paraganglioma and Sporadic Presentation: A Population-Based Study in Western Sweden , 2012, World Journal of Surgery.

[18]  E. Maher,et al.  The genetics of phaeochromocytoma: using clinical features to guide genetic testing. , 2011, European journal of endocrinology.

[19]  K. Nathanson,et al.  Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. , 2012, Cancer genetics.

[20]  S. Richard,et al.  von Hippel–Lindau disease: A clinical and scientific review , 2011, European Journal of Human Genetics.

[21]  A. Chou,et al.  Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. , 2010, Human pathology.

[22]  C. Eng,et al.  Clinical Predictors and Algorithm for the Genetic Diagnosis of Pheochromocytoma Patients , 2009, Clinical Cancer Research.

[23]  M. Rothmund,et al.  Mutations and polymorphisms in the SDHB, SDHD, VHL, and RET genes in sporadic and familial pheochromocytomas , 2009, Endocrine.

[24]  R. Letón,et al.  Rationalization of Genetic Testing in Patients with Apparently Sporadic Pheochromocytoma/Paraganglioma , 2009, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[25]  H. Lehnert,et al.  Phaeochromocytoma, new genes and screening strategies , 2006, Clinical endocrinology.

[26]  B. Robinson,et al.  Genetic basis of phaeochromocytoma and paraganglioma. , 2006, Best practice & research. Clinical endocrinology & metabolism.

[27]  C. A. Koch,et al.  Molecular pathogenesis of MEN2-associated tumors , 2004, Familial Cancer.

[28]  J. Schipper,et al.  Germ-line mutations in nonsyndromic pheochromocytoma. , 2002, The New England journal of medicine.

[29]  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.

[30]  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.

[31]  R. Aguiar,et al.  Analysis of the SDHD gene, the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas. , 2001, The Journal of clinical endocrinology and metabolism.

[32]  A. Vortmeyer,et al.  Genetic aspects of pheochromocytoma. , 2001, Endocrine regulations.

[33]  C. Mathew,et al.  Accurate diagnosis of carriers of deletions and duplications in Duchenne/Becker muscular dystrophy by fluorescent dosage analysis. , 1996, Journal of medical genetics.