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Genotype phenotype correlation in Asian Indian von Hippel–Lindau (VHL) syndrome patients with pheochromocytoma/paraganglioma

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Abstract

The data in genotype-phenotype correlation in Indian von Hippel–Lindau (VHL) patients is limited. We have retrospectively studied 31 genetically proven VHL patients with pheochromocytoma/paraganglioma (PCC/PGL) from families and have reviewed the World literature on PCC/PGL in patients with large VHL deletions. Three patients had large deletions and 28 patients had other mutations [missense mutations in 25, 3 bp deletion in 2 and single bp duplication in one]. Unilateral PCC were significantly more common in patients with large VHL deletions whereas multiple PCC (bilateral PCC or PCC + sympathetic PGL) were significantly more common in those with other mutations. World literature review confirmed the rarity of PCC/PGL in patients with large deletions and we report the first definitive case of PCC associated with complete VHL deletion. Pancreatic neuroendocrine tumours were more common, often metastatic and the most common cause of death in our cohort. Our study had eight parent off-spring pairs from five families. The off-springs were significantly younger at presentation and had significantly higher number of PCC/PGL. In conclusion, PCC/PGL are rare in patients with large VHL deletions and if occur are most likely to be solitary. Patients with bilateral PCC or multifocal PCC/PGL are least likely to have large VHL deletions. Our study also provides additional evidence for existence of the phenomenon of anticipation in VHL syndrome.

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References

  1. Maher ER, Iselius L, Yates JR et al (1991) Von Hippel–Lindau disease: a genetic study. J Med Genet 28(7):443–447

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Ong KR, Woodward ER, Killick P, Lim C, Macdonald F, Maher ER (2007) Genotype–phenotype correlations in von Hippel–Lindau disease. Hum Mutat 28(2):143–149

    Article  PubMed  CAS  Google Scholar 

  3. Maher ER, Yates JR, Harries R et al (1990) Clinical features and natural history of von Hippel–Lindau disease. Q J Med 77(283):1151–1163

    Article  PubMed  CAS  Google Scholar 

  4. Gläsker S, Neumann HPH, Koch CA, Vortmeyer AO (2000) Von Hippel–Lindau Disease. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A (eds) Endotext [Internet]. MDText.com, Inc., South Dartmouth, MA

    Google Scholar 

  5. Chou A, Toon C, Pickett J, Gill AJ (2013) Von Hippel–Lindau syndrome. Front Horm Res 41:30–49

    Article  PubMed  CAS  Google Scholar 

  6. Gossage L, Eisen T, Maher ER (2015) VHL, the story of a tumour suppressor gene. Nat Rev Cancer 15(1):55–64

    Article  PubMed  CAS  Google Scholar 

  7. McNeill A, Rattenberry E, Barber R, Killick P, MacDonald F, Maher ER (2009) Genotype–phenotype correlations in VHL exon deletions. Am J Med Genet A 149A(10):2147–2151

    Article  PubMed  CAS  Google Scholar 

  8. Pandit R, Khadilkar K, Sarathi V, Kasaliwal R et al (2016) Germline mutations and genotype–phenotype correlation in Asian Indian patients with pheochromocytoma and paraganglioma. Eur J Endocrinol 175(4):311–323

    Article  PubMed  CAS  Google Scholar 

  9. Vikkath N, Valiyaveedan S, Nampoothiri S et al (2015) Genotype–phenotype analysis of von Hippel–Lindau syndrome in fifteen Indian families. Fam Cancer 14(4):585–594

    Article  PubMed  Google Scholar 

  10. Ebenazer A, Rajaratnam S, Pai R et al (2013) Detection of large deletions in the VHL gene using a real–time PCR with SYBR green. Fam Cancer 12(3):519–524

    Article  PubMed  CAS  Google Scholar 

  11. Janavicius R, Adomaitis R, Jankevicius F, Griskevicius L (2009) Extremely low risk of pheochromocytomas in complete VHL gene deletion cases. Hum Mutat 30(9):1365–1366. https://doi.org/10.1002/humu.21050

    Article  PubMed  CAS  Google Scholar 

  12. Untergasser A, Nijveen H, Rao X et al (2007) Primer3Plus, an enhanced web interface to Primer3. Nucleic Acids Res 35:W71–W74

    Article  PubMed  PubMed Central  Google Scholar 

  13. Schwarz JM, Cooper DN, Schuelke M et al (2014) MutationTaster2: mutation prediction for the deep–sequencing age. Nat Methods 11:361–362

    Article  PubMed  CAS  Google Scholar 

  14. Adzhubei IA, Schmidt S, Peshkin L et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding nonsynonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081

    Article  PubMed  CAS  Google Scholar 

  16. Stenson PD, Mort M, Ball EV et al (2014) The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 133:1–9

    Article  PubMed  CAS  Google Scholar 

  17. Beroud C, Joly D, Gallou C et al (1998) Software and database for the analysis of mutations in the VHL gene. Nucleic Acids Res 26:256–258

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Gossage L, Pires DE, Olivera–Nappa Á (2014) An integrated computational approach can classify VHL missense mutations according to risk of clear cell renal carcinoma. Hum Mol Genet 15(22):5976–5988

    Article  CAS  Google Scholar 

  19. Nordstrom–O’Brien M, van der Luijt RB, van Rooijen E et al (2010) Genetic analysis of von Hippel–Lindau disease. Hum Mutat 31(5):521–537

    PubMed  Google Scholar 

  20. Wong M, Chu YH, Tan HL et al (2016) Clinical and molecular characteristics of East Asian patients with von Hippel–Lindau syndrome. Chin J Cancer 35:79

    Article  PubMed  PubMed Central  Google Scholar 

  21. Crossey PA, Richards FM, Foster K, Green JS et al (1994) Identification of intragenic mutations in the von Hippel–Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet 3(8):1303–1308

    Article  PubMed  CAS  Google Scholar 

  22. Chen F, Kishida T, Yao M, Hustad T, Glavac D et al (1995) Germline mutations in the von Hippel–Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat 5(1):66–75

    Article  PubMed  CAS  Google Scholar 

  23. Franke G, Bausch B, Hoffmann MM et al (2009) Alu Alu recombination underlies the vast majority of large VHL germline deletions: Molecularcharacterization and genotype–phenotype correlations in VHL patients. Hum Mutat 30(5):776–786

    Article  PubMed  CAS  Google Scholar 

  24. Hes F, Zewald R, Peeters T, Sijmons R et al (2000) Genotype–phenotype correlations in families with deletions in the von Hippel–Lindau (VHL) gene. Hum Genet 106(4):425–431

    Article  PubMed  CAS  Google Scholar 

  25. Cybulski C, Krzystolik K, Murgia A, Górski B, Debniak T et al (2002) Germline mutations in the von Hippel–Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene. J Med Genet 39(7):E38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Rocha JC, Silva RL, Mendonça BB, Marui S et al (2003) High frequency of novel germline mutations in the VHL gene in the heterogeneous population of Brazil. J Med Genet 40(3):e31

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Maranchie JK, Afonso A, Albert PS, Kalyandrug S et al (2004) Solid renal tumor severity in von Hippel–Lindau disease is related to germline deletion length and location. Hum Mutat 23(1):40–46

    Article  PubMed  CAS  Google Scholar 

  28. Hes FJ, van der Luijt RB, Janssen AL et al (2007) Frequency of Von Hippel–Lindau germline mutations in classic and non–classic Von Hippel–Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation–dependent probe amplification. Clin Genet 72(2):122–129

    Article  PubMed  CAS  Google Scholar 

  29. Cascón A, Escobar B, Montero–Conde C et al (2007) Loss of the actin regulator HSPC300 results in clear cell renal cell carcinoma protection in Von Hippel–Lindau patients. Hum Mutat 28(6):613–621

    Article  PubMed  CAS  Google Scholar 

  30. Huang JS, Huang CJ, Chen SK, Chien CC (2007) Associations between VHL genotype and clinical phenotype in familial von Hippel–Lindau disease. Eur J Clin Invest 37(6):492–500

    Article  PubMed  CAS  Google Scholar 

  31. Cho HJ, Ki CS, Kim JW (2009) Improved detection of germline mutations in Korean VHL patients by multiple ligation–dependent probe amplification analysis. J Korean Med Sci 24(1):77–83

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Gergics P, Patocs A, Toth M, Igaz P, Szucs N, Liko I et al (2009) Germline VHL gene mutations in Hungarian families with von Hippel–Lindau disease and patients with apparently sporadic unilateral pheochromocytomas. Eur J Endocrinol 161(3):495–502

    Article  PubMed  CAS  Google Scholar 

  33. Gomy I, Molfetta GA, de Andrade Barreto E et al (2010) Clinical and molecular characterization of Brazilian families with von Hippel–Lindau disease: a need for delineating genotype–phenotype correlation. Fam Cancer 9(4):635–642

    Article  PubMed  Google Scholar 

  34. Wu P, Zhang N, Wang X, Ning X, Li T, Bu D et al (2012) Family history of von Hippel–Lindau disease was uncommon in Chinese patients: suggesting the higher frequency of de novo mutations in VHL gene in these patients. J Hum Genet 57(4):238–243

    Article  PubMed  CAS  Google Scholar 

  35. Wang X, Zhang N, Ning X, Li T, Wu P, Peng S et al (2014) Higher prevalence of novel mutations in VHL gene in Chinese Von Hippel–Lindau disease patients. Urology 83(3):675-e1

    Article  Google Scholar 

  36. Hwang S, Ku CR, Lee JI, Hur KY, Lee MS, Lee CH, Koo KY et al (2014) Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel–Lindau (VHL) disease. J Hum Genet 59(9):488–493. https://doi.org/10.1038/jhg.2014.61

    Article  PubMed  CAS  Google Scholar 

  37. Kruizinga RC, Sluiter WJ, de Vries EG, Zonnenberg BA, Lips CJ et al (2013) Calculating optimal surveillance for detection of von Hippel–Lindau–related manifestations. Endocr Relat Cancer 21(1):63–71

    Article  PubMed  Google Scholar 

  38. Wittström E, Nordling M, Andréasson S (2014) Genotype–phenotype correlations, and retinal function and structure in von Hippel–Lindau disease. Ophthalmic Genet 35(2):91–106

    Article  PubMed  CAS  Google Scholar 

  39. Krzystolik K, Jakubowska A, Gronwald J et al (2014) Large deletion causing von Hippel–Lindau disease and hereditary breast cancer syndrome. Hered Cancer Clin Pract 12(1):16

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Ning XH, Zhang N, Li T, Wu PJ, Wang X, Li XY et al (2014) Telomere shortening is associated with genetic anticipation in Chinese Von Hippel–Lindaudisease families. Cancer Res 74(14):3802–3809

    Article  PubMed  CAS  Google Scholar 

  41. Lee JS, Lee JH, Lee KE, Kim JH, Hong JM, Ra EK et al (2016) Genotype–phenotype analysis of von Hippel–Lindau syndrome in Korean families: HIFα bindingsite missense mutations elevate age–specific risk for CNS hemangioblastoma. BMC Med Genet 17(1):48

    Article  PubMed  PubMed Central  Google Scholar 

  42. Peng S, Shepard MJ, Wang J, Li T, Ning X et al (2017) Genotype–phenotype correlations in Chinese von Hippel–Lindau disease patients. Oncotarget. https://doi.org/10.18632/oncotarget.16594

    Article  PubMed  PubMed Central  Google Scholar 

  43. Igarashi H, Ito T, Nishimori I et al (2014) Pancreatic involvement in Japanese patients with von Hippel–Lindau disease: results of a nationwide survey. J Gastroenterol 49(3):511–516

    Article  PubMed  CAS  Google Scholar 

  44. Binkovitz LA, Johnson CD, Stephens DH (1990) Islet cell tumors in von Hippel–Lindau disease: increased prevalence and relationship to the multiple endocrine neoplasias. AJR Am J Roentgenol 155(3):501–505

    Article  PubMed  CAS  Google Scholar 

  45. Charlesworth M, Verbeke CS, Falk GA et al (2012) Pancreatic lesions in von Hippel–Lindau disease? A systematic review and meta–synthesis of the literature. J Gastrointest Surg 16(7):1422–1428

    Article  PubMed  Google Scholar 

  46. Blansfield JA, Choyke L, Morita SY, Choyke PL, Pingpank JF et al (2007) Clinical, genetic and radiographic analysis of 108 patients with von Hippel–Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs). Surgery 142(6):814–818

    Article  PubMed  Google Scholar 

  47. Richards FM, Payne SJ, Zbar B, Affara NA et al (1995) Molecular analysis of de novo germline mutations in the von Hippel–Lindau disease gene. Hum Mol Genet 4(11):2139–2143

    Article  PubMed  CAS  Google Scholar 

  48. Oberlé I, Rousseau F, Heitz D, Kretz C, Devys D et al (1991) Instability of a 550 bp DNA segment and abnormal methylation in fragile X syndrome. Science 252(5009):1097–1102

    Article  PubMed  Google Scholar 

  49. La Spada AR, Wilson EM, Lubahn DB et al (1991) Androgen receptor gene mutations in X–linked spinal and bulbar muscular atrophy. Nature 352(6330):77–79

    Article  PubMed  Google Scholar 

  50. Mahadevan M, Tsilfidis C, Sabourin L, Shutler G et al (1992) Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255(5049):1253–1255

    Article  PubMed  CAS  Google Scholar 

  51. Ranen NG, Stine OC, Abbott MH et al (1995) Anticipation and instability of IT–15 (CAG)n repeats in parent–offspring pairs with Huntington disease. Am J Hum Genet 57(3):593–602

    PubMed  PubMed Central  CAS  Google Scholar 

  52. Tabori U, Nanda S, Druker H, Lees J, Malkin D (2007) Younger age of cancer initiation is associated with shorter telomere length in Li–Fraumeni syndrome. Cancer Res 67(4):1415–1418

    Article  PubMed  CAS  Google Scholar 

  53. Martinez–Delgado B, Yanowsky K, Inglada–Perez L et al (2011) Genetic anticipation is associated with telomere shortening in hereditary breast cancer. PLoS Genet 7(7):e1002182

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Seguí N, Pineda M, Guinó E, Borràs E, Navarro M et al (2013) Telomere length and genetic anticipation in Lynch syndrome. PLoS ONE 8(4):e61286

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Nilbert M, Timshel S, Bernstein I, Larsen K (2009) Role for genetic anticipation in Lynch syndrome. J Clin Oncol 27(3):360–364

    Article  PubMed  Google Scholar 

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Funding

The funding was provided by Scientific and Engineering Research Board (SERB), Department of Science and Technology, Government of India (Grant No. # SB/SO/HS/041/2013).

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Authors and Affiliations

  1. Department of Endocrinology, Seth G.S. Medical College & KEM hospital, Parel, Mumbai, Maharashtra, 4000012, India

    Nilesh Lomte, Sanjeet Kumar, Reshma Pandit, Manjunath Goroshi, Swati Jadhav, Anurag R. Lila, Tushar Bandgar & Nalini S. Shah

  2. Department of Endocrinology, Vydehi Institute of Medical Sciences and Research Center, Bengaluru, Karnataka, India

    Vijaya Sarathi

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  1. Nilesh Lomte
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  2. Sanjeet Kumar
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Correspondence to Tushar Bandgar.

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Lomte, N., Kumar, S., Sarathi, V. et al. Genotype phenotype correlation in Asian Indian von Hippel–Lindau (VHL) syndrome patients with pheochromocytoma/paraganglioma. Familial Cancer 17, 441–449 (2018). https://doi.org/10.1007/s10689-017-0058-y

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