Drivers of Hypoxia-induced Angiogenesis in Tumor Development

NCT03979833 | Unknown

• 1 other identifier: 514-0356/19-3000
• Study Type: observational
• Target: 10
• Locations: 1 country
• Sites: 2

Brief Summary

The study aims to elucidate hypoxia-induced angiogenesis in tumor development using central nervous system (CNS) hemangioblastoma tumorgenesis as a model. In a pilot-project the investigators will identify genetic drivers of CNS hemangioblastoma progression and associated cyst development using whole genome sequencing and copy number profiling of tumor DNA paired with clinical information about each tumor's growth pattern. The investigators will look for recurrent mutations across tumors to identify common genetic mechanisms involved in early tumorigenesis.

Conditions

Von Hippel-Lindau Disease

Outcome Measures

Primary Outcomes (1)

• Somatic variants

  somatic genetic variants

  July 2019-December 2019

Study Arms (1)

1

Individuals currently living, over the age of 18 years and known carriers of a pathogenic variant in the VHL gene.

Genetic: Whole exome sequencing

Interventions

Whole exome sequencing GENETIC

DNA from CNS hemangioblastomas and normal tissue (blood) will be analysed using whole exome sequencing.

1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Living individuals previously identified as having a pathogenic variant in the VHL gene and who have had at least one CNS hemnagioblatoma removed.

You may qualify if:

• Currently living, carrier of a pathogenic variant in the VHL gene, at least one surgically removed CNS hemangioblastoma that is accessible for the study.

You may not qualify if:

• Under the age of 18 years, deceased individuals

Sponsors & Collaborators

• University of Copenhagen: lead
• Odense University Hospital: collaborator

Study Sites (2)

Department of Cellular and Molecular Medicine

Copenhagen, 2200, Denmark

Location

Odense University hospital, department of clinical genetics

Odense, 5000, Denmark

Location

Related Publications (18)

• Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70. doi: 10.1016/s0092-8674(00)81683-9. No abstract available.

  PMID: 10647931 BACKGROUND

• Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011 Jun;19(6):617-23. doi: 10.1038/ejhg.2010.175. Epub 2011 Mar 9.

  PMID: 21386872 BACKGROUND

• Nordstrom-O'Brien M, van der Luijt RB, van Rooijen E, van den Ouweland AM, Majoor-Krakauer DF, Lolkema MP, van Brussel A, Voest EE, Giles RH. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010 May;31(5):521-37. doi: 10.1002/humu.21219.

  PMID: 20151405 BACKGROUND

• Ammerman JM, Lonser RR, Dambrosia J, Butman JA, Oldfield EH. Integra Foundation Award: Long-term natural history of hemangioblastomas in Von Hippel-Lindau disease: implications for treatment. Clin Neurosurg. 2006;53:324-31. No abstract available.

  PMID: 17380770 BACKGROUND

• Wanebo JE, Lonser RR, Glenn GM, Oldfield EH. The natural history of hemangioblastomas of the central nervous system in patients with von Hippel-Lindau disease. J Neurosurg. 2003 Jan;98(1):82-94. doi: 10.3171/jns.2003.98.1.0082.

  PMID: 12546356 BACKGROUND

• Glasker S, Klingler JH, Muller K, Wurtenberger C, Hader C, Zentner J, Neumann HP, Velthoven VV. Essentials and pitfalls in the treatment of CNS hemangioblastomas and von Hippel-Lindau disease. Cent Eur Neurosurg. 2010 May;71(2):80-7. doi: 10.1055/s-0029-1234040. Epub 2010 Mar 12.

  PMID: 20229452 BACKGROUND

• Vortmeyer AO, Falke EA, Glasker S, Li J, Oldfield EH. Nervous system involvement in von Hippel-Lindau disease: pathology and mechanisms. Acta Neuropathol. 2013 Mar;125(3):333-50. doi: 10.1007/s00401-013-1091-z. Epub 2013 Feb 12.

  PMID: 23400300 BACKGROUND

• Vortmeyer AO, Yuan Q, Lee YS, Zhuang Z, Oldfield EH. Developmental effects of von Hippel-Lindau gene deficiency. Ann Neurol. 2004 May;55(5):721-8. doi: 10.1002/ana.20090.

  PMID: 15122713 BACKGROUND

• Vortmeyer AO, Tran MG, Zeng W, Glasker S, Riley C, Tsokos M, Ikejiri B, Merrill MJ, Raffeld M, Zhuang Z, Lonser RR, Maxwell PH, Oldfield EH. Evolution of VHL tumourigenesis in nerve root tissue. J Pathol. 2006 Nov;210(3):374-82. doi: 10.1002/path.2062.

  PMID: 16981244 BACKGROUND

• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013.

  PMID: 21376230 BACKGROUND

• Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990 Jun 1;61(5):759-67. doi: 10.1016/0092-8674(90)90186-i. No abstract available.

  PMID: 2188735 BACKGROUND

• Sun M, Monzon F, Zhou L et al. Identification of molecular drivers of human hemangioblastoma. Conference abstract: The 11th International VHL Symposium 2014 . 23-10-2014.

  BACKGROUND

• Zhou J, Wang J, Li N, Zhang X, Zhou H, Zhang R, Ma H, Zhou X. Molecularly genetic analysis of von Hippel-Lindau associated central nervous system hemangioblastoma. Pathol Int. 2010 Jun;60(6):452-8. doi: 10.1111/j.1440-1827.2010.02540.x.

  PMID: 20518900 BACKGROUND

• Lemeta S, Jarmalaite S, Pylkkanen L, Bohling T, Husgafvel-Pursiainen K. Preferential loss of the nonimprinted allele for the ZAC1 tumor suppressor gene in human capillary hemangioblastoma. J Neuropathol Exp Neurol. 2007 Sep;66(9):860-7. doi: 10.1097/nen.0b013e318149ee64.

  PMID: 17805016 BACKGROUND

• Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JMC, Papaemmanuil E, Brewer DS, Kallio HML, Hognas G, Annala M, Kivinummi K, Goody V, Latimer C, O'Meara S, Dawson KJ, Isaacs W, Emmert-Buck MR, Nykter M, Foster C, Kote-Jarai Z, Easton D, Whitaker HC; ICGC Prostate Group; Neal DE, Cooper CS, Eeles RA, Visakorpi T, Campbell PJ, McDermott U, Wedge DC, Bova GS. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015 Apr 16;520(7547):353-357. doi: 10.1038/nature14347. Epub 2015 Apr 1.

  PMID: 25830880 BACKGROUND

• Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer. 2015 Jan;15(1):55-64. doi: 10.1038/nrc3844.

  PMID: 25533676 BACKGROUND

• Fisher R, Horswell S, Rowan A, Salm MP, de Bruin EC, Gulati S, McGranahan N, Stares M, Gerlinger M, Varela I, Crockford A, Favero F, Quidville V, Andre F, Navas C, Gronroos E, Nicol D, Hazell S, Hrouda D, O'Brien T, Matthews N, Phillimore B, Begum S, Rabinowitz A, Biggs J, Bates PA, McDonald NQ, Stamp G, Spencer-Dene B, Hsieh JJ, Xu J, Pickering L, Gore M, Larkin J, Swanton C. Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution. Genome Biol. 2014 Aug 27;15(8):433. doi: 10.1186/s13059-014-0433-z.

  PMID: 25159823 BACKGROUND

• Poulsen ML, Gimsing S, Kosteljanetz M, Moller HU, Brandt CA, Thomsen C, Bisgaard ML. von Hippel-Lindau disease: surveillance strategy for endolymphatic sac tumors. Genet Med. 2011 Dec;13(12):1032-41. doi: 10.1097/GIM.0b013e31822beab1.

  PMID: 21912262 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

DNA extracted from periferal blood and CNS hemangioblastomas removed as part of the participants treatment for their condition.

MeSH Terms

Conditions

von Hippel-Lindau Disease

Interventions

Exome Sequencing

Condition Hierarchy (Ancestors)

Neurocutaneous Syndromes; Nervous System Diseases; Angiomatosis; Vascular Diseases; Cardiovascular Diseases; Ciliopathies; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Whole Genome Sequencing; Sequence Analysis, DNA; Sequence Analysis; Genetic Techniques; Investigative Techniques

Study Officials

• Ole William Petersen, MD, PhD

  Head of department

  STUDY DIRECTOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Postdoc researcher

Study Record Dates

• First Submitted: June 5, 2019
• First Posted: June 7, 2019
• Study Start: June 14, 2019
• Primary Completion: August 31, 2019
• Study Completion: May 31, 2020
• Last Updated: September 27, 2019

Record last verified: 2019-09

Locations

DK (2)