Tracy Tucker

TRACY TUCKER- PhD DEFENSE

“Pathogenesis of Neurofibromatosis 1 Associated Neurofibromas”

B. Sc. University of Waterloo, 2000
Tuesday, December 5, 2006, 4pm Room 203, Graduate Student Centre

Tracy Tucker- PhD defense program- pdf

SUPERVISORY COMMITTEE

Dr Jan M Friedman, Research Supervisor (Medical Genetics)

Dr Carolyn Brown (Medical Genetics)

Dr Connie Eaves (Medical Genetics)

Dr Keith Humphries (Medical Genetics)

EXAMINING COMMITTEE

Chair: To be completed by FoGS
Supervisory Committee: Dr. Jan M Friedman, Research Supervisor (Medical Genetics), Dr. Carolyn Brown (Medical Genetics)
University Examiners: Dr. Barb McGillivray (Medical Genetics), Dr. Blake Gilks (Pathology & Laboratory Medicine)
External Examiner: Dr. Nancy Ratner. Department of Cell Biology, Neurobiology, Anatomy University of Cincinnati Cincinnati, Ohio, USA

ABSTRACT

Neurofibromatosis 1 (NF1) is an autosomal dominant disease. Neurofibromas, benign tumours that develop from peripheral nerves, are a hallmark feature of NF1. Malignant peripheral nerve sheath tumours (MPNSTs) are one of the leading causes of death in people with NF1. Clinical evidence suggests that most MPNSTs develop from pre-existing plexiform neurofibromas. Most studies treat all NF1-associated neurofibromas as a single entity, ignoring important differences between pathological details, clinical presentation and natural history. I analysed clinical information on 476 probands with NF1 from the Henri Mondor database and found that individuals with subcutaneous neurofibromas were 3 times more likely to have internal plexiform neurofibromas and that individuals with internal plexiform neurofibromas were 20 times more likely to have MPNSTs than individuals without such tumours. These findings suggest that pathogenic differences in some neurofibromas may lead to different risks of progressing to malignancy. I collected formalin-fixed paraffin-embedded samples from NF1 patients and classified them histologically as nodular or diffuse neurofibromas. By using histochemistry, I found that mast cells were absent in MPNSTs and significantly more abundant in diffuse neurofibromas than in nodular neurofibromas. Mast cells were located at the periphery of nodular neurofibromas but were evenly distributed throughout diffuse neurofibromas. Double immunofluorescent staining of S100 (a marker of Schwann cells, the presumed tumour progenitor cell type) and neurofibromin (the protein product of the NF1 gene) showed that diffuse neurofibromas had significantly more S100 positive- neurofibromin positive cells and fewer S100 negative-neurofibromin negative cells than nodular neurofibromas. Using laser microdissection of immunofluorescently stained slides, I found that some neurofibromas show evidence of clonal (presumably neoplastic) proliferation of S100 positive-neurofibromin negative cells, while other neurofibromas appear to be neurofibromin haploinsufficient and polyclonal, and thus may be hyperplastic rather than neoplastic lesions. The results presented in this thesis support the hypothesis that neurofibromas in people with NF1 are pathogenically heterogeneous and that some kinds of neurofibromas are more likely then others to give rise to MPNSTs. These findings have important implications for the surveillance and treatment of people with NF1.

PUBLICATIONS

Tucker T, Brown CJ, Fee J et al. Pathogenetic heterogeneity of NF1-associated neurofibromas. Submitted for publication.

Tucker T, Riccardi VM, Sutcliffe M et al. Heterogeneity of mast cell distribution in NF1 neurofibromas. Submitted for publication.

Chang SC, Tucker T, Thorogood NP, Brown CJ. (2006) Mechanisms of X- chromosome inactivation. Frontiers in Bioscience. 11: 852-66.

Tucker T, Wolkenstein P, Revuz J, Zeller J, Friedman JM. (2005). Association between benign and malignant peripheral nerve sheath tumours in NF1. Neurology. 65:205-11.

Tucker T, Friedman JM. (2002). Pathogenesis of hereditary tumours: beyond the "two-hit" hypothesis. Clinical Genetics. 62: 345-57.

SELECTED PRESENTATIONS

Platform presentation at the Children’s Tumour Foundation Symposium; “Neurofibromas from NF1 patients retain neurofibromin expression.” (2005)
Platform presentation at the Children’s Tumour Foundation Symposium;

“Association between the occurrence of malignant peripheral nerve sheath tumours and subcutaneous and internal neurofibromas in NF1.” (2003)
Platform presentation at European Neurofibromatosis Meeting;

“Association between the occurrence of malignant peripheral nerve sheath tumours and subcutaneous and internal neurofibromas in NF1.” (2003)

AWARDS

James Miller Memorial Award (2006)

University Graduate Fellowship (2004-2005)

University of British Columbia, Department of Pathology Fellowship Award (2003)

GRADUATE STUDIES

Field of Study: Neurofibromatosis

Courses:
MEDG505 Genome Analysis, Dr. P. Heiter
MEDG520 Advanced Human Molecular Genetics, Dr C. Brown
MEDG521 Molecular & Cellular Biology of Cancer, Dr F. Takei
MEDG530 Advanced Human Genetics, Dr. B. Simpson
MEDG540 Seminar, Dr. F. Dill
MEDG548 Directed Studies, Dr. C. Brown

Tracy Tucker- PhD defense program- pdf