Doctor of Philosophy(PhD) / Hyperparathyroidism, a disease of the parathyroid glands, is one of the most common endocrinopathies, having a prevalence of 1 – 3 per 1000 individuals. It is characterised by calcium insensitive hypersecretion of parathyroid hormone, and increased cell proliferation. While the treatment for familial as well as many sporadic tumours associated with hyperparathyroidism includes parathyroidectomy, the extent of surgery and the follow-up monitoring regime, are dependent on accurate clinical and histopathological classification of the lesion. However, overlaps in histopathological and morphological features confound distinctions between the three main classifications of adenoma, hyperplasia and carcinoma and differential diagnosis of these lesions remains challenging. At the start of this candidature in January 2002, the genes associated with two familial syndromes in which hyperparathyroidism may feature, Multiple Endocrine Neoplasia (MEN) 1 and 2 had been identified, respectively MEN1 and RET. In addition, overexpression or translocation of cyclin D1 had been identified in both benign and malignant sporadic lesions, indicating a role for cyclin D1 in parathyroid tumorigenesis. However, the underlying events leading either directly, or indirectly, to the development of a large proportion of parathyroid lesions are still largely unknown. The work described in this thesis has contributed to the understanding of parathyroid lesions and the diagnosis and prognosis of affected individuals. During this candidature, constitutive mutation of HRPT2 was associated with Hyperparathyroidism–Jaw Tumour syndrome (HPT-JT). HRPT2 mutation analysis and loss of heterozygosity studies at 1q24-32 in parathyroid tumours presented in this thesis identified the strong association of HRPT2 mutation with sporadic parathyroid malignancy. In addition, 2-hits affecting HRPT2 were identified in several tumours suggestive of a role for HRPT2 as a tumour suppressor gene in sporadic parathyroid tumorigenesis. Microarray analysis of parathyroid tumours presented in this thesis identified three broad clusters of tumours. Cluster 1 comprised predominantly hyperplastic specimens and also included the normal tissue. Cluster 2, the most robust of the clusters, consisted of tumours harbouring HRPT2 mutations. The HPT-JT-associated tumours, both benign and malignant, and sporadic carcinomas, comprised this cluster. Cluster 3 contained the majority of the sporadic adenoma specimens, some hyperplasia, as well as all of the MEN 1-associated tumours. The cluster data is strongly suggestive that parathyroid tumours with somatic HRPT2 mutation, or tumours developing on a background of germline HRPT2 mutation, follow pathways distinct from those involved in mutant MEN 1-related parathyroid tumours. The results of this work provide strong evidence for an adenoma to carcinoma progression model for parathyroid tumorigenesis in the presence of a germline HRPT2 mutation. With the knowledge that both HRPT2 and MEN1 have significant roles in familial as well as sporadic parathyroid tumorigenesis, assays for mutation screening of these two genes have been developed as part of this thesis. These assays will facilitate a rapid molecular diagnosis for patients with one of these familial syndromes. Furthermore, novel putative biomarkers for different parathyroid tumour subtypes have also been identified. VCAM1 and UCHL1 (PGP9.5) were found to be significantly overexpressed in tumours harbouring an HRPT2 mutation at both the transcript and protein level. These two molecules are suggested as putative biomarkers for the discrimination of sporadic carcinoma or HPT-JT-associated tumours. RALDH2 transcript and protein were highly significantly overexpressed in the hyperplasia class relative to the adenoma class, and this molecule is suggested as a putative biomarker for discrimination of these classes of parathyroid tumours. These biomarkers may assist in the accurate diagnosis and prognosis of hyperparathyroidism. Large cohort studies of these putative biomarkers will be required to determine their robustness in discriminating parathyroid tumour subtypes. Further studies of their putative role in parathyroid tumorigenesis may identify them as novel molecular targets for future therapeutics to treat both hyperplastic and neoplastic parathyroid lesions.
| Identifer | oai:union.ndltd.org:ADTP/272904 |
| Date | January 2005 |
| Creators | Howell, Viive Maarika |
| Publisher | University of Sydney., Kolling Institute of Medical Research |
| Source Sets | Australiasian Digital Theses Program |
| Detected Language | English |
| Rights | The author retains copyright of this thesis., http://www.library.usyd.edu.au/copyright.html |
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