RICERCA ITALIANA     

Studies on the molecular mechanisms of abnormal parathyroid proliferation and function, and identification and clinical use of molecular markers of sporadic and familial parathyroid cancer. New insights on the prevalence of skeletal, neuropsychological and metabolic manifestations of primary hyperparathyroidism, their relationship with calcium sensing receptor polymorphisms and course after parathyroidectomy.

Università di Pisa

Abstract

The mechanisms underlying parathyroid proliferation and tumorigenesis are not yet entirely understood. Reduced expression in calcium sensing receptor (CASR), inactivation of the Rb1 gene, over-expression of cyclin D1and mutation in MEN1 and HRPT2 genes have been identified in parathyroid neoplasia. HRPT2 gene and its protein, parafibromin, are particularly involved in sporadic parathyroid cancer (PC), showing somatic mutations in 70-80% of cases. Interestingly 20% of PC patients carry the same mutation germline.

The objectives of this research project are: 1) to further investigate molecular mechanisms of normal and neoplastic parathyroid cell proliferation; 2) to identify molecular markers for early diagnosis of PC using the genomic and proteomic approaches and immunohistochemistry; 3) to identify environmental/genetics factors influencing the penetrance of germline HRPT2 mutations; 4) to evaluate retrospectively and prospectively the risk of vertebral fracture and metabolic abnormalities in patients with primary hyperparathyroidism (PHPT); 5) to evaluate the effect of parathyroidectomy on the prevalence of skeletal and metabolic abnormalities and quality of life in patients with PHPT; 6) to investigate the role of the polymorphic variants of the CASR on the phenotypic expression of PHPT.

The objectives detailed above will be pursued as follows:
1.Task 1. Functional studies will be performed in cell systems in order: a) to define the >>>

Principal Investigator

Claudio Marcocci Università degli Studi di PISA

Research Objectives

The research project is aimed to identify new molecular markers associated with the neoplastic transformation of parathyroid cells, to clarify the cellular mechanisms involved in this process, and their application in clinical practice to improve the accuracy of differential diagnosis between benign and malignant parathyroid tumors and to early detect the tumor in carriers of HRPT2 germline mutations. Moreover, a large prospective study in patients with primary hyperparathyroidism (PHPT) will allow to evaluate the risk of vertebral fracture and metabolic abnormalities in these patients according to the severity of the disease and to the polymorphic variants of the tail of the calcium sensing receptor (CASR). Finally, the effect of parathyroidectomy on the prevalence of skeletal and metabolic abnormalities and quality of life will be also evaluated. The latter point will include a randomized trial in patients who do not meet the 2002 surgical guidelines, comparing the impact of parathyroidectomy or surveillance in these patients.
The project consists of several subprojects that will be performed either in a single unit or in collaboration among the Units.

Herein is a more detailed outline of the objectives of the project:
a)To identify molecular markers for early diagnosis of parathyroid cancer using the genomic and proteomic approaches, and immunohistochemistry. The availability of new diagnostic tools will allow to correctly classify those >>>

First Results

The studies that will be performed within the present research project should increase our knowledge on the molecular mechanisms of parathyroid proliferation and tumorigenesis and provide novel instruments of potential application in clinical practice. The expected results will be detailed according to the various objectives of the project, which is composed of a basic section and of a clinical section.

BASIC SECTION

1.Identification of molecular markers for early diagnosis of parathyroid tumors. The availability of new diagnostic tools, identified through the genomic and proteomic approaches, will allow to correctly classify those tumors in which the histology cannot distinguish between benign and malignant lesions. This will be of help in the design of the patient’s follow up and, eventually, to introduce appropriate management procedures at early times in patients with malignant tumors. These improvement in patient’s care could increase life expectancy of patients with parathyroid cancer.

2.Identification of environmental/genetics factors influencing the penetrance of germline HRPT2 mutations. These studies could clarify why some carriers develop the neoplasm early in life, whereas others remain healthy during all the life. The identification of genetic components leading to the disease would represent not only a prompt advantage for the patient, through an early detection and management of parathyroid tumor , but also for the >>>

Timescale

24 months

National and international background

Primary hyperparathyroidism (PHPT) is generally due to a sporadic adenoma and occasionally to carcinoma. In 5-10% of cases PHPT is familial (1). PHPT in characterized by increased parathyroid cell proliferation and calcium insensitive hypersecretion of parathyroid hormone (PTH) (1). Parathyroid cell function and cell proliferation are under the control of extracellular ionized calcium concentrations (Ca2+), through a specific calcium sensing receptor (CASR) (2). CaR is expressed at the cell surface of parathyroid cells and other cells, like renal tubular cells and osteoblasts. CASR gene polymorphisms is associated with different sensitivity to Ca2+ and might determine the variable clinical presentation of PHPT and the risk of kidney and bone complications. Indeed, the association between the CASR990 variant, where valine residue is substituted with glycine, and the presence of kidney stones and hypercalciuria has been described (3). In vitro studies demonstrated that the CASR990 variant shows an activating phenotype, though it is not known how the 990 polymorphism induces a higher CASR sensitivity to Ca2+(4). CASR desensitization and internalization might be differently regulated by its polymorphic variant.
CASR expression is variably down-regulated in tumoral parathyroid cells and at least in part account for the reduced inhibitory effect of elevated Ca2+ on PTH release. It has been demonstrated that the mitogen activated protein (MAP) kinase MEK/ERK pathway and the >>>