Parathyroid Tumor Clonal Status as a Biomarker in Primary Hyperparathyroidism

甲状旁腺肿瘤克隆状态作为原发性甲状旁腺功能亢进症的生物标志物

• 批准号: 10299604
• 负责人: JOHN A. OLSON
• 金额: $ 55.16万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10299604
• 关键词: Biochemical; Biological Assay; Biological Markers; Cardiovascular Diseases; Cells; Characteristics; Chief Cell; Copy Number Polymorphism; Data; Development; Disease; Disease Outcome; Endocrine System Diseases; Etiology; Excision; Feedback; Foundations; Fracture; Frequencies; Genomic approach; Genomics; Gland; Heterogeneity; Histologic; Hypercalcemia; Hyperparathyroidism; Incidence; Individual; Kidney; Kidney Calculi; Knowledge; Laboratories; Lead; Metabolic Diseases; Modeling; Molecular; Molecular Analysis; Morbidity - disease rate; Multicenter Studies; Neoplasms; Neurocognitive; Neurocognitive Deficit; Operative Surgical Procedures; Outcome; Outcome Study; Oxyphil Cells; Parathyroid Adenoma; Parathyroid Neoplasms; Parathyroid gland; Parathyroidectomy; Pathogenesis; Pathologic; Patients; Persons; Physiological; Postmenopause; Postoperative Period; Prospective Studies; Publishing; Recurrence; Symptoms; Testing; Treatment outcome; Woman; Work; X Inactivation; base; bone loss; clinically relevant; cohort; comparative genomics; exome sequencing; functional genomics; indexing; novel; prospective; response; skeletal; tumor; tumorigenesis

Project Summary/Abstract Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia in ambulatory patients, and may lead to bone loss and fracture, cardiovascular disease, kidney stones, and neurocognitive impairment (1). PHPT is the third most common endocrine disorder with an annual incidence between 34 to 120 per 100,000 person-years that is rising, especially among postmenopausal women. Since the first description of PHPT and its surgical treatment in the 1920s, the pathogenesis of PHPT has been viewed simply: A parathyroid tumor develops from a single transformed clone (i.e. monoclonal) that expands and secretes excessive PTH causing hypercalcemia and the symptoms and sequellae of PHPT. This paradigm predicts that PHPT develops from a single tumor (single gland disease, SGD) and that removal of this single tumor by parathyroidectomy (PTX) cures the disease. Although conceptually attractive, this simple approach does not explain several observations including: 1. The presence of multiple gland disease (MGD) in up to 20% of PHPT patients; 2. The observation that PTH remains elevated following PTX in up to 30% of patients; 3. The reality that symptoms and sequellae of PHPT often do not improve following PTX; and 4. The development of recurrent PHPT in up to 15% of patients (2). These observations, combined with data from our laboratory describing the molecular heterogeneity of parathyroid tumors have led us to suspect that PHPT may represent several different diseases that can be distinguished based on characteristics of the parathyroid tumor. The foundation for the proposed work has been published by our group in two studies. Our first study characterized isolated parathyroid cells from parathyroid adenomas in PHPT and showed that a significant proportion (40%, 5/14) of these tumors were comprised of multiple clones (i.e. polyclonal). Our second study of 119 patients confirmed that up to 46% of PHPT patients have polyclonal tumors and that the clonal status (i.e. monoclonal versus polyclonal) of the tumor predicts MGD that is often missed at surgery. These findings support the premise that parathyroid tumor clonal status reflects different types of PHPT with different etiologies, disease presentation and treatment outcomes. We now propose to characterize PHPT patients with these tumor types and test the novel hypothesis that PHPT can better be understood and treated by classifying the disorder in terms of the clonal status of the underlying parathyroid tumor.

项目总结/文摘