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

基本信息

批准号：
10524748
负责人：
JOHN A. OLSON
金额：
$ 66.24万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524748
关键词：
Biochemical Biological Assay Biological Markers Cardiovascular Diseases Cell Separation 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 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 bone loss clinically relevant cohort comparative genomics disease classification exome sequencing improved indexing novel primary outcome prospective response skeletal tumor tumorigenesis

项目摘要

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.

项目摘要/摘要原发性甲状旁腺功能亢进（PHPT）是卧床患者高钙血症的最常见原因，并且可能导致骨质流失和骨折，心血管疾病，肾结石和神经认知障碍（1）。 PHPT是第三大常见的内分泌障碍，每年发病率在每100,000 人年正在上升，尤其是在绝经后妇女中。自PHPT的第一个描述和它在1920年代的手术治疗中已被简单地观察到PHPT的发病机理：甲状旁腺肿瘤由单个转换的克隆（即单克隆）发展出来，该克隆扩展并分泌过多的PTH 高钙血症以及PHPT的症状和后遗症。该范式预测PHPT从单肿瘤（单腺疾病，SGD），以及甲状旁腺切除术（PTX）治疗的单个肿瘤疾病。尽管从概念上有吸引力，但这种简单的方法不能解释几个观察结果包括：1。多达20％的PHPT患者存在多种腺病（MGD）； 2。观察在PTX之后，该PTH在多达30％的患者中保持升高。 3。症状和后遗症的现实 PHPT的PTX通常不会改善；和4。多达15％的患者的复发性PHPT的发展（2）。这些观察结果与我们实验室的数据相结合，描述了分子异质性甲状旁腺肿瘤使我们怀疑PHPT可能代表几种可能是的疾病根据甲状旁腺肿瘤的特征进行区分。拟议工作的基础是由我们小组在两项研究中发表。我们的第一个研究表征了甲状旁腺的孤立甲状旁腺细胞 pHPT中的腺瘤，表明这些肿瘤的显着比例（40％，5/14）由多个克隆（即多克隆）。我们对119名患者的第二次研究证实，最多46％的PHPT患者具有多克隆肿瘤，肿瘤的克隆状态（即单克隆与多克隆）预测MGD 这在手术中通常会错过。这些发现支持甲状旁腺肿瘤克隆状态反映的前提具有不同病因，疾病表现和治疗结果的不同类型的PHPT。我们现在建议为了表征具有这些肿瘤类型的PHPT患者，并检验了新的假设，即PHPT可以更好地是通过根据基础状态对疾病进行分类来理解和治疗甲状旁腺肿瘤。