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: 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
• 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

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.

项目概要/摘要 原发性甲状旁腺功能亢进症 (PHPT) 是门诊患者高钙血症的最常见原因， 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 是第三大常见内分泌疾病，年发病率为每 100,000 人 34 至 120 例 人年正在上升，尤其是绝经后妇女。自从首次描述 PHPT 以来 在 20 年代的外科治疗中，PHPT 的发病机制被简单地视为：甲状旁腺肿瘤 由单个转化克隆（即单克隆）发展而来，可扩展并分泌过多的 PTH，导致 高钙血症以及 PHPT 的症状和后遗症。这个范式预测 PHPT 从 单一肿瘤（单一腺体疾病，SGD）并且通过甲状旁腺切除术（PTX）切除该单一肿瘤可以治愈 这种疾病。尽管在概念上很有吸引力，但这种简单的方法并不能解释一些观察结果 包括： 1. 高达 20% 的 PHPT 患者存在多发性腺病 (MGD)； 2.观察 高达 30% 的患者在 PTX 后 PTH 仍然升高； 3.现实症状及后遗症 PHPT 通常不会改善后续的 PTX； 4. 高达 15% 的患者出现复发性 PHPT （2）。这些观察结果与我们实验室描述分子异质性的数据相结合 甲状旁腺肿瘤使我们怀疑 PHPT 可能代表几种不同的疾病，这些疾病可以 根据甲状旁腺肿瘤的特征进行鉴别。拟议工作的基础是 我们小组在两项研究中发表。我们的第一项研究描述了从甲状旁腺中分离出的甲状旁腺细胞 PHPT 中的腺瘤，并表明这些肿瘤的很大一部分（40%，5/14）由 多个克隆（即多克隆）。我们对 119 名患者进行的第二项研究证实，高达 46% 的 PHPT 患者 患有多克隆肿瘤，并且肿瘤的克隆状态（即单克隆与多克隆）可预测 MGD 这在手术中经常被遗漏。这些发现支持甲状旁腺肿瘤克隆状态反映的前提 不同类型的 PHPT 具有不同的病因、疾病表现和治疗结果。我们现在提议 描述患有这些肿瘤类型的 PHPT 患者的特征，并测试 PHPT 可以更好地治疗这一新假设 通过根据潜在的克隆状态对疾病进行分类来理解和治疗 甲状旁腺肿瘤。

项目成果

Digital spatial profiling of human parathyroid tumors reveals cellular and molecular alterations linked to vitamin D deficiency.

人类甲状旁腺肿瘤的数字空间分析揭示了与维生素 D 缺乏相关的细胞和分子变化。

• 发表时间: 2023-03
• 作者: Tu, Chia;Chang, Wenhan;Sosa, Julie A;Koh, James
• 通讯作者: Koh, James

Ex Vivo Intact Tissue Analysis Reveals Alternative Calcium-sensing Behaviors in Parathyroid Adenomas.

离体完整组织分析揭示了甲状旁腺腺瘤中的替代钙感应行为。

• 发表时间: 2021-10-21
• 作者: Koh, James;Zhang, Run;Roman, Sanziana;Duh, Quan;Gosnell, Jessica;Shen, Wen;Suh, Insoo;Sosa, Julie A
• 通讯作者: Sosa, Julie A