Parathyroid Tumor Clonal Status as a Biomarker in Primary Hyperparathyroidism

项目摘要/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， 可能导致骨质丢失和骨折、心血管疾病、肾结石和神经认知障碍(1)。 PHPT是第三种最常见的内分泌疾病，年发病率在34/10万到120/10万之间 人-年龄在上升，特别是在绝经后的妇女中。自从第一次描述PHPT和 PHPT在20世纪20年代的外科治疗中，其发病机制一直被简单地视为甲状旁腺肿瘤。 从单个转化的克隆(即单克隆性)发育而来，该克隆扩张并分泌过量的甲状旁腺素，导致 高钙血症与PHPT的症状和后遗症。这一范式预测，PHPT是从一个 单发肿瘤(单腺病，SGD)和甲状旁腺切除术(PTX)切除该单发肿瘤 这种疾病。尽管在概念上很吸引人，但这种简单的方法并不能解释几个观察结果 包括：1.多达20%的PHPT患者存在多发性腺病(MGD)；2.观察 PTX后高达30%的患者甲状旁腺素持续升高；3.症状和后遗症 PTX后的PHPT通常没有改善；以及4.高达15%的患者出现复发的PHPT (2)。这些观察，结合我们实验室描述的分子异质性的数据 甲状旁腺肿瘤使我们怀疑PHPT可能代表几种不同的疾病， 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。我们的第一项研究描述了甲状旁腺细胞的分离特征。 PHPT中的腺瘤，并显示很大比例(40%，5/14)的这些肿瘤包括 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 有多克隆性肿瘤，并且肿瘤的克隆状态(即单克隆性与多克隆性)预示着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 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 描述这些肿瘤类型的PHPT患者的特征，并检验PHPT可以更好地 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。

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.