Parathyroid Tumor Clonal Status as a Biomarker in Primary Hyperparathyroidism

项目总结/摘要 原发性甲状旁腺功能亢进（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是第三常见的内分泌疾病，年发病率为每10万人34至120人 人-年，这是上升，特别是在绝经后妇女。自从第一次描述PHPT和 在20世纪20年代的外科治疗中，PHPT的发病机制被简单地认为是：甲状旁腺肿瘤 从单个转化的克隆（即单克隆）发展而来，其扩增并分泌过量的PTH， 高钙血症及PHPT的症状和后遗症。这种范式预测PHPT是从一个 单个肿瘤（单腺体疾病，SGD）和通过甲状旁腺切除术（PTX）切除该单个肿瘤治疗 这种疾病虽然概念上有吸引力，但这种简单的方法无法解释几个观察结果 包括：1.在高达20%的PHPT患者中存在多腺体疾病（MGD）; 2.观察 在高达30%的患者中，PTX后PTH仍然升高; 3.症状和后遗症 的PHPT通常在PTX后不改善;和4.高达15%的患者发生复发性PHPT （二）、这些观察结果，结合我们实验室的数据，描述了 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 由我们的团队在两项研究中发表。我们的第一项研究的特点是分离的甲状旁腺细胞从甲状旁腺 PHPT中的腺瘤，并显示这些肿瘤的显著比例（40%，5/14）由以下组成： 多克隆（即多克隆）。我们对119名患者的第二项研究证实，高达46%的PHPT患者 患有多克隆肿瘤，肿瘤的克隆状态（即单克隆与多克隆）可预测MGD 这在手术中经常被忽略。这些发现支持了甲状旁腺肿瘤克隆状态反映了 不同类型的PHPT具有不同的病因、疾病表现和治疗结果。我们现建议 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 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.