甲状旁腺功能亢进-颌骨肿瘤综合征的表型分析及分子机制
Phenotypic Profiling and Molecular Mechanisms in Hyperparathyroidism-jaw Tumor Syndrome.
作者信息
Tora Rana, Welch James, Sun Jian, Agarwal Sunita K, Bell Debra A, Merino Maria, Weinstein Lee S, Simonds William F, Jha Smita
机构信息
Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
NIAID Collaborative Bioinformatics Resource (NCBR), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
出版信息
J Clin Endocrinol Metab. 2023 Nov 17;108(12):3165-3177. doi: 10.1210/clinem/dgad368.
CONTEXT
Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism caused by germline inactivating mutations in CDC73 encoding parafibromin and is associated with an increased risk of parathyroid cancer. There is little evidence to guide the management of patients with the disease.
OBJECTIVE
(1) Characterize the natural history of HPT-JT, (2) correlate genotype and histology of parathyroid tumors with parafibromin immunostaining, (3) understand molecular changes downstream to CDC73 loss.
DESIGN
Retrospective study of patients with HPT-JT syndrome (genetically confirmed or affected first-degree relatives). Independent review of uterine tumor from 2 patients and staining for parafibromin on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas) was performed. RNA-sequencing was performed in 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas with wild-type CDC73).
RESULTS
We identified 68 patients from 29 kindreds with HPT-JT with median age at last follow-up of 39 [interquartile range, 29-53] years. A total of 55/68 (81%) developed primary hyperparathyroidism; 17/55 (31%) had parathyroid carcinoma. Twelve of 32 (38%) females developed uterine tumors. Of the 11 patients who had surgical resection for uterine tumors, 12/24 (50%) tumors were rare mixed epithelial mesenchymal polypoid lesions. Four of 68 patients (6%) developed solid kidney tumors; 3/4 had a CDC73 variant at p.M1 residue. Parafibromin staining of parathyroid tumors did not correlate with tumor histology or genotype. RNA-sequencing showed a significant association of HPT-JT-related parathyroid tumors with transmembrane receptor protein tyrosine kinase signaling pathway, mesodermal commitment pathway, and cell-cell adhesion.
CONCLUSIONS
Multiple, recurrent atypical adenomyomatous uterine polyps appear to be enriched in women with HPT-JT and appear characteristic of the disease. Patients with CDC73 variants at p.M1 residue appear predisposed to kidney tumors.
CLINICAL TRIAL NUMBER
NCT04969926.
背景
甲状旁腺功能亢进-颌骨肿瘤（HPT-JT）综合征是一种遗传性原发性甲状旁腺功能亢进症，由编码 parafibromin 的 CDC73 基因种系失活突变引起，且与甲状旁腺癌风险增加相关。几乎没有证据可指导该病患者的管理。
目的
（1）描述 HPT-JT 的自然病史，（2）将甲状旁腺肿瘤的基因型和组织学与 parafibromin 免疫染色相关联，（3）了解 CDC73 缺失下游的分子变化。
设计
对 HPT-JT 综合征患者（基因确诊或受影响的一级亲属）进行回顾性研究。对 2 例患者的子宫肿瘤进行独立评估，并对 19 例患者（13 例腺瘤，6 例癌）的甲状旁腺肿瘤进行 parafibromin 染色。对 21 个甲状旁腺样本（8 个与 HPT-JT 相关的腺瘤，6 个与 HPT-JT 相关的癌，以及 7 个具有野生型 CDC73 的散发性癌）进行 RNA 测序。
结果
我们从 29 个家族中确定了 68 例 HPT-JT 患者，末次随访时的中位年龄为 39[四分位间距，29 - 53]岁。共有 55/68（81%）发生原发性甲状旁腺功能亢进；17/55（31%）患有甲状旁腺癌。32 名女性中有 12 名（38%）发生子宫肿瘤。在 11 例接受子宫肿瘤手术切除的患者中，12/24（50%）的肿瘤为罕见的混合上皮间质息肉样病变。有 4 例 68 例患者（6%）发生实性肾肿瘤；其中 3/4 在 p.M1 残基处有 CDC73 变异。甲状旁腺肿瘤的 parafibromin 染色与肿瘤组织学或基因型无关。RNA 测序显示，与 HPT-JT 相关的甲状旁腺肿瘤与跨膜受体蛋白酪氨酸激酶信号通路、中胚层定向通路和细胞间黏附存在显著关联。
结论
多发性、复发性非典型腺肌性子宫息肉在 HPT-JT 女性中似乎更为常见，且似乎是该疾病的特征。在 p.M1 残基处有 CDC73 变异的患者似乎易患肾肿瘤。
临床试验编号
NCT04969926。
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