Howell V M, Haven C J, Kahnoski K, Khoo S K, Petillo D, Chen J, Fleuren G J, Robinson B G, Delbridge L W, Philips J, Nelson A E, Krause U, Hammje K, Dralle H, Hoang-Vu C, Gimm O, Marsh D J, Morreau H, Teh B T
Laboratory of Cancer Genetics, Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, Michigan 49503, USA.
J Med Genet. 2003 Sep;40(9):657-63. doi: 10.1136/jmg.40.9.657.
Hyperparathyroidism is a common endocrinopathy characterised by the formation of parathyroid tumours. In this study, we determine the role of the recently identified gene, HRPT2, in parathyroid tumorigenesis.
Mutation analysis of HRPT2 was undertaken in 60 parathyroid tumours: five HPT-JT, three FIHP, three MEN 1, one MEN 2A, 25 sporadic adenomas, 17 hyperplastic glands, two lithium associated tumours, and four sporadic carcinomas. Loss of heterozygosity at 1q24-32 was performed on a subset of these tumours.
HRPT2 somatic mutations were detected in four of four sporadic parathyroid carcinoma samples, and germline mutations were found in five of five HPT-JT parathyroid tumours (two families) and two parathyroid tumours from one FIHP family. One HPT-JT tumour with germline mutation also harboured a somatic mutation. In total, seven novel and one previously reported mutation were identified. "Two-hits" (double mutations or one mutation and loss of heterozygosity at 1q24-32) affecting HRPT2 were found in two sporadic carcinomas, two HPT-JT-related and two FIHP related tumours.
The results in this study support the role of HRPT2 as a tumour suppressor gene in sporadic parathyroid carcinoma, and provide further evidence for HRPT2 as the causative gene in HPT-JT, and a subset of FIHP. In light of the strong association between mutations of HRPT2 and sporadic parathyroid carcinoma demonstrated in this study, it is hypothesised that HRPT2 mutation is an early event that may lead to parathyroid malignancy and suggest intragenic mutation of HRPT2 as a marker of malignant potential in both familial and sporadic parathyroid tumours.
甲状旁腺功能亢进是一种常见的内分泌疾病，其特征是甲状旁腺肿瘤的形成。在本研究中，我们确定了最近鉴定出的基因HRPT2在甲状旁腺肿瘤发生中的作用。
对60例甲状旁腺肿瘤进行HRPT2突变分析：5例遗传性甲状旁腺功能亢进-颌骨肿瘤综合征（HPT-JT）、3例家族性孤立性甲状旁腺功能亢进（FIHP）、3例多发性内分泌腺瘤1型（MEN 1）、1例多发性内分泌腺瘤2A型（MEN 2A）、25例散发性腺瘤、17例增生性腺、2例锂相关性肿瘤和4例散发性癌。对其中一部分肿瘤进行了1q24-32杂合性缺失检测。
在4例散发性甲状旁腺癌样本中检测到HRPT2体细胞突变，在5例HPT-JT甲状旁腺肿瘤（2个家系）和1个FIHP家系的2例甲状旁腺肿瘤中发现了胚系突变。1例有胚系突变的HPT-JT肿瘤也存在体细胞突变。总共鉴定出7个新突变和1个先前报道的突变。在2例散发性癌、2例与HPT-JT相关和2例与FIHP相关的肿瘤中发现了影响HRPT2的“双打击”（双重突变或一个突变以及1q24-32杂合性缺失）。
本研究结果支持HRPT2作为散发性甲状旁腺癌中的肿瘤抑制基因的作用，并为HRPT2作为HPT-JT和一部分FIHP的致病基因提供了进一步证据。鉴于本研究中显示的HRPT2突变与散发性甲状旁腺癌之间的强关联，推测HRPT2突变是可能导致甲状旁腺恶性肿瘤的早期事件，并提示HRPT2基因内突变作为家族性和散发性甲状旁腺肿瘤恶性潜能的标志物。
