Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma
Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma
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DOI：
10.1056/nejmoa031237
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发表时间：
2003-10-30
影响因子：
158.5
通讯作者：
Arnold, A
中科院分区：
文献类型：
--
作者：
Shattuck, TM;Välimäki, S;Arnold, A
背景：我们在散发性甲状旁腺癌中寻找编码副纤维蛋白的HRPT2基因突变，因为在家族性甲状旁腺功能亢进-甲状旁腺功能亢进-颌肿瘤（HPT-JT）综合征中发现了种系失活HRPT2突变，这种突变会增加甲状旁腺癌的风险。方法：我们直接对15例21例甲状旁腺癌患者的HRPT2基因的全编码和侧接连接区进行测序，这些患者在发病时没有已知的原发性甲状旁腺功能亢进家族史或HPT-JT综合征。我们还试图确认所鉴定的突变的体细胞性质，并测试了肿瘤特异性的HRPT2杂合性缺失。结果：15名患者中有10名甲状旁腺癌患者有HRPT2突变，所有这些突变都被预测会使编码的副纤白蛋白失活。在5例患者的肿瘤中发现了两种不同的HRPT2突变，并且在一个肿瘤中发现了由于突变和杂合性丧失而导致的双等位基因失活。至少有一个HRPT2突变在6例患者的癌中被证明是体细胞的。出乎意料的是，3例甲状旁腺癌患者的HRPT2突变被鉴定为种系突变。结论：散发性甲状旁腺癌经常有HRPT2突变，这可能具有重要的发病意义。某些明显散发的甲状旁腺癌患者携带HRPT2的种系突变，可能具有HPT-JT综合征或表型变异。
BACKGROUND:We looked for mutations of the HRPT2 gene, which encodes the parafibromin protein, in sporadic parathyroid carcinoma because germ-line inactivating HRPT2 mutations have been found in a type of familial hyperparathyroidism -- hyperparathyroidism-jaw tumor (HPT-JT) syndrome -- that carries an increased risk of parathyroid cancer.METHODS:We directly sequenced the full coding and flanking splice-junctional regions of the HRPT2 gene in 21 parathyroid carcinomas from 15 patients who had no known family history of primary hyperparathyroidism or the HPT-JT syndrome at presentation. We also sought to confirm the somatic nature of the identified mutations and tested the carcinomas for tumor-specific loss of heterozygosity at HRPT2.RESULTS:Parathyroid carcinomas from 10 of the 15 patients had HRPT2 mutations, all of which were predicted to inactivate the encoded parafibromin protein. Two distinct HRPT2 mutations were found in tumors from five patients, and biallelic inactivation as a result of a mutation and loss of heterozygosity was found in one tumor. At least one HRPT2 mutation was demonstrably somatic in carcinomas from six patients. Unexpectedly, HRPT2 mutations in the parathyroid carcinomas of three patients were identified as germ-line mutations.CONCLUSIONS:Sporadic parathyroid carcinomas frequently have HRPT2 mutations that are likely to be of pathogenetic importance. Certain patients with apparently sporadic parathyroid carcinoma carry germ-line mutations in HRPT2 and may have the HPT-JT syndrome or a phenotypic variant.