Somatic Mutation and Germline Sequence Abnormalities in CDKN1B, Encoding p27Kip1, in Sporadic Parathyroid Adenomas
Somatic Mutation and Germline Sequence Abnormalities in CDKN1B, Encoding p27Kip1, in Sporadic Parathyroid Adenomas
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DOI：
10.1210/jc.2010-1338
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发表时间：
2011-04-01
影响因子：
5.8
通讯作者：
Arnold, Andrew
中科院分区：
文献类型：
--
作者：
Costa-Guda, Jessica;Marinoni, Ilaria;Arnold, Andrew
背景：典型的非家族性（散发性）甲状旁腺腺瘤是一种常见的内分泌肿瘤，没有易感的种系DNA变异，只有少数克隆改变的基因驱动甲状旁腺瘤的发生。编码周期蛋白依赖性激酶抑制剂p27（kip1）的CDKN1B，最近被认为与大鼠的多发性内分泌肿瘤表型有关，很少与人类家族性MEN1（多发性内分泌肿瘤1型）样疾病有关。目的：我们试图确定CDKN1B突变是否可能促进常见散发性甲状旁腺腺瘤的发展。患者和设计：我们对86例典型散发性原发性甲状旁腺功能亢进患者的甲状旁腺瘤的CDKN1B基因进行了测序。确定的改变被分类为体细胞或种系，并检查其功能后果。结果：在4例甲状旁腺瘤中发现CDKN1B序列异常。在一个肿瘤中检测到CDKN1B的获得性双等位基因改变，这是由体细胞突变和杂合性丧失引起的。尽管有非家族性表现，但在两例病例中记录了种系起源。在正常个体的240个CDKN1B等位基因中没有发现任何观察到的改变，在之前报道的2000多个等位基因中也没有发现。大多数鉴定的变异降低了p27（kip1）蛋白水平或改变了体外稳定性。结论：在典型的散发性甲状旁腺腺瘤中，CDKN1B突变可以是体细胞的，也可以是克隆的，这表明在甲状旁腺肿瘤发生中具有直接的选择优势。此外，在散发性患者中发现的种系CDKN1B变异提供了CDKN1B在典型甲状旁腺瘤发展中作为易感基因的证据。[J] .中华内分泌杂志，2011,31(5):571 - 571。
Context: Typical nonfamilial (sporadic) parathyroid adenomas are common endocrine tumors for which no predisposing germline DNA variants and only a few clonally altered genes that drive parathyroid tumorigenesis have been identified. CDKN1B, encoding cyclin-dependent kinase inhibitor p27(kip1), has recently been implicated in a multiple endocrine tumor phenotype in rats and, rarely, in a human familial MEN1 (multiple endocrine neoplasia type 1)-like disorder.Objective: We sought to determine whether mutation of CDKN1B might contribute to the development of common sporadic parathyroid adenomas.Patients and Design: We sequenced the CDKN1B gene in 86 parathyroid adenomas from patients with typical, sporadic presentations of primary hyperparathyroidism. Identified alterations were categorized as somatic or germline, and their functional consequences were examined.Results: CDKN1B sequence abnormalities were identified in four parathyroid adenomas. Acquired biallelic alteration of CDKN1B, resulting from somatic mutation plus loss of heterozygosity, was detected in one tumor. Germline origin was documented in two cases despite nonfamilial presentations. None of the observed alterations were found in 240 CDKN1B alleles from normal individuals, nor among more than 2,000 previously reported alleles. Most identified variants reduced p27(kip1) protein levels or altered in vitro stability.Conclusions: In typical, sporadic parathyroid adenomas, CDKN1B mutation can be somatic and clonal, indicative of a directly conferred selective advantage in parathyroid tumorigenesis. Additionally, the identification of germline CDKN1B variants in patients with sporadic presentations provides evidence for CDKN1B as a susceptibility gene in the development of typical parathyroid adenomas. (J Clin Endocrinol Metab 96: E701-E706, 2011)