Germline and somatic mutations in cyclin-dependent kinase inhibitor genes CDKN1A, CDKN2B, and CDKN2C in sporadic parathyroid adenomas.
Germline and somatic mutations in cyclin-dependent kinase inhibitor genes CDKN1A, CDKN2B, and CDKN2C in sporadic parathyroid adenomas.
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DOI：
10.1007/s12672-013-0147-9
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发表时间：
2013-10
影响因子：
3
通讯作者：
Arnold A
中科院分区：
文献类型：
--
作者：
Costa-Guda J;Soong CP;Parekh VI;Agarwal SK;Arnold A
散发性甲状旁腺腺瘤的分子发病机制尚不完全清楚。通过将细胞周期蛋白 D1 识别为甲状旁腺癌基因，以及在多发性内分泌肿瘤 1 型患者中鉴定出 CDKI 基因的罕见种系突变，提出了细胞周期蛋白依赖性激酶抑制剂 (CDKI) 基因的可能作用；在啮齿动物中，Cdknlb 突变导致甲状旁腺肿瘤；随后通过鉴定散发性人甲状旁腺腺瘤中罕见的易感种系序列变异和编码 p27kip1 的 CDKN1B 体细胞突变。因此，我们试图确定分别编码 p21、p57、p14ARF/p16、p15、p18 和 p19 的其他 6 个 CDKI 基因 CDKN1A、CDKN1C、CDKN2A、CDKN2B、CDKN2C 和 CDKN2D 的突变/变异是否有助于典型甲状旁腺腺瘤的发生。在一系列 85 个散发性甲状旁腺腺瘤中，直接 DNA 测序发现了 5 个腺瘤 (6%) 的改变：其中两个包含 CDKN1A 的明显杂合性变化，一个是种系，一个是未确定的种系状态；其中一个存在 CDKN2B 种系改变，并伴有肿瘤中正常等位基因的丢失 (LOH)；其中两种具有 CDKN2C 变异，一种是体细胞变异，另一种是生殖细胞系带有 LOH。三种突变蛋白的异常现象在体外很容易得到证实。因此，CDKN1A、CDKN2B和CDKN2C的种系突变/罕见变异可能导致常见散发性甲状旁腺腺瘤的重要亚组的发展，而CDKN2C的体细胞突变进一步表明CDKI改变在赋予甲状旁腺细胞选择性生长优势方面的直接作用，为多种CDKI在人类肿瘤中发挥主要作用的概念提供了新的支持。
The molecular pathogenesis of sporadic parathyroid adenomas is incompletely understood. The possible role of cyclin-dependent kinase inhibitor (CDKI) genes was raised by recognition of cyclin D1 as a parathyroid oncogene, identification of rare germline mutations in CDKI genes in patients with multiple endocrine neoplasia type 1; that in rodents, mutation in Cdknlb caused parathyroid tumors; and subsequently through identification of rare predisposing germline sequence variants and somatic mutation of CDKN1B, encoding p27kip1, in sporadic human parathyroid adenoma. We therefore sought to determine whether mutations/variants in the other six CDKI genes CDKN1A, CDKN1C, CDKN2A, CDKN2B, CDKN2C, and CDKN2D, encoding p21, p57, p14ARF/p16, p15, p18, and p19, respectively, contribute to the development of typical parathyroid adenomas. In a series of 85 sporadic parathyroid adenomas, direct DNA sequencing identified alterations in five adenomas (6 %): Two contained distinct heterozygous changes in CDKN1A, one germline and one of undetermined germline status; one had a CDKN2B germline alteration, accompanied by loss of the normal allele in the tumor (LOH); two had variants of CDKN2C, one somatic and one germline with LOH. Abnormalities of three of the mutant proteins were readily demonstrable in vitro. Thus, germline mutations/rare variants in CDKN1A, CDKN2B, and CDKN2C likely contribute to the development of a significant subgroup of common sporadic parathyroid adenomas, and somatic mutation in CDKN2C further suggests a direct role for CDKI alteration in conferring a selective growth advantage to parathyroid cells, providing novel support for the concept that multiple CDKIs can play primary roles in human neoplasia.
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影响因子：
5.8
作者：
Costa-Guda, Jessica;Marinoni, Ilaria;Arnold, Andrew
通讯作者：
Arnold, Andrew
影响因子：
5.8
作者：
Georgitsi, Marianthi;Raitila, Anniina;Aaltonen, Lauri A.
通讯作者：
Aaltonen, Lauri A.
影响因子：
5.3
作者：
Franklin, DS;Godfrey, VI;Xiong, Y
通讯作者：
Xiong, Y
DOI：
10.1126/science.1217283
发表时间：
2012-05-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Keinan A;Clark AG
通讯作者：
Clark AG
影响因子：
14.9
作者：
Forbes SA;Bindal N;Bamford S;Cole C;Kok CY;Beare D;Jia M;Shepherd R;Leung K;Menzies A;Teague JW;Campbell PJ;Stratton MR;Futreal PA
通讯作者：
Futreal PA