Mutational analysis of the RET proto-oncogene in 71 Japanese patients with medullary thyroid carcinoma
Mutational analysis of the RET proto-oncogene in 71 Japanese patients with medullary thyroid carcinoma
复制标题
71例日本甲状腺髓样癌患者RET原癌基因突变分析
DOI：
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发表时间：
1998
影响因子：
3.5
通讯作者：
Yusuke Nakamura
中科院分区：
文献类型：
--
作者：
S. Shirahama;K. Ogura;H. Takami;Kunihiko Ito;T. Tohsen;A. Miyauchi;Yusuke Nakamura
摘要多发性内分泌肿瘤2A型和2B型（MEN 2A和MEN 2B）以及家族性甲状腺髓样癌（FMTC）是由RET原癌基因的生殖系突变引起的。为了研究日本患者的RET突变谱，我们在71例甲状腺癌患者中筛选了RET基因。该小组包括44个携带FMTC或MEN 2的家庭，22个散发性甲状腺髓样癌（MTCs）和5个没有家族信息的MTCs的代表。在34名MEN 2A患者中的33名和6名FMTC患者中的5名中发现了编码RET蛋白胞外结构域中三个特定半胱氨酸残基之一的核苷酸序列突变。密码子918处的突变，导致蛋白质的酪氨酸激酶结构域中的苏氨酸取代甲硫氨酸，在所有4名MEN 2B患者和22名散发性MTCs患者中的2名的生殖系DNA中发现;密码子918在来自其他3名散发性病例的肿瘤DNA中发生体细胞突变。在1例FMTC、1例散发性MTC患者和1例无家族信息的患者中检测到密码子768的种系突变，GAG至GAC（Glu至Asp）。两个体细胞突变，在密码子631的天冬氨酸到甘氨酸的取代和在密码子634的半胱氨酸到精氨酸的取代，以前没有报道。在22例散发病例中发现的5个种系突变中，有4个被确认为从头突变，因为在每例病例中，父母都不携带突变。由于近四分之一的散发性MTC患者携带生殖系突变，并且预计他们的子女中有50%会发展为MTC和其他内分泌肿瘤，因此这些结果表明对任何MTC患者的家庭成员进行仔细临床监测的重要性。
AbstractMultiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) and familial medullary thyroid carcinomas (FMTC) are caused by germline mutations in the RET proto-oncogene. To investigate the spectrum of RET mutations among Japanese patients, we screened the RET gene in 71 patients with thyroid carcinomas. The panel included representatives of 44 families carrying FMTC or MEN2, 22 sporadic medullary thyroid carcinomas (MTCs), and five MTCs without familial information. Mutations in nucleotide sequences encoding one of three specific cysteine residues in the extracellular domain of the RET protein were found in 33 of the 34 MEN2A patients and in five of the six FMTC patients examined. A mutation at codon 918, causing the substitution of threonine for methionine in the tyrosine kinase domain of the protein, was found in germline DNAs of all four patients with MEN2B and in two of the 22 patients with sporadic MTCs; codon 918 was mutated somatically in tumor DNAs from three other sporadic cases. Germline mutations of codon 768, GAG to GAC (Glu to Asp), were detected in one FMTC, in one patient with sporadic MTC, and in one of the patients without familial information. Two somatic mutations, an Asp to Gly substitution at codon 631 and a Cys to Arg substitution at codon 634, had not been reported previously. Of five germline mutations found among the 22 sporadic cases, four were confirmed as de novo mutations since in each case neither parent carried the mutation. As nearly one-fourth of the patients with sporadic MTCs carried germline mutations and 50% of their children are expected to develop MTC and other endocrine tumors, these results indicated the importance of careful clinical surveillance of family members of any patient with MTC.
DOI：
10.1073/pnas.91.4.1579
发表时间：
1994-02-15
影响因子：
11.1
作者：
CARLSON, KM;DOU, SS;DONISKELLER, H
通讯作者：
DONISKELLER, H
影响因子：
3.5
作者：
DONISKELLER, H;DOU, SS;WELLS, SA
通讯作者：
WELLS, SA