对甲状腺髓样癌患者 RET 原癌基因关键外显子的分子分析：对伊朗人群的综合研究。

Molecular analysis of the RET proto-oncogene key exons in patients with medullary thyroid carcinoma: a comprehensive study of the Iranian population.

机构信息

Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.

出版信息

Thyroid. 2011 Apr;21(4):373-82. doi: 10.1089/thy.2010.0267.

DOI:10.1089/thy.2010.0267

PMID:21309721

Abstract

BACKGROUND

Germ-line mutations of RET proto-oncogene are the known cause of hereditary medullary thyroid carcinoma (MTC), which account for approximately 25% of all MTC cases and occur as multiple endocrine neoplasia type 2 syndromes. Here, we present the first comprehensive genetic screening and analysis of MTC among Iranian families.

METHODS

A total of 55 patients with MTC (male to female ratio=1:1.6; average age of disease onset = 33 ± 13 years) from 53 independent families participated in this study. All of the patients had undergone total thyroidectomy between 1999 and 2006, and 51 of them were clinically characterized as apparently sporadic cases. Genomic DNA samples were obtained and following highly-specific polymerase chain reaction amplification of the 6 RET key exons (10, 11, 13, 14, 15, and 16) were subjected to direct DNA sequencing without a requirement for a purification step.

RESULTS

Sequence analysis revealed that 9 (17.6%) of the apparently sporadic cases (from 8 kindreds) carried an RET germ-line mutation. Of the seven different mutations identified among all of the families studied, five were in the cysteine codons, with Cys634Arg having the highest prevalence (45.5%) among the afflicted families. Mutation carriers have an earlier age of onset (21 ± 6) versus the sporadic cases (37 ± 12).

CONCLUSIONS

This is the first comprehensive genetic screening and analysis of MTC among Iranian families. The results further confirm the need and advantages of DNA sequencing for identification of hereditary MTC cases. There does not seem to be a meaningful correlation between single nucleotide polymorphism patterns and the average age of disease onset. Geographical distribution of the sporadic cases, however, shows a significant concentration toward the Northern regions of the country, noticeably the provinces situated directly to the south of the Caspian Sea.

摘要

背景

RET 原癌基因的种系突变是遗传性甲状腺髓样癌（MTC）的已知病因，约占所有 MTC 病例的 25%，并作为多发性内分泌肿瘤 2 型综合征发生。在这里，我们首次对伊朗家族的 MTC 进行了全面的遗传筛查和分析。

方法

共有 55 名 MTC 患者（男女比例为 1:1.6；疾病发病的平均年龄=33±13 岁）参加了这项研究，他们来自 53 个独立的家族。所有患者均于 1999 年至 2006 年间接受了全甲状腺切除术，其中 51 例临床特征为明显散发性病例。获得基因组 DNA 样本，对 6 个 RET 关键外显子（10、11、13、14、15 和 16）进行高度特异性聚合酶链反应扩增，无需纯化步骤，直接进行 DNA 测序。

结果

序列分析显示，9 例（8 个家族）明显散发性病例（来自 8 个家族）携带 RET 种系突变。在所研究的所有家族中，共发现了 7 种不同的突变，其中 5 种位于半胱氨酸密码子，受影响家族中 Cys634Arg 的患病率最高（45.5%）。突变携带者的发病年龄较早（21±6），而散发性病例为（37±12）。