Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683, Nicosia, Cyprus.
Division of Pediatric Endocrinology, Paedi Center for Specialized Pediatrics, Nicosia, Cyprus.
J Endocrinol Invest. 2018 Oct;41(10):1149-1157. doi: 10.1007/s40618-018-0841-0. Epub 2018 Feb 2.
Multiple endocrine neoplasia type 2 (MEN2) affects patients with RET proto-oncogene mutations. This cohort study refers to patients who were diagnosed with familial medullary thyroid carcinoma (MTC) and underwent RET genetic testing in Cyprus between years 2002 and 2017.
Forty patients underwent RET testing by Sanger sequencing of exons 10-11 and 13-16. Genotyping with STR genetic markers flanking the RET gene along with Y-chromosome genotyping and haplogroup assignment was also performed.
RET mutations were identified in 40 patients from 11 apparently unrelated Cypriot families and two non-familial sporadic cases. Nine probands (69.2%) were heterozygous for p.Cys618Arg, one (7.7%) for p.Cys634Phe, one (7.7%) for the somatic delE632-L633 and two (15.4%) for p.Met918Thr mutations. The mean age at MTC diagnosis of patients carrying p.Cys618Arg was 36.8 ± 14.2 years. The age of pheo diagnosis ranged from 26 to 43 years and appeared simultaneously with MTC in 5/36 (13.9%) cases. The high frequency of the p.Cys618Arg mutation suggested a possible ancestral mutational event. Haplotype analysis was performed in families with and without p.Cys618Arg. Six microsatellite markers covering the RET gene and neighboring regions identified one core haplotype associated with all patients carrying p.Cys618Arg mutation.
The mutation p.Cys618Arg is by far the most prevalent mutation in Cyprus followed by other reported mutations of variable clinical significance. The provided molecular evidence speculates p.Cys618Arg mutation as an ancestral mutation that has spread in Cyprus due to a possible founder effect.
多发性内分泌肿瘤 2 型（MEN2）影响 RET 原癌基因突变的患者。本队列研究涉及 2002 年至 2017 年间在塞浦路斯被诊断为家族性甲状腺髓样癌（MTC）并接受 RET 基因检测的患者。
40 名患者接受了 RET 检测，通过 Sanger 测序外显子 10-11 和 13-16。还进行了侧翼 RET 基因的 STR 遗传标记基因分型以及 Y 染色体基因分型和单倍型群分配。
在 11 个明显无关的塞浦路斯家族和 2 个非家族性散发性病例中发现了 40 名患者的 RET 突变。9 名先证者（69.2%）为杂合子 p.Cys618Arg，1 名（7.7%）为 p.Cys634Phe，1 名（7.7%）为体细胞 delE632-L633，2 名（15.4%）为 p.Met918Thr 突变。携带 p.Cys618Arg 的患者 MTC 诊断的平均年龄为 36.8±14.2 岁。pheo 的诊断年龄从 26 岁到 43 岁不等，在 5/36（13.9%）例中与 MTC 同时出现。p.Cys618Arg 突变的高频率表明可能存在祖先突变事件。对携带和不携带 p.Cys618Arg 的家族进行了单倍型分析。覆盖 RET 基因和邻近区域的 6 个微卫星标记确定了一个与所有携带 p.Cys618Arg 突变的患者相关的核心单倍型。
p.Cys618Arg 突变是迄今为止在塞浦路斯最常见的突变，其次是其他具有不同临床意义的报道突变。提供的分子证据推测 p.Cys618Arg 突变是一种祖先突变，由于可能的创始人效应，该突变已在塞浦路斯传播。
