Analysis of RET polymorphisms and haplotypes in the context of sporadic medullary thyroid carcinoma.
Analysis of RET polymorphisms and haplotypes in the context of sporadic medullary thyroid carcinoma.
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散发性甲状腺髓样癌背景下 RET 多态性和单倍型分析。
DOI：
10.1089/thy.2006.16.411
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Borrego,Salud
中科院分区：
文献类型：
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作者：
Fernandez,RaquelM;Pecina,Ana;Antinolo,Guillermo;Navarro,Elena;Borrego,Salud
背景人们对散发性甲状腺髓样癌（sMTC）的病因知之甚少。虽然 RET 原癌基因的种系功能获得性突变会导致遗传性 MTC，但导致散发形式的分子机制仍不清楚。我们小组有证据表明，sMTC 存在与 RET 变体 S836S/IVS1-126G>T 连锁不平衡的低外显率易感位点，并且可能在这两种变体的 5' 端。在这项研究中，我们试图确定这样的基因座。另一方面，由于先前报道过 sMTC 患者中 G691S/S904S 变异的比例过高，因此我们试图确定这种关联是否存在于我们的系列中。设计我们进行了一项病例对照研究，分析了基因 5' 区域中的广泛 RET 变异以及 G691S/S904S 变异。还分析了单倍型分布。该研究总共纳入了 58 名 sMTC 患者。此外，还评估了 100 个未选择的、不相关的种族、年龄和性别匹配的正常对照。 主要结果虽然在我们当前的 sMTC 系列中仍然存在 IVS1-126G>T 的过度表达，从而支持了我们之前的假设，但在该位置上游测试的变异分布方面，病例和对照之间没有获得差异。另一方面，G691S/S904S 变体的频率和分布在两组研究中相似，导致在我们的系列中排除它们在 sMTC 中的作用。结论这些发现表明，导致 sMTC 出现的主要遗传事件可能位于几个不同的 RET 位点。通过这种方式，我们可以假设存在至少两个 sMTC 基因座，分别与 S836S-IVS1-126G>T 或 G691S-S904S 相关。
ContextLittle is known about the etiology of sporadic medullary thyroid carcinoma (sMTC). While germline gain-of-function mutations in theRETproto-oncogene cause hereditary MTC, the molecular mechanisms leading to the sporadic forms remain obscure. Our group had evidence about the existence of a low-penetrance susceptibility locus for sMTC in linkage disequilibrium with RET variants S836S/IVS1-126G>T, and probably in 5′ with respect to both variants. In this study we sought to identify such locus. On the other hand, because an overrepresentation of G691S/S904S variants in patients with sMTC had been previously reported, we sought to determine if such association was present in our series.DesignWe performed a case-control study analysing a wide spectrum ofRETvariants in the 5′ region of the gene, as well as the variants G691S/S904S. Haplotype distribution were also analyzed. A total of 58 patients with sMTC were included in the study. In addition, 100 unselected, unrelated race-, age-, and gender-matched normal controls were also evaluated.Main outcomeAlthough the overrepresentation of IVS1-126G>T remains present in our current sMTC series, thus supporting our previous hypothesis, no differences were obtained among cases and controls in the distribution of the variants tested upstream this position. On the other hand, the frequency and distribution of G691S/S904S variants were similar in both groups of study, leading to exclude their role in sMTC in our series.ConclusionsThese findings would suggest that the major genetic events contributing to the appearance of sMTC may reside in several differentRETloci. In this way, we could hypothesize about the existence of at least two sMTC loci, linked to S836S-IVS1-126G>T, or to G691S-S904S, respectively.