Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance.
Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance.
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DOI：
10.1371/journal.pone.0061920
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
de la Chapelle A
中科院分区：
文献类型：
--
作者：
He H;Li W;Wu D;Nagy R;Liyanarachchi S;Akagi K;Jendrzejewski J;Jiao H;Hoag K;Wen B;Srinivas M;Waidyaratne G;Wang R;Wojcicka A;Lattimer IR;Stachlewska E;Czetwertynska M;Dlugosinska J;Gierlikowski W;Ploski R;Krawczyk M;Jazdzewski K;Kere J;Symer DE;Jin V;Wang Q;de la Chapelle A
甲状腺癌具有高遗传性，但致病基因仍然很大程度上未知。根据一个常见的假设，甲状腺癌的遗传易感性具有高度异质性。部分原因是许多不同的稀有等位基因。在这里，我们使用连锁分析和靶向深度测序来检测显示非髓样甲状腺癌 (NMTC) 的大型家系中染色体 4q32 (4q32A>C) 中的新单核苷酸突变。这种突变通常极为罕见。在 38 个 NMTC 家族、2676 个散发性 NMTC 病例或 2470 个对照中未发现该基因。该突变位于长程增强子元件中，其结合转录因子 POU2F 和 YY1 的能力显着受损，与野生型 A 等位基因相比，C 等位基因存在时活性降低。增强子 RNA (eRNA) 在该区域的甲状腺组织中转录，并且在 NMTC 肿瘤中大幅下调。我们认为，这是一种极其罕见的突变，易患甲状腺癌，且外显率很高。
Thyroid cancer shows high heritability but causative genes remain largely unknown. According to a common hypothesis the genetic predisposition to thyroid cancer is highly heterogeneous; being in part due to many different rare alleles. Here we used linkage analysis and targeted deep sequencing to detect a novel single-nucleotide mutation in chromosome 4q32 (4q32A>C) in a large pedigree displaying non-medullary thyroid carcinoma (NMTC). This mutation is generally ultra-rare; it was not found in 38 NMTC families, in 2676 sporadic NMTC cases or 2470 controls. The mutation is located in a long-range enhancer element whose ability to bind the transcription factors POU2F and YY1 is significantly impaired, with decreased activity in the presence of the C- allele compared with the wild type A-allele. An enhancer RNA (eRNA) is transcribed in thyroid tissue from this region and is greatly downregulated in NMTC tumors. We suggest that this is an example of an ultra-rare mutation predisposing to thyroid cancer with high penetrance.