Exome sequencing reveals mutant genes with low penetrance involved in MEN2A-associated tumorigenesis
Exome sequencing reveals mutant genes with low penetrance involved in MEN2A-associated tumorigenesis
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外显子组测序揭示了参与 MEN2A 相关肿瘤发生的低外显率突变基因
DOI：
10.1530/erc-14-0225
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发表时间：
2015-02-01
影响因子：
3.9
通讯作者：
Ning, Guang
中科院分区：
文献类型：
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作者：
Cai, Jie;Li, Lin;Ning, Guang
转染期间激活重排（RET）突变作为多发性内分泌腺瘤2A型（MEN 2A）的起始致病突变。然而，尚未报告关于非RET遗传事件的结论性发现。据我们所知，这是第一项研究，检查匹配的MEN 2A相关肿瘤的基因组改变。我们对匹配的MEN 2A肿瘤和种系DNA进行了外显子组测序和SNP阵列分析。使用桑格测序在一组独立的患者中验证体细胞改变。进一步评估功能性目的基因。生殖系RET突变在所有MEN 2A组分肿瘤中发现。在9例MEN 2A相关肿瘤中发现了32例体细胞突变，其中28例（87.5%）为点突变，4例（12.5%）为小插入、重复或缺失。我们对35例甲状腺髓样癌（20例MEN 2A）和34例PCCs（22例MEN 2A）的12个基因的所有突变和编码序列区进行了测序，但未发现复发突变。在13个基因中发现了复发性改变，这些基因具有突变或拷贝数改变，包括EIF 4G 1突变（p.E1147V）。在TT、MZ-CRC 1和PC-12细胞中，EIF 4G 1的突变导致细胞增殖和RET/MAPK磷酸化增加，而EIF 4G 1的敲低导致细胞增殖和RET/MAPK磷酸化减少。我们发现，与非内分泌肿瘤相比，内分泌肿瘤的体细胞突变较少。RET是MEN 2A相关肿瘤的主要驱动因素。然而，低频改变如EIF 4G 1可能参与MEN 2A相关的肿瘤发生，可能通过调节RET通路的活性。
Activating rearranged during transfection (RET) mutations function as the initiating causative mutation for multiple endocrine neoplasia type 2A (MEN2A). However, no conclusive findings regarding the non-RET genetic events have been reported. This is the first study, to our knowledge, examining genomic alterations in matched MEN2A-associated tumors. We performed exome sequencing and SNP array analysis of matched MEN2A tumors and germline DNA. Somatic alterations were validated in an independent set of patients using Sanger sequencing. Genes of functional interest were further evaluated. The germline RET mutation was found in all MEN2A-component tumors. Thirty-two somatic mutations were identified in the nine MEN2A-associated tumors, of which 28 (87.5%) were point mutations and 4 (12.5%) were small insertions, duplications, or deletions. We sequenced all the mutations as well as coding sequence regions of the 12 genes in an independent sample set including 35 medullary thyroid cancers (20 MEN2A) and 34 PCCs (22 MEN2A), but found no recurrent mutations. Recurrent alterations were found in 13 genes with either mutations or alterations in copy number, including an EIF4G1 mutation (p. E1147V). Mutation of EIF4G1 led to increased cell proliferation and RET/MAPK phosphorylation, while knockdown of EIF4G1 led to reduced cell proliferation and RET/MAPK phosphorylation in TT, MZ-CRC1, and PC-12 cells. We found fewer somatic mutations in endocrine tumors compared with non-endocrine tumors. RET was the primary driver in MEN2A-associated tumors. However, low-frequency alterations such as EIF4G1 might participate in MEN2A-associated tumorigenesis, possibly by regulating the activity of the RET pathway.