A Germline CHEK2 Mutation in a Family with Papillary Thyroid Cancer
A Germline CHEK2 Mutation in a Family with Papillary Thyroid Cancer
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甲状腺乳头状癌家族中的种系 CHEK2 突变
DOI：
10.1089/thy.2019.0774
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发表时间：
2020-03-11
期刊：
影响因子：
6.6
通讯作者：
Miao, Gang
中科院分区：
文献类型：
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作者：
Zhao, Yanyang;Yu, Tian;Miao, Gang
大约5%的甲状腺乳头状癌（PTC）病例是遗传的。然而，非综合征型家族性PTC（FPTC）的易感基因尚不清楚。我们对两名PTC患者的外周血DNA样本进行了全基因组测序。CHEK 2转录表达和蛋白质水平的CHK 2和p53进行了评估，在甲状腺组织从两个受影响的成员的亲属和散发性PTC案件。通过桑格测序对来自242名散发性PTC患者的血液DNA样品中的整个CHEK 2编码序列进行了检查。我们在CHEK 2中鉴定了一种新的杂合种系突变（c.417C -> A），该突变在FPTC家族的所有受影响成员中检测到。在基因组聚合数据库和NHLBI Trans-Omics for Precision Medicine项目中，264，200人中只有1人发现了这种变异。CHEK 2 c.417C -> A变体引入提前终止密码子（Y139 X）。我们发现，与没有变异的散发病例相比，携带变异的两名患者的肿瘤样本中CHK 2蛋白表达减少。Y139 X功能丧失变体导致p53磷酸化减少和p53蛋白水平降低。此外，在242例散发性PTC患者中的5例（2%）中鉴定出CHEK 2中的两种罕见错义变体（R180 C和H371 Y）。我们的研究结果表明，CHEK 2 Y139 X变异可能与FPTC相关。
Approximately 5% of all cases of papillary thyroid cancer (PTC) are inherited. However, the susceptibility gene(s) for nonsyndromic familial PTC (FPTC) remain unclear. We performed whole genome sequencing of peripheral blood DNA samples from two affected family members with PTC. CHEK2 transcript expression and the protein levels of CHK2 and p53 were evaluated in the thyroid tissues from two affected members of the kindred and sporadic PTC cases. The entire CHEK2 coding sequence was examined by Sanger sequencing in blood DNA samples from 242 sporadic PTC patients. We identified a novel heterozygous germline mutation in CHEK2 (c.417C -> A) that was detected in all available affected members of a kindred with FPTC. This variant was found in only 1 out of 264,200 persons in the Genome Aggregation Database and the NHLBI Trans-Omics for Precision Medicine program. The CHEK2 c.417C -> A variant introduces a premature termination codon (Y139X). We found reduced CHK2 protein expression in tumor samples from the two patients who carried the variant as compared with sporadic cases without the variant. The Y139X loss-of-function variant led to reduced p53 phosphorylation and decreased p53 protein level. In addition, two rare missense variants (R180C and H371Y) in CHEK2 were identified in 5 (2%) of 242 patients with sporadic PTC. Our findings suggest that the CHEK2 Y139X variant may be associated with FPTC.