A Truncating Germline Mutation of TINF2 in Individuals with Thyroid Cancer or Melanoma Results in Longer Telomeres
A Truncating Germline Mutation of TINF2 in Individuals with Thyroid Cancer or Melanoma Results in Longer Telomeres
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DOI：
10.1089/thy.2019.0156
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发表时间：
2020-02-01
期刊：
影响因子：
6.6
通讯作者：
de la Chapelle, Albert
中科院分区：
文献类型：
--
作者：
He, Huiling;Li, Wei;de la Chapelle, Albert
背景资料：我们的基因组测序分析显示，在一个大家庭中，个体患有甲状腺乳头状癌（PTC）和黑色素瘤的shelterin基因TINF 2发生移码突变。方法：采用桑格测序技术，对24个家系的6个shelterin基因进行突变分析和编码变异筛查。定量逆转录-聚合酶链反应（PCR）用于TNF 2基因表达分析。外源性表达和免疫共沉淀技术用于评估TINF 2与TERF 1的结合。通过使用定量实时PCR定量来自淋巴细胞的DNA中的相对端粒长度（RTL）。全外显子组测序（WES）进行了7个家庭与个人受PTC和其他癌症类型。结果：TINF 2突变（TINF 2 p.Trp198fs）在关键家系中与PTC和黑色素瘤完全共分离。这种突变在数据库中没有报道，在我们筛选的其他23个家庭中也没有发现。在携带突变的个体中，TINF 2的表达呈临界性降低。截短的TINF 2蛋白显示与TERF 1的结合消失。与来自同一家族的无突变个体以及与62名健康对照者相比，突变个体的RTL显著延长。结论：TINF 2基因罕见的移码突变和端粒长度延长提示端粒异常可能是PTC和黑色素瘤的易感机制之一。shelterin基因中的DNA编码变体是罕见的。需要进一步的研究来评估shelterin基因变异在甲状腺癌和黑色素瘤中的作用。
Background: Our genome sequencing analysis revealed a frameshift mutation in the shelterin gene TINF2 in a large family with individuals affected with papillary thyroid carcinoma (PTC) and melanoma. Here, we further characterized the mutation and screened for coding variants in the 6 shelterin genes in 24 families.Methods: Sanger sequencing was performed to screen for the TINF2 mutation in the key family. Quantitative reverse transcription-polymerase chain reaction (PCR) was used for TINF2 gene expression analysis. Exogenous expression and co-immunoprecipitation techniques were used for assessing TINF2 binding to TERF1. Relative telomere length (RTL) was quantified in DNAs from lymphocytes by using quantitative real-time PCR. Whole exome sequencing (WES) was performed in seven families with individuals affected with PTC and other cancer types. Screening for DNA variants in shelterin genes was performed by using whole genome sequencing data from 17 families and WES data from 7 further families.Results: The TINF2 mutation (TINF2 p.Trp198fs) showed complete co-segregation with PTC and melanoma in the key family. The mutation is not reported in databases and not identified in 23 other families we screened. The expression of TINF2 was borderline reduced in individuals with the mutation. The truncated TINF2 protein showed abolished binding to TERF1. The RTL in the individuals with the mutation was significantly longer when compared with those without the mutation from the same family as well as compared with 62 healthy controls. Among the 24 families, we identified 3 missense and 1 synonymous variant(s) in 2 shelterin genes (TINF2 and ACD).Conclusions: The rare frameshift mutation in the TINF2 gene and the associated longer telomere length suggest that dysregulated telomeres could be a mechanism predisposing to PTC and melanoma. DNA coding variants in shelterin genes are rare. Further studies are required to evaluate the roles of variants in shelterin genes in thyroid cancer and melanoma.