Srivastava Aayushi, Miao Beiping, Skopelitou Diamanto, Kumar Varun, Kumar Abhishek, Paramasivam Nagarajan, Bonora Elena, Hemminki Kari, Försti Asta, Bandapalli Obul Reddy
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Hopp Children's Cancer Center (KiTZ), 69120 Heidelberg, Germany.
Cancers (Basel). 2020 Jun 1;12(6):1441. doi: 10.3390/cancers12061441.
Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole-genome sequencing study of five families with occurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of the () gene in one of the families. The results showed a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293T cells carrying showed increased telomere length in comparison to wild-type cells, suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. While one germline mutation in has already been reported in a melanoma-prone family with prevalence of thyroid cancers, we report the first of such mutations in a family affected solely by NMTCs, thus expanding current knowledge on shelterin complex-associated cancers.
非髓样甲状腺癌（NMTC）是一种常见的内分泌恶性肿瘤，其遗传基础尚未明确确立。在最近一项对五个发生NMTC的家族进行的全基因组测序研究中，我们借助生物信息学工具筛选出了有潜力的变异。在此，我们报告了对其中一个家族中（）基因高度保守的寡核苷酸/寡糖结合域中的一个新型种系变异（p.V29L）进行的计算机分析和体外实验。结果显示，与野生型对应物相比，突变蛋白中端粒结合的POT1水平降低。携带的HEK293T细胞与野生型细胞相比，端粒长度增加，这表明该突变导致端粒功能障碍，可能在这个家族患NMTC的易感性中起作用。虽然在一个甲状腺癌患病率较高的易患黑色素瘤家族中已经报道了中的一个种系突变，但我们报告了在一个仅受NMTC影响的家族中首次出现这种突变，从而扩展了目前关于保护素复合物相关癌症的知识。
