甲状腺未分化癌综合治疗药物选择的分子基础研究

Anaplastic thyroid cancer (ATC) is one of the most aggressive cancer types with the median survival time of 5 months. About 14-50% of thyroid cancer related death was accounted to ATC and the dedifferentiation of papillary thyroid cancer (PTC). The systematic evaluation of pathogenesis of ATC will improve the level of diagnosis and treatment of thyroid cancer. Due to the lower incidence and advanced stage of ATC, the samples of ATC for research are limited. Most of researches of ATC are the validation of the results of other cancer types. The applicant and his hospital use the multi-discipline management of ATC and improve the median survival time of ATC to 9 months and have collected a lot of clinical samples. The whole exome sequencing of ATC showed that the ATC have different gene mutation panel, mRNA expression panel, gene fusion and lncRNA panel. Every ATC case has kinases mutation which could be targeted by small molecular inhibitors. The whole genome sequencing and transcriptome sequencing will be used for molecular classification of ATC in current research project. The usage of target drugs based on the typing of molecular classification of ATC will be tested in ATC cell lines, and the guideline of drugs used will be drawn. The differences of ATC and PTC will be compared by integrated genome analysis of ATC and PTC data. The biomarkers for detecting the dedifferentiation possibility of PTC will be founded. This project will improve the diagnosis and treatment of ATC and PTC.

甲状腺未分化癌（ATC）恶性程度极高，中位生存期仅5个月，文献报道14-50%的甲状腺癌相关的死亡是由ATC或者乳头状癌（PTC）的去分化造成的，因此系统研究ATC的发病机制将会全面提高甲状腺癌的诊治结果。但由于ATC发病率较低、研究样本的缺乏使得ATC的研究长期处于将其他肿瘤研究结果在ATC验证的状态。申请者所在单位应用多学科协作的模式将ATC的中位生存期延长至9个月，积累了一定临床资源，前期对5例样本的深度测序分析显示ATC有独特的基因突变谱、转录组、融合基因和lncRNA表达谱，同时每个病例都有可以被小分子抑制剂靶向的激酶基因突变。本课题将继续应用全基因组和转录组测序的方法，进行ATC的分子分型；对ATC细胞系进行分子分型为基础的靶向药物实验，建立用药指导；应用整合基因组分析方法，比较PTC与ATC的异同，筛选PTC去分化的分子标记，课题将全面提高ATC以及PTC的诊治水平。

甲状腺癌是人类发病率最高的内分泌系统恶性肿瘤。不同病理类型的甲状腺癌预后各异，其中甲状腺乳头状癌（PTC）的预后较好，而甲状腺未分化癌（ATC）中位生存时间仅有3-6月。因而对ATC高致死性的生物学机制研究颇有意义。本项课题中，申请者通过全基因组测序和全转录组测序，明确了ATC的基因突变、转录组改变，并针对LncRNA做了进一步研究；鉴定了ATC中特异性高表达的MANCR，并对MANCR对甲状腺肿瘤相关的功能、机制影响做了进一步研究。本项目还通过自主构建甲状腺滤泡上皮特异性BRAF突变、TERT过表达转基因小鼠，明确了TERT在去分化过程中的作用。使用单细胞测序明确了PTC/ATC的转录组景观，并进一步鉴定了PTC-ATC的动态演进过程。基于单细胞测序和临床试验的结果，进一步探索了靶向Tip ECs联合aPD-1的治疗效果。本研究有助于优化ATC临床诊疗流程，同时探索了ATC的免疫治疗新方案。