家族性甲状腺非髓样癌易感基因全基因组精细定位

Thyroid cancer is increasing dramatically over the past 10 years, with the rapidest growth rate among female malignance. The mortality of thyroid cancer is also increasing gradually, indicating the necessity of more advanced screening system. For the difficulty in collecting large non-medullary thyroid cancer pedigrees, the susceptible gene for early screening has not been found. With over 5 years survey, we have collected several large pedigrees with more than 3 affected first-degree relatives in each pedigree, especially some with patients in three generations, which is essential for successful mapping susceptible genes. We firstly plan to screen patients sharing and generations transmitting mutations using whole genome sequencing of 5 pedigrees, then verify the mutations in another 5 independent pedigrees by target sequencing. Furthermore, we test the mutations in early thyroid cancer or micro-carcinoma tissues, so as to find functional mutations or variations. Finally we investigate the prevalence of mutations using Sequenom MassArray Genotyping Platform in patients with family history of thyroid caner and sporadic patients respectively, and analyze their possibility in screening. To the best of our knowledge, the project for the first time investigates the susceptible genes of familial non-medullary thyroid cancer at whole genome sequence level, which will provide candidate biomarkers for early screening and prevention of thyroid cancer.

甲状腺癌是最近十年中国女性发病率上升最快的恶性肿瘤，死亡率也逐年升高，提示早筛系统仍需完善。能用于早筛的家族性甲状腺非髓样癌易感基因尚未定位，其主要原因在于甲状腺非髓样癌大家系的收集困难重重。课题组经过长达5年的调查随访，收集到一批一级亲属患病≥3人的甲状腺非髓样癌大家系，部分家系连续3代均有患者，为易感基因的定位提供了先决条件。本申请课题拟首先对5个大家系进行全基因组高通量测序，筛选患者共享且代间传递的新变异，进而在另外5个独立大家系应用高通量靶向测序技术进行验证，并在家系早期癌／微小癌组织中检测变异位点是否存在，以筛选功能性变异位点/基因，最后应用Sequenom质谱分型平台对家族史人群和散发病例检测变异位点频率，评估其人群解析度和用于早筛的可能性。本申请项目首次在全基因组序列水平全面解析家族性甲状腺非髓样癌易感基因并评估其人群解析度，将为甲状腺癌的早筛和预防提供候选易感标记。

研究背景：甲状腺癌是最近十年中国女性发病率上升最快的恶性肿瘤，死亡率也逐年升高，提示早筛系统仍需完善。能用于早筛的家族性甲状腺非髓样癌易感基因尚未定位，其主要原因在于甲状腺非髓样癌大家系的收集困难重重。课题组前期收集到一批一级亲属患病≥3人的甲状腺非髓样癌大家系，为易感基因的定位提供了先决条件。..研究内容：首先对5个甲状腺非髓样癌大家系进行全基因组或全外显子高通量测序，筛选患者共享且代间传递的新变异；进而在另外5个大家系及家系早期癌／微小癌组织中应用靶向测序进行验证；最后在家族史人群和散发病例中检测变异位点频率，评估其人群解析度和用于早筛的可能性。..重要结果：对甲状腺非髓样癌大家系全基因组/外显子测序发现两两家系共享18个候选易感基因：FOXO6、HRNR、ZNF384、ATF7IP、HERC2、KDM6B、MADCAM1、ZNF544、TRAK1、ZNF141、GPRIN1、CNPY3、ARHGEF5、MNX1、CNTNAP3B、ARMCX4、TPSD1、MANSC1；需要更多的家系验证。特殊组织学类型甲状腺乳头状癌（筛状-桑葚型）家系存在APC基因胚系Y622*终止突变和体系L760fs移码突变。在年龄<20岁的甲状腺非髓样癌组织中除检出RET、BRAF、TERT突变外，还检出NTRK1融合和TP53突变。..关键数据：5个大家系共23例样本进行全基因组或全外显子测序，检出677个功能性突变，两两家系共享21个突变，位于18个候选易感基因。从11219例甲状腺癌中筛选出25例年龄小于20岁的散发甲状腺癌患者，进行8-168个基因突变/融合检测；发现10例CCDC6-RET或NCOA4-RET融合；4例BRAF基因V600E突变；1例TERT基因C228T突变；1例TFG-NTRK1融合；1例TP53基因Q331*终止突变；其余8例检测范围内未检出功能性突变。..科学意义：首次在全基因组序列水平全面解析家族性甲状腺非髓样癌易感基因，发现的18个候选易感基因为进一步研究家族性甲状腺癌发病机制提供了方向。特殊类型甲状腺乳头状癌检出APC胚系突变，提示APC胚系突变者在常规体检时应增加甲状腺相关检查，具有重要的早筛意义。低龄甲状腺癌患者检出的BRAF突变、RET、NTRK1融合是明确的肿瘤靶点，对晚期患者临床治疗方案选择具有重大指导意义。

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