青少年鼻咽癌是一种临床少见的特殊类型鼻咽癌。利用全外显子测序，我们发现一部分青少年鼻咽癌患者携带MED12基因5’端突变，且与放疗后局部复发相关。前期工作提示：转染MED12基因5’端突变体的青少年鼻咽癌细胞干性增强并对放射线更加抵抗，同时Notch1通路核心分子NICD1表达上升。该过程可能与MED12-CDK8激酶复合物对NICD1降解的磷酸化调控有关。我们提出，MED12基因5’端突变可能通过CDK8介导的Notch1通路调控肿瘤细胞干性并促进青少年鼻咽癌放疗抵抗。本课题拟证实该猜想：研究MED12突变在青少年鼻咽癌中的临床意义；明确MED12突变在青少年鼻咽癌干性维持及放疗抵抗中的作用；揭示MED12突变通过CDK8/Notch1通路调控肿瘤细胞干性参与青少年鼻咽癌放疗抵抗的机制。本项目将初步探索青少年鼻咽癌遗传背景并聚焦MED12，拟揭示该疾病放疗抵抗新机制并为其治疗提供新靶点。

Juvenile nasopharyngeal carcinoma (NPC) is a rare and distinct type of NPC. By using whole exome sequencing, we identified a group of juvenile NPC patients harboring mutations in the 5’ end of the MED12 gene, and these patients were associated with local recurrence after radiotherapy. Preliminary data suggested that juvenile NPC cells transfected with a MED12 5’ mutant construct showed enhanced cancer cell stemness and increased radiation resistance. Notch1 intracellular domain (NICD1), which is the signaling hub of Notch1 pathway, was also upregulated. This process might be routed through the regulation of NICD1 degradation by phosphorylation of the MED12-CDK8 kinase complex. We infer that MED12 5’ mutations may regulate cancer cell stemness and promote radiation resistance in juvenile NPC by activating Notch1 signaling mediated by CDK8. To test this hypothesis, we will investigate the clinical significance of MED12 5’ mutations in patients with juvenile NPC, study the role of MED12 5’ mutations in cancer cell stemness and radiation resistance of juvenile NPC, and explore the mechanism of MED12 5’ mutations in regulating cancer cell stemness and radiation resistance through CDK8/Notch1 pathway. This project will explore the genomic background of juvenile NPC and focus on MED12. It will help to elucidate a novel radiation resistance mechanism of juvenile NPC and provide new targets in the management of this disease.