Paget’s病驱动突变基因鉴定及分子机制研究

Paget's disease is a cutaneous carcinoma that usually found on the apocrine-rich skin, and can occur on breast and extramammary. It is still presenting a challenge for clinical practices of Paget's disease with high rate of wrong diagnosis, recurrence and second primary malignancy. Basically, we have built the tissue sample bank and clinical information database for Paget's disease, and four candidate driver genes (FBXW4、SLC22A11、GLOD4、MLLT4) have been found by exome sequencing on 3 spatially separated biopsy samples from primary non-invasive and multicentric occurrence invasive sites tumors. In this study, our goal is to validate the mutation frequencies of the four candidate genes in the other 400 independent samples, to provide the functional evidences for driver mutations in proliferation, and to screen the therapeutic inhibitors for driver genes. Our research may contribute to more robust evidences for carcinogenesis and therapeutic targets for tailored drugs in the future management of patients with Paget's disease to increase their survival and life quality.

Paget’s病又称湿疹样癌，是好发于乳腺、腹股沟等部位的皮肤恶性肿瘤。Paget’s病虽发病率不高，但因其临床表现不特异而误诊率高，肿瘤细胞跳跃式生长致手术切除不彻底而复发率高，合并第二原发恶性肿瘤发生率高。目前对其发病机制研究匮乏，课题组率先构建了Paget’s病组织样本与信息库；首次利用外显子组测序定位出1例Paget’s病患者表皮内癌与真皮浸润癌组织中共有的4个驱动突变基因(FBXW4、SLC22A11、GLOD4、MLLT4)。本项目拟验证候选基因在400个患者肿瘤组织中的突变频率；解析驱动突变对细胞增殖的影响；筛选以驱动突变基因为分子靶点的抑制剂；评估驱动突变与Paget’s病复发、转移、生存及第二原发肿瘤发生间的关联。本申请项目研究成果将完善Paget’s病驱动基因突变谱，有助于阐明Paget’s病发生的分子机制，为个体化治疗提供分子靶点与抑制剂，使更广泛的患者获益。