乳房外Paget病（EMPD）是一种罕见的皮肤肿瘤。我们发现DNA错配修复（MMR）基因胚系突变和蛋白表达下降在EMPD具有较高的检出率，并发现5-FU化疗敏感性在EMPD患者中存在明显差异。我们提出假说认为MMR异常可能是影响EMPD 5-FU敏感性的重要机制。本研究拟首先分析EMPD患者的MMR状态，明确5-FU敏感性与MMR状态的关联；通过体外和体内（裸鼠模型）实验，揭示MMR基因突变、MMR蛋白表达下降和MMR正常的EMPD细胞在5-FU诱导的细胞凋亡和自噬性死亡通路的差异；最后，评价MMR功能分析在预测EMPD对5-FU敏感性的价值。本研究将探索MMR功能异常在EMPD对5-FU敏感性的影响及机制，为EMPD治疗提供新思路。

Extramammary Paget's disease (EMPD) is a rare skin cancer. We have found that the germline mutations and reduced expression of DNA mismatch repair (MMR) genes were common in EMPD, and also found that there was a significantly discrepancy in the sensitivity of 5-FU chemotherapy in patients with EMPD. We propose that MMR abnormalities may play an important role in affecting the 5-FU chemotherapeutic sensitivity in EMPD. The aims of our study are firstly to analyze the correlation between MMR status and 5-FU sensitivity; to reveal the different mechanisms and effects between the MMR genes mutations and decreased proteins expression on EMPD cells in 5-FU induced cell apoptosis and autophagic cell death pathways via in vitro and in vivo (nude mice) tests; finally, to evaluate the predictive value of MMR analysis in the 5-FU sensitivity in EMPD. This study will explore the mechanisms and effects of MMR alterations in EMPD on the 5-FU chemotherapeutic sensitivity, and provide new ideas for the treatment of this cancer.