CHEK2基因突变对乳腺癌新辅助化疗的预测作用及相关机制

Neoadjuvant chemotherapy is increasing used for operable primary breast cancer. However, due to the biological heterogeneity of breast cancer, individual patients belonging to the same stage of disease may exhibit completely different response to the same regimens. Currently there is a lack of accurate predictors in clinical settings. Hence, it is necessery to indentify factors to select the right patients who will benefit from a certain types of regimens and to spare the patients from receiving an ineffective treatment. CHEK2(Cell cycle checkpoint kinase 2),a moderate breast cancer susceptibility gene, plays an important role in cell cycle regulation, apoptosis, and DNA repair. We previously identified one recurrent germline mutation, CHEK2 1111C/T (H371Y), which decrease the kinase activity of CHEK2, confers a moderate risk of breast cancer in Chinese women, especialy in Chinese familial breast cancer, suggesting that CHEK2 gene germline mutation may involed in the biological behavior of breast cancer. Based on the previous data,in the current study we plan to detect CHEK2 gene somatic mutation and CHEK2 gene expression in the tumors from a cohort of breast cancer patients receiving neoadjuvant chemotherapy, to investegate whether there was an association between CHEK2 somatic mutation or expression level and pathological response in the neoadjuvant chemotherapy regimens, and further to study the related molecular mechanisms. The purpose of this study is to provide more precise markers for neoadjuvant chemotherapy.

新辅助化疗越来越多的用于II-III期可手术乳腺癌患者，但由于乳腺癌个体异质性，不同患者对相同化疗方案的反应差异甚远，临床上还缺乏为患者选择合适化疗方案的有效指标。细胞周期检查点激酶2 基因(CHEK2)是继BRCA1/2基因之后发现的另一重要的乳腺癌易感基因，在细胞DNA损伤修复中起关键的介导和调控作用，CHEK2基因胚系突变可中等程度增加乳腺癌特别是家族性乳腺癌患病风险。我们前期工作发现了中国人群特有的CHEK2基因突变1111C/T(H371Y)，该突变可降低CHEK2基因磷酸化功能，且与乳腺癌发病风险显著相关，尤其是家族性乳腺癌。本课题将进一步利用乳腺癌术前穿刺样本检测CHEK2 基因体细胞突变及表达水平，研究其与乳腺癌新辅助化疗疗效的相关性，CHEK2 基因是否存在与化疗疗效密切相关的突变热点，并探索其分子机制。本研究旨在为乳腺癌新辅助化疗的患者提供更有效的预测指标。

背景：细胞周期检查点激酶2 基因(CHEK2) 是继BRCA1/2基因之后发现的另一重要的乳腺癌易感基因。它编码一个能被ATM蛋白激活的多功能酶CHEK2蛋白，在细胞DNA损伤修复中起关键的介导和调控作用。我们前期研究发现CHEK2 H371Y突变是一种中国人群特有的增加乳腺癌发病风险的致病性突变。本研究的目的是探索携带CHEK2 H371Y突变是否影响乳腺癌患者对新辅助化疗的敏感性。.方法：我们检测了5341例可手术的乳腺癌患者CHEK2 H371Y胚系突变状况，其中2334例患者接受了新辅助化疗。新辅助化疗结束，将病理完全缓解定义为在新辅助化疗完成时在乳腺原位已检测不到肿瘤细胞。同时随访患者生存信息，分析该基因突变在乳腺癌化疗疗效预测和预后中的作用。.结果：5341例乳腺癌患者CHEK2 基因突变，发现84例患者携带CHEK2 H371Y 突变，突变率为1.57%（84/5341）。在2334名接受新辅助化疗乳腺癌患者中，有39名患者(1.7%)携带了CHEK2 H371Y胚系突变，460例患者达到完全病理缓解（pCR）（19.7%，460/2334）。分析发现在该研究人群中，携带CHEK2 H371Y突变的患者较非携带者的病理完全缓解率高（33% vs 19.5%，P=0.031）。在多因素分析中，CHEK2 H371Y突变是病理完全缓解的独立预后因素（OR=3.01,95%CI：1.34-6.78，P=0.008）。CHEK2 H371Y突变携带者较非携带者的远处无复发生存率稍差（HR=1.24,95%CI：0.59-2.63）。.结论：CHEK2 H371Y突变携带者有可能较非携带者对新辅助化疗敏感。

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