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DNA损伤应答（DDR）是由DNA损伤信号引发的所有分子响应、生物化学过程和细胞学反应，可修复内源和外源DNA损伤以防止基因组不稳定。乳腺癌与正常组织相比，DNA损伤和复制应激显著增加，不断累积的DNA损伤可诱导细胞凋亡和死亡。不同形式的DNA损伤可引发不同的修复机制和信号通路。DNA修复信号传导通路主要有六种：处理修饰核苷酸的核苷酸切除修复信号传导通路、修复DNA链间交联的范可尼贫血信号传导通路、负责DNA单链断裂的碱基切除修复信号传导通路、解决复制错误的错配修复信号传导通路、同源重组修复信号传导通路、处理DNA双链断裂的非同源末端连接信号传导通路。细胞周期检查点对于DDR也很重要，其允许有时间进行修复以防止DNA损伤。既往研究表明，DDR基因突变常见于各种癌症且至关重要。种系DDR基因突变可能易患乳腺癌、卵巢癌、胰腺癌和前列腺癌。众所周知，负责同源重组修复的重要基因BRCA突变与乳腺癌风险密切相关，并可作为DNA靶向治疗（包括铂类化疗、多腺苷二磷酸核糖聚合酶PARP抑制剂）生物学预测标志物。中度外显的乳腺癌易感基因如ATM、PALB2、CHEK2也属于DDR基因并参与对DDR靶向治疗的反应。除了已在乳腺癌被充分研究的种系BRCA突变，完整的DDR基因突变状态和其他DDR基因突变，尤其是在体细胞环境中，尚未得到很好的探索。DDR基因表达失调对DNA损伤抗癌疗效也发挥重要作用。同源重组修复蛋白表达下调可导致同源重组缺陷，从而增加对铂类和PARP抑制剂的敏感性。相反，错配修复和非同源末端连接蛋白质表达缺失以及核苷酸切除修复信号传导通路过度表达可导致PARP抑制剂耐药。因此，如何调控这些DDR基因的最佳表达值得深入研究。 随着免疫治疗时代到来，DDR基因突变对免疫治疗的作用受到关注。根据既往研究报告，DDR基因突变与实体肿瘤突变负荷增加有关。错配修复缺陷或微卫星高度不稳定已被确定为免疫细胞程序性死亡受体PD-1及其配体PD-L1抑制剂疗效的生物学预测标志物。考虑到乳腺癌免疫疗效较差，如何提高乳腺癌免疫疗效并确定可能符合条件的患者仍需要进一步探索。因此，阐明DDR基因突变与免疫学特征之间的相互作用将为乳腺癌免疫治疗提供新方向。 2023年1月18日，美国癌症学会《癌症》在线发表复旦大学附属肿瘤医院金娟、 曹佳宁、李彬、李婷、张剑、曹君、赵明川、王磊苹、王碧芸、陶中华、胡夕春等学者的研究报告，首次对未经筛选的晚期乳腺癌患者种系和体细胞DDR基因突变进行了全面剖析。 该研究对2017年9月～2019年7月复旦大学附属肿瘤医院520个癌症相关基因二代测序（大规模平行测序）数据库连续438例晚期乳腺癌患者和美国癌症基因组图谱（TCGA）数据库1091例早期乳腺癌患者的DDR信号传导通路分子变化特征进行全面剖析。 结果发现，种系DDR基因突变较多见于年轻患者和HER2阴性乳腺癌患者。 种系DDR基因突变肿瘤较多同时存在体细胞DDR基因突变，尤其种系范可尼贫血信号传导通路基因突变肿瘤。 值得注意的是，三分之二的种系PALB2突变患者肿瘤同时携带体细胞PALB2突变。 种系或肿瘤体细胞DDR基因突变患者与未突变患者相比，无病生存和总生存相似。 
晚期乳腺癌与早期乳腺癌相比，体细胞DDR基因突变率显著较高（24.89%比16.02%，P<0.001）。 体细胞DDR基因突变乳腺癌与种系DDR基因突变乳腺癌相比，肿瘤突变率显著较高。 此外，体细胞DDR基因突变肿瘤抗癌免疫表现型丰度显著较高。 体细胞范可尼贫血和错配修复信号传导通路基因突变与免疫检查点分子表达增加显著相关。 虽然大多数DDR基因与细胞增殖相关基因表达水平显著成正比，但是PARP3表达与MKI67表达成反比。 通过多因素比例风险回归分析，PARP3表达较低与较高相比，TCGA数据库患者无进展生存和总生存显著较差。 因此，该研究结果表明，种系范可尼贫血信号传导通路基因突变患者较多同时存在体细胞DDR基因突变肿瘤。体细胞DDR基因突变可导致乳腺癌抗癌免疫表现型。未发现种系或体细胞DDR基因突变与未突变患者生存显著差异。Cancer. 2023 Jan 18. IF: 6.921Landscape of DNA damage response gene alterations in breast cancer: A comprehensive investigation.Jin J, Cao J, Li B, Li T, Zhang J, Cao J, Zhao M, Wang L, Wang B, Tao Z, Hu X.Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China.BACKGROUND: DNA damage response (DDR) gene alterations are prevalent in breast cancer (BC) and important for treatment decisions. Intensive studies on DDR alterations in BC are still needed.METHODS: The authors included 438 patients with metastatic breast cancer from their next-generation sequencing database and 1091 patients with early-stage breast cancer from The Cancer Genome Atlas (TCGA) database in the analysis to characterize molecular alterations in the DDR pathway.RESULTS: Germline DDR mutations were more prevalent in younger patients and those with HER2-negative cancers. Tumors with germline DDR mutations more commonly had somatic DDR mutations, especially those with germline Fanconi anemia (FA) pathway mutations. Notably, 66.67% (four of six) of patients with germline PALB2 mutations had tumors that harbored somatic PALB2 mutations. No differences in prognosis were observed in patients with germline or tumor somatic DDR mutations compared to patients and tumors that were wild-type. Compared to early BC, the frequency of somatic DDR mutations in metastatic cancers was significantly higher (24.89% vs. 16.02%, p < .001). Higher tumor mutation burdens were observed in cancers with somatic DDR mutations, but not in cancers with germline DDR mutations. Furthermore, tumors with somatic DDR mutations showed an abundance of anticancer immunological phenotypes. Somatic FA and mismatch repair pathway mutations were associated with increased expression of immune checkpoint molecules. Although most DDR genes were significantly positively associated with expression of proliferation-related genes, PARP3 expression was negatively correlated with MKI67 expression. Lower PARP3 expression was associated with a worse prognosis in TCGA database by multivariate Cox analysis.CONCLUSIONS: Patients with germline FA mutations more frequently have tumors with somatic DDR mutations. Somatic DDR mutations lead to anticancer immunological phenotypes in BC. No differences in prognosis according to germline or somatic DDR mutations were found.KEYWORDS: BRCA1/2; PALB2; germline DDR mutations; immune checkpoint molecules; somatic DDR mutations
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