Abstract：
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.
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.
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.
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.
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.
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.
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.
摘要：
背景：DNA损伤反应（DDR）基因改变在乳腺癌（BC）中很普遍，对治疗决策很重要。仍需要对BC中DDR改变进行深入研究。
方法：作者从下一代测序数据库中纳入438例转移性乳腺癌患者和从癌症基因组图谱（TCGA）数据库中纳入1091例早期乳腺癌患者的分析，以表征DDR通路的分子改变。
结果：生殖系DDR突变在年轻患者和HER2阴性癌症患者中更为普遍。具有种系DDR突变的肿瘤更常见的是体细胞DDR突变，尤其是那些有种系范可尼贫血（FA）途径突变。值得注意的是,有种系PALB2突变的患者中66.67%(6例患者中的4例)有携带体细胞PALB2突变的肿瘤。与野生型患者和肿瘤相比，具有种系或肿瘤体细胞DDR突变的患者的预后没有差异。与公元前早期相比,转移性癌症中体细胞DDR突变的频率显着升高（24.89％vs.16.02%,p<.001)。在具有体细胞DDR突变的癌症中观察到更高的肿瘤突变负担，但在有生殖系DDR突变的癌症中没有。此外，具有体细胞DDR突变的肿瘤显示出丰富的抗癌免疫表型。体细胞FA和错配修复途径突变与免疫检查点分子的表达增加有关。尽管大多数DDR基因与增殖相关基因的表达呈显著正相关,PARP3表达与MKI67表达呈负相关。通过多变量Cox分析,在TCGA数据库中,较低的PARP3表达与较差的预后相关。
结论：具有种系FA突变的患者更频繁地出现具有体细胞DDR突变的肿瘤。体细胞DDR突变导致BC中的抗癌免疫表型。根据种系或体细胞DDR突变，未发现预后差异。
方法：作者从下一代测序数据库中纳入438例转移性乳腺癌患者和从癌症基因组图谱（TCGA）数据库中纳入1091例早期乳腺癌患者的分析，以表征DDR通路的分子改变。
结果：生殖系DDR突变在年轻患者和HER2阴性癌症患者中更为普遍。具有种系DDR突变的肿瘤更常见的是体细胞DDR突变，尤其是那些有种系范可尼贫血（FA）途径突变。值得注意的是,有种系PALB2突变的患者中66.67%(6例患者中的4例)有携带体细胞PALB2突变的肿瘤。与野生型患者和肿瘤相比，具有种系或肿瘤体细胞DDR突变的患者的预后没有差异。与公元前早期相比,转移性癌症中体细胞DDR突变的频率显着升高（24.89％vs.16.02%,p<.001)。在具有体细胞DDR突变的癌症中观察到更高的肿瘤突变负担，但在有生殖系DDR突变的癌症中没有。此外，具有体细胞DDR突变的肿瘤显示出丰富的抗癌免疫表型。体细胞FA和错配修复途径突变与免疫检查点分子的表达增加有关。尽管大多数DDR基因与增殖相关基因的表达呈显著正相关,PARP3表达与MKI67表达呈负相关。通过多变量Cox分析,在TCGA数据库中,较低的PARP3表达与较差的预后相关。
结论：具有种系FA突变的患者更频繁地出现具有体细胞DDR突变的肿瘤。体细胞DDR突变导致BC中的抗癌免疫表型。根据种系或体细胞DDR突变，未发现预后差异。
