Ziemke Michael, Patil Tejas, Nolan Kyle, Tippimanchai Darinee, Malkoski Stephen P
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, United States.
Division of General Internal Medicine and Divison of Medical Oncology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, United States.
Lung Cancer. 2017 Jul;109:28-35. doi: 10.1016/j.lungcan.2017.04.017. Epub 2017 Apr 25.
Smad4 is a tumor suppressor that transduces transforming growth factor beta signaling and regulates genomic stability. We previously found that Smad4 knockdown in vitro inhibited DNA repair and increased sensitivity to DNA topoisomerase inhibitors. In this study, we assessed the association between reduced Smad4 expression and DNA topoisomerase inhibitor sensitivity in human non-small cell lung cancer (NSCLC) patients and evaluated the relationship between genomic alterations of Smad4 and molecular alterations in DNA repair molecules.
We retrospectively identified NSCLC patients who received etoposide or gemcitabine. Chemotherapeutic response was quantified by RECIST 1.1 criteria and Smad4 expression was assessed by immunohistochemistry. Relationships between Smad4 mutation and DNA repair molecule mutations were evaluated using publically available datasets.
We identified 28 individuals who received 30 treatments with gemcitabine or etoposide containing regimens for NSCLC. Reduced Smad4 expression was seen in 13/28 patients and was not associated with significant differences in clinical or pathologic parameters. Patients with reduced Smad4 expression had a larger response to DNA topoisomerase inhibitor containing regimens then patients with high Smad4 expression (-25.7% vs. -6.8% in lesion size, p=0.03); this relationship was more pronounced with gemcitabine containing regimens. The overall treatment response was higher in patients with reduced Smad4 expression (8/14 vs 2/16 p=0.02). Analysis of data from The Cancer Genome Atlas revealed that Smad4 mutation or homozygous loss was mutually exclusive with genomic alterations in DNA repair molecules.
Reduced Smad4 expression may predict responsiveness to regimens that contain DNA topoisomerase inhibitors. That Smad4 signaling alterations are mutually exclusive with alterations in DNA repair machinery is consistent with an important role of Smad4 in regulating DNA repair.
Smad4是一种肿瘤抑制因子，可转导转化生长因子β信号并调节基因组稳定性。我们之前发现，体外敲低Smad4可抑制DNA修复并增加对DNA拓扑异构酶抑制剂的敏感性。在本研究中，我们评估了人类非小细胞肺癌（NSCLC）患者中Smad4表达降低与DNA拓扑异构酶抑制剂敏感性之间的关联，并评估了Smad4的基因组改变与DNA修复分子的分子改变之间的关系。
我们回顾性鉴定了接受依托泊苷或吉西他滨治疗的NSCLC患者。化疗反应根据RECIST 1.1标准进行量化，Smad4表达通过免疫组织化学进行评估。使用公开可用的数据集评估Smad4突变与DNA修复分子突变之间的关系。
我们鉴定出28例接受含吉西他滨或依托泊苷方案治疗NSCLC的患者，共进行了30次治疗。13/28例患者出现Smad4表达降低，且与临床或病理参数的显著差异无关。Smad4表达降低的患者对含DNA拓扑异构酶抑制剂方案的反应大于Smad4表达高的患者（病变大小分别为-25.7% vs. -6.8%，p=0.03）；这种关系在含吉西他滨方案中更为明显。Smad4表达降低的患者总体治疗反应更高（8/14 vs 2/16，p=0.02）。对癌症基因组图谱数据的分析显示，Smad4突变或纯合缺失与DNA修复分子的基因组改变相互排斥。
Smad4表达降低可能预测对含DNA拓扑异构酶抑制剂方案的反应性。Smad4信号改变与DNA修复机制改变相互排斥，这与Smad4在调节DNA修复中的重要作用一致。
