DNA mismatch repair deficiency in surgically resected lung adenocarcinoma: Microsatellite instability analysis using the Promega panel
DNA mismatch repair deficiency in surgically resected lung adenocarcinoma: Microsatellite instability analysis using the Promega panel
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DOI：
10.1016/j.lungcan.2017.05.016
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发表时间：
2017-08-01
期刊：
影响因子：
5.3
通讯作者：
Suzuki, Kenji
中科院分区：
文献类型：
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作者：
Takamochi, Kazuya;Takahashi, Fumiyuki;Suzuki, Kenji
目的：DNA错配修复（MMR）缺陷作为预测免疫检查点抑制剂对各种恶性肿瘤治疗效果的重要生物标志物，近年来受到越来越多的关注。为了评估MMR状态，我们分析了肺腺癌的微卫星不稳定性（MSI）。材料与方法：从2007 - 2015年间手术治疗的341例患者中获得肺腺癌和相应的正常肺的冷冻组织，其中141例肿瘤含有驱动基因改变（50例EGFR基因突变，50例KRAS基因突变，21例ALK融合，10例ROS1融合，10例RET融合），200例泛阴性肿瘤（100例从不吸烟或轻度吸烟，100例重度吸烟）。从肿瘤和相应的正常肺组织中提取基因组DNA，使用Promega panel（5个单核苷酸标记：BAT-25、BAT-26、NR-21、NR-24和MONO-27； 2个五核苷酸标记：Penta C和Penta D）进行MSI分析。结果：一名64岁男性重度吸烟者仅在1例泛阴性肿瘤中发现MSI。在4个单核苷酸标记物中发现MSI。虽然Lynch综合征的临床背景不明显，但体细胞MLH1基因突变被确定。MLH1在肿瘤浸润淋巴细胞中表达，在癌细胞中不表达。PD-Ll在癌细胞中不表达，PD-1在肿瘤浸润淋巴细胞中不表达。结论：MSI在肺腺癌中是一种罕见的事件，与吸烟状况和驱动癌基因突变状况无关。因此，MMR缺乏状态不能作为免疫检查点抑制剂治疗肺腺癌的生物标志物。
Objectives: DNA mismatch repair (MMR) deficiency has recently received increasing attention as a significant biomarker to predict the treatment effect of immune checkpoint inhibitors for various malignant neoplasms. To evaluate MMR status, we analyzed the microsatellite instability (MSI) of lung adenocarcinomas.Materials and methods: Frozen tissues of lung adenocarcinoma and corresponding normal lung were obtained from 341 patients, including 141 with tumors harboring driver gene alterations (50 EGFR gene mutations, 50 KRAS gene mutations, 21 ALK fusions, 10 ROS1 fusions, and 10 RET fusions) and 200 with pan-negative tumors (100 never- or light-smokers and 100 heavy-smokers), who were surgically treated between 2007 and 2015. Genomic DNA extracted from tumors and corresponding normal lung tissues were used for MSI analysis using the Promega panel (5 mononucleotide markers: BAT-25, BAT-26, NR-21, NR-24, and MONO-27; and 2 pentanucleotide markers: Penta C and Penta D).Results: MSI was identified in only 1 pan-negative tumor from a 64-year-old male heavy smoker. MSI was found in 4 mononucleotide markers. Although no clinical background of Lynch syndrome was evident, somatic MLH1 gene mutation was identified. MLH1 was expressed in tumor-infiltrating lymphocytes and was not expressed in cancer cells. PD-Ll was not expressed in cancer cells, and PD-1 was not expressed in tumor-infiltrating lymphocytes.Conclusion: MSI is a rare event in lung adenocarcinoma regardless of smoking status and mutation status of driver oncogenes. Accordingly, MMR deficiency status cannot be used as a biomarker for immune checkpoint inhibitor treatment for lung adenocarcinoma.