Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China.
Department of Pathology, Zhejiang Cancer Hospital, Hangzhou 310022, China.
Lung Cancer. 2018 Apr;118:57-61. doi: 10.1016/j.lungcan.2018.02.004. Epub 2018 Feb 6.
Mutations in polymerase ε (POLE), a DNA polymerase involved in DNA replication and repair, have been investigated in endometrial cancers and response to programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1) immunotherapy. However, the frequency of POLE gene mutation in patients with non-small cell lung cancer (NSCLC) has not been reported.
We assessed POLE mutation in 319 patients with NSCLC by next-generation sequencing (NGS) of 416 cancer-associated genes. Expression of PD-L1, DNA mismatch repair proteins (MMR), and the abundance of CD8-positive tumor infiltrating lymphocytes (TILs) were assayed by immunohistochemistry. Progression-free survival (PFS) was evaluated using the Kaplan-Meier method and compared among groups using log-rank tests.
Nine of the 319 patients (2.8%) harbored POLE mutation. All nine had adenocarcinomas. The median tumor mutational burdens (TMBs) were 12.2/Mb and 7.8/Mb in patients with and without POLE mutation, respectively (P = 0.026). PD-L1, MMR (including MSH2, MSH6, MLH1 and PMS2), and CD8-positive TILs were evaluated in all nine patients. No microsatellite instability was detected, but seven patients had high levels of CD8-positive TILs and five demonstrated PD-L1 staining >25%. One patient receiving the PD-L1 antibody atezolizumab demonstrated a partial response, with a PFS of >8 months.
POLE mutation represents an uncommon phenotype in NSCLC. TMB, PD-L1 expression, and CD8-positive TILs were all higher in patients with mutant compared with wild-type POLE. POLE mutation may thus represent a candidate biomarker for response to immunotherapy in patients with NSCLC.
聚合酶 ε（POLE）是一种参与 DNA 复制和修复的 DNA 聚合酶，其突变已在子宫内膜癌和程序性死亡蛋白 1（PD-1）/PD-1 配体（PD-L1）免疫治疗的反应中进行了研究。然而，POLE 基因突变在非小细胞肺癌（NSCLC）患者中的频率尚未报道。
我们通过对 416 个癌症相关基因的下一代测序（NGS）评估了 319 名 NSCLC 患者的 POLE 突变。通过免疫组织化学检测 PD-L1、DNA 错配修复蛋白（MMR）和 CD8 阳性肿瘤浸润淋巴细胞（TIL）的丰度。使用 Kaplan-Meier 方法评估无进展生存期（PFS），并通过对数秩检验比较各组之间的差异。
319 名患者中有 9 名（2.8%）存在 POLE 突变。这 9 名患者均患有腺癌。有和没有 POLE 突变的患者的肿瘤突变负担（TMB）中位数分别为 12.2/Mb 和 7.8/Mb（P=0.026）。对所有 9 名患者评估了 PD-L1、MMR（包括 MSH2、MSH6、MLH1 和 PMS2）和 CD8 阳性 TILs。未检测到微卫星不稳定性，但 7 名患者具有高水平的 CD8 阳性 TILs，5 名患者 PD-L1 染色>25%。一名接受 PD-L1 抗体 atezolizumab 治疗的患者表现出部分缓解，PFS 超过 8 个月。
POLE 突变是 NSCLC 中一种罕见的表型。与野生型 POLE 相比，突变型 POLE 患者的 TMB、PD-L1 表达和 CD8 阳性 TILs 均更高。因此，POLE 突变可能是 NSCLC 患者对免疫治疗反应的候选生物标志物。
