Department of Genetics, Howard Hughes Medical Institute, Maryland
Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Ann Oncol. 2017 Jan 1;28(1):83-89. doi: 10.1093/annonc/mdw437.
Lung squamous cell carcinoma (LUSC) accounts for 20–30% of non-small cell lung cancers (NSCLCs). There are limited treatment strategies for LUSC in part due to our inadequate understanding of the molecular underpinnings of the disease. We performed whole-exome sequencing (WES) and comprehensive immune profiling of a unique set of clinically annotated early-stage LUSCs to increase our understanding of the pathobiology of this malignancy.
Matched pairs of surgically resected stage I-III LUSCs and normal lung tissues (n = 108) were analyzed by WES. Immunohistochemistry and image analysis-based profiling of 10 immune markers were done on a subset of LUSCs (n = 91). Associations among mutations, immune markers and clinicopathological variables were statistically examined using analysis of variance and Fisher’s exact test. Cox proportional hazards regression models were used for statistical analysis of clinical outcome.
This early-stage LUSC cohort displayed an average of 209 exonic mutations per tumor. Fourteen genes exhibited significant enrichment for somatic mutation: TP53, MLL2, PIK3CA, NFE2L2, CDH8, KEAP1, PTEN, ADCY8, PTPRT, CALCR, GRM8, FBXW7, RB1 and CDKN2A. Among mutated genes associated with poor recurrence-free survival, MLL2 mutations predicted poor prognosis in both TP53 mutant and wild-type LUSCs. We also found that in treated patients, FBXW7 and KEAP1 mutations were associated with poor response to adjuvant therapy, particularly in TP53-mutant tumors. Analysis of mutations with immune markers revealed that ADCY8 and PIK3CA mutations were associated with markedly decreased tumoral PD-L1 expression, LUSCs with PIK3CA mutations exhibited elevated CD45ro levels and CDKN2A-mutant tumors displayed an up-regulated immune response.
CONCLUSION(S): Our findings pinpoint mutated genes that may impact clinical outcome as well as personalized strategies for targeted immunotherapies in early-stage LUSC.
肺鳞状细胞癌（LUSC）占非小细胞肺癌（NSCLC）的 20-30%。由于我们对该疾病的分子基础了解不足，因此 LUSC 的治疗策略有限。我们对一组具有临床注释的早期 LUSC 进行了全外显子组测序（WES）和全面免疫分析，以增进我们对这种恶性肿瘤的病理生物学的理解。
对 108 对手术切除的 I-III 期 LUSC 和正常肺组织进行 WES 分析。对 91 例 LUSC 进行了 10 种免疫标志物的免疫组化和图像分析分析。使用方差分析和 Fisher 精确检验对突变、免疫标志物和临床病理变量之间的关联进行统计学检验。使用 Cox 比例风险回归模型对临床结果进行统计分析。
该早期 LUSC 队列显示每个肿瘤平均有 209 个外显子突变。14 个基因的体细胞突变明显富集：TP53、MLL2、PIK3CA、NFE2L2、CDH8、KEAP1、PTEN、ADCY8、PTPRT、CALCR、GRM8、FBXW7、RB1 和 CDKN2A。在与无复发生存不良相关的突变基因中，MLL2 突变在 TP53 突变和野生型 LUSC 中均预测预后不良。我们还发现，在接受治疗的患者中，FBXW7 和 KEAP1 突变与辅助治疗反应不良相关，尤其是在 TP53 突变型肿瘤中。对突变与免疫标志物的分析表明，ADCY8 和 PIK3CA 突变与肿瘤 PD-L1 表达明显降低相关，PIK3CA 突变的 LUSC 显示 CD45ro 水平升高，CDKN2A 突变的肿瘤显示免疫反应上调。
我们的研究结果确定了可能影响临床结局的突变基因，以及早期 LUSC 靶向免疫治疗的个体化策略。
