Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas

Abstract

To compare lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC) and to identify new drivers of lung carcinogenesis, we examined exome sequences and copy number profiles of 660 lung ADC and 484 lung SqCC tumor/normal pairs. Recurrent alterations in lung SqCCs were more similar to other squamous carcinomas than to lung ADCs. Novel significantly mutated genes included PPP3CA, DOT1L, and FTSJD1 in lung ADC, RASA1 in lung SqCC, and KLF5, EP300, and CREBBP in both tumor types. Novel amplification peaks encompassed MIR21 in lung ADC, MIR205 in lung SqCC, and MAPK1 in both. Lung ADCs lacking receptor tyrosine kinase/Ras/Raf alterations revealed mutations in SOS1, VAV1, RASA1, and ARHGAP35. Regarding neoantigens, 47% of the lung ADC and 53% of the lung SqCC tumors had at least 5 predicted neoepitopes. While targeted therapies for lung ADC and lung SqCC are largely distinct, immunotherapies may aid in treatment for both subtypes.

Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications

“…To explore the implication of JAK2 mutations in lung cancers in the context of immunotherapy, we analyzed the TCGA cohort of 515 lung adenocarcinomas with both exome sequencing and RNA-seq data available [5]. While no activating JAK2 mutation is present in the TCGA cohort, JAK2 is amplified in three tumors.…”

“…At the molecular pathway level, RTK/RAS/RAF, PI3K-mTOR, and cell cycle pathways are the most frequently altered in lung adenocarcinomas [4]. In addition, the differences of genomic alterations in smokers and nonsmokers have also been investigated [5,7].…”

“…NSCLC is further classified into several subtypes, with adenocarcinoma and squamous cell carcinoma being the two main subclasses [2]. The genetic landscape of lung cancers has been extensively characterized by cancer genomic sequencing studies including those from the Cancer Genome Atlas (TCGA) research network [3][4][5][6]. For example, comprehensive molecular profiling of 230 lung adenocarcinomas confirmed TP53, KRAS, and EGFR as the most frequently mutated genes and identified 15 other significantly mutated genes, including oncogenes BRAF, MET, and PIK3CA and tumor suppressors STK11, KEAP1, NF1, RB1, and CDKN2A [4].…”

Lung Cancer Management: where are we in 2017?

“…In this context, the IASLC, together with diagnostic companies and pharmaceutical industries, is currently involved in comparing, optimizing and homogenizing different PD-L1 immunohistochemical diagnostic assays. Beside PD-L1 evaluation, other potential predictive tools such as the analysis of tumour nonsynonymous mutation burden 79,80 as well as neo-epitope load 81 , are under investigation. In the near future, additional areas of clinical investigation for immune checkpoint inhibitors will focus on the duration of treatment, as well as on the sequencing of immunotherapy, chemotherapy and targeted therapies.…”

Tumor-associated macrophages—additional effectors at anti-PD-1/PD-L1 therapy?

“…Since these experiments utilized mouse models with subcutaneous injection of cancer cells, they may not have site-specific features (such as colon-specific or lung-specific) of the tumor immune microenvironment. In addition, a recent large scale comprehensive genomic study reported that the significantly mutated genes in lung adenocarcinomas were most similar to those in glioblastoma and colorectal cancer (19). Therefore, I propose that the roles of PD-1 positive TAMs, and the effects of anti-PD-1/anti-PD-L1 drugs on these TAMs in NSCLC patients are worthy of investigation in future studies, at least in lung adenocarcinoma patients.…”