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Non-Small Cell Lung Cancer Mutations, Tumor Microenvironment Profiled in China

NEW YORK (GenomeWeb) – A team from China, the US, and Malaysia has profiled the mutation patterns and tumor microenvironment features found in non-small cell lung cancer (NSCLC) cases treated at half a dozen hospitals in China.

The researchers used exome sequencing, RNA sequencing, array-based copy number profiling, immunohistochemical staining on the PD-L1 immune checkpoint protein, and other approaches to characterize samples from up to 245 Chinese NSCLC patients, comparing alterations and apparent immune cell infiltration in cases classified as adenocarcinomas or squamous cell carcinomas. The findings, published online yesterday in Nature Communications, revealed recurrent alterations that typically coincide with reduced or improved predicted immune cell infiltration in the NSCLC subtypes.

The findings so far point to microenvironment diversity in the NSCLC cases in China, senior and corresponding author Yi-Long Wu, a researcher at the Guangdong Lung Cancer Institute, and his co-authors explained, revealing immune cell enrichment subtypes and microenvironment features that coincide with various tumor cell alterations.

Some three-quarters of the lung cancers diagnosed around the world each year are classified as NSCLC, the team noted, and many of those cases are caught at advanced stages. But despite the poor outcomes associated with NSCLC and the large number of lives it claims in China, questions remain about the suite of tumor alterations and microenvironment features found in NSCLC cases in China — insights that may inform future treatment strategies.

"It is important to understand the immunological landscape of NSCLC in the Chinese population, as this information might reveal the mechanism of response and resistance to specific immunomodulatory agents and inform future development of more effective combination approaches," the authors explained.

In an effort to better understand the molecular and microenvironment features associated with NSCLC cases in China, the researchers used Illumina instruments to sequence protein-coding sequences captured from matched tumor and normal samples from 245 NSCLC patients treated at six hospitals in China from September 2013 to October 2016, including 131 patients with adenocarcinoma and 114 squamous cell carcinoma patients.

Some 97 percent of those with squamous cell carcinoma had a history of tobacco use, the team noted, as did 64 percent of the adenocarcinoma patients.

Along with mutations identified in the exome sequence data, the researchers did RNA sequencing on tumor-normal samples to get a look at gene expression and fusion patterns. To that, they added Affymetrix array-based CNV profiles for 238 of the tumors and IHC staining and imaging on 147 resected tumor samples.

With these data, the team compared the frequently mutated genes, gene fusions, and other recurrent alterations in the adenocarcinoma and squamous cell carcinoma cases. It also considered molecular similarities and differences between tumors from smokers and non-smokers and got a look at mutations that were more common in the Chinese NSCLC cases compared to those profiled for the Cancer Genome Atlas project, which mainly included cases from populations in the West.

For example, the researchers noted that recurrent chromosome 8 losses appeared to be particularly common in the NSCLC cases from China, as were adenocarcinomas containing EGFR mutations.

Consistent with past research, which reported a higher prevalence of adenocarcinomas and more frequent EGFR mutations in East Asian women who develop lung cancer in the absence of a smoking history, authors of the new study saw relatively high rates of EGFR mutations in non-smoker women with adenocarcinoma, but cautioned that "the effect of gender remains unclear," in part due to high non-smoking rates in Asian women.

With the help of adaptive and innate immune signatures gleaned from gene-set enrichment analyses, the researchers profiled immune cell types — including tumor-infiltrating lymphocytes — in the samples, and delved into potential relationships between tumor alterations and specific immune microenvironment features.

In the squamous cell carcinomas, for example, they saw PTEN losses or PIK3CA amplifications that coincided with low immune activity in squamous cell carcinomas. Among the other squamous cell carcinoma subsets was a group of cases marked by enhanced immune activity despite relatively low overall mutational burdens.

In the adenocarcinomas, meanwhile, the team identified potential ties between EGFR mutations and relatively low levels of immune cell infiltration, despite the higher levels of tumor-infiltrating lymphocytes estimated across the broader set of adenocarcinomas. In contrast, adenocarcinoma tumors with KRAS mutations or amplifications appeared to have immune cell enrichment.

Overall, they noted that an immune signature associated with tumor-infiltrating lymphocyte activity turned up in almost 73 percent of adenocarcinomas, but just 54 percent of the squamous cell carcinomas.

Patient survival times also appeared to stretch out in the adenocarcinoma and squamous cell carcinoma patients who had tumors classified as immune "high," the researchers reported, at least over the two years or more of follow up for the study's participants. 

Even so, the authors cautioned that the gene signatures used to estimate immune content can "only suggest the relative presence of a given immune cell type" and may need to be refined further to get a clearer look at immune cells in and around the NSCLC tumors.