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Integrated Proteomic Papers Define Lung Cancer Features Across Populations, Smoking Histories

NEW YORK – Independent research teams led by investigators in China, Taiwan, the UK, and the US have started to untangle the proteomic profiles for lung adenocarcinomas in a collection of papers published online today in Cell, identifying potential drivers, treatment targets, and distinct molecular features in cases occurring in non-smokers.

For the first of the studies, researchers from the Chinese Academy of Sciences, the Beijing Institute of Lifeomics, Shanghai Jiao Tong University, and elsewhere used a combination of reverse-phase high-throughput liquid chromatography, liquid chromatography tandem mass spectrometry, targeted enrichment, RNA sequencing, or exome sequencing to assess proteomic, phosphoproteomic, transcriptomic, and protein-coding sequence mutation patterns in matched tumor and adjacent normal samples of up to 103 lung adenocarcinoma cases in China.

The team's analysis highlighted three proteomics-based lung adenocarcinoma subtypes with different prognostic implications and underlying molecular patterns, while the broader integrated multi-omic analyses offered a look at the pathways being altered in lung adenocarcinoma, along with related drug targets and potential molecular markers related to treatment outcomes that could be picked up in patient blood plasma.

"Our data provide a resource to explore the relationships between genetic variation and transcriptional/translational regulations," the authors wrote. "Further analysis of the proteomics uncovered [lung adenocarcinoma]-related molecular characteristics and their associated clinical outcomes in subgroups with different genotypes." 

In another Cell study, a team from Taiwan, the UK, and Norway outlined findings from its own analysis of 103 non-small cell lung cancer cases in East Asia. That cohort of prospectively enrolled lung adenocarcinoma patients from Taiwan included an over-representation of cases in non-smokers, who were often female and diagnosed with relatively early-stage disease.

"We carried out the most comprehensive study ever conducted into the biology of lung cancers in an East-Asian population with a high proportion of non-smokers, and found that their disease is molecularly diverse, and distinct from what we classically see in smokers," co-corresponding author Jyoti Choudhary, a functional proteomics researcher at the Institute of Cancer Research, London, said in a statement.

While tumors in the male patients considered for that study were often marked by KRAS and APC gene mutations, the researchers reported, female lung adenocarcinoma cases from Taiwan were more prone to EGFR gene mutations. And in women with tumors that did not contain EGFR alterations, they saw a mutational signature stemming from APOBEC enzyme changes — a signature linked to drug resistance.

Likewise, that team detected tumor mutation differences in young and older women with lung cancer. In particular, the APOBEC-related mutational signature turned up more frequently in tumors from younger females with lung adenocarcinoma, while older females tended to have mutational signatures corresponding to past exposure to carcinogens in the environment. It also narrowed in on a few dozen genes with enhanced activity across the full tumor collection, highlighting potential treatment targets.

"[I]ntegrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention," Choudhary and her co-authors wrote, adding that the "multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma."

For a study centered on lung adenocarcinoma cases in current smoker, former-smoker, and never-smoker individuals from eight countries, on the other hand, researchers at the Broad Institute, Massachusetts General Hospital, and elsewhere brought together proteomic, phosphoproteomic, and acetylproteomic data for as many as 110 untreated tumors and 101 matched normal samples from patients in eight countries — protein profiles that were analyzed alongside available exome sequence, whole-genome sequence, RNA-seq, microRNA sequence, and array-based methylation patterns for the same samples.

"The samples represented diverse demographic and clinical characteristics, including country of origin and smoking status," authors of that study explained, noting that their integrative analyses focused mainly on clinically actionable proteomic or post-translational modifications, along with features not found in prior lung adenocarcinoma studies with more limited proteomic profiling.

That work, done through the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium, revealed four main tumor clusters that differed in their DNA driver mutations, geographical origins, and gender prevalence, but largely tracked with tumor clusters previously defined by transcriptomic features.

The team also uncovered proteomic and immune cell profiles that appeared to provide diagnostic and treatment clues. In addition to potentially targetable alterations affecting the EGFR, KRAS, and STK11 genes, for example, a phosphoproteomics-centered analysis unearthed recurrent fusions between ALK and genes such as EML4 or HMBOX1, as well as in-frame or frameshift fusions involving still other kinase enzyme-coding genes.

With a broader integrated genomic, proteomic, and epigenetic analysis, the researchers narrowed in on more refined clusters made up of tumors with shared immune features, proteomic shifts, or gene expression changes, corresponding to more or less pronounced immune responses.

"Integrated proteogenomics further allowed extensive characterization of the immune landscape of [lung adenocarcinomas] and identification of a number of potential therapeutic vulnerabilities, including anti-CTLA4 therapy and IDO1 inhibition in immune-hot tumors.

In the subset of tumors related to smoking, meanwhile, they noted that mutational signatures and stem cell-like features extended into nearby "normal" tissue, consistent with a "field cancerization effect" that may ultimately provide new clues to cancer development.

Authors of that paper cautioned that "associations of the sort described through this manuscript are hypothesis generating and generally cannot be understood as providing firm biological conclusions."

Still, they concluded, "We hope that both the specific observations and hypotheses delineated in this manuscript, and the data that underlie them, will be a rich resource for those investigating [lung adenocarcinoma] and for the larger research community, including the development of targeted chemo- and immuno-therapies."