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Lung Cancer Progression, Prognostic Features Investigated in Proteogenomic Studies

NEW YORK – In a pair of new studies, independent research teams have demonstrated the potential for using proteogenomic approaches to characterize distinct forms of lung cancer — one focusing on the progression of lung adenocarcinoma the other on features found in small cell lung cancer.

For a paper published in Cell Reports Medicine on Friday, a team from Fudan University and other centers in China used exome sequencing, RNA sequencing, proteomic profiling, and phosphoproteomic analyses to characterize the progression from pre-invasive to invasive lung adenocarcinoma, a common form of non-small cell lung cancer (NSCLC).

"Our analysis provides a comprehensive multiomic landscape for pre-invasive and invasive lung adenocarcinoma, encompassing somatic gene mutations and signatures, arm-level events, proteome-based pathways, and the immune microenvironment," senior and co-corresponding author Haiquan Chen, a researcher with the Fudan University Shanghai Cancer Center, and his colleagues wrote.

The team's analyses included proteogenomic data on matched tumor and normal adjacent tissue samples from 98 pre-invasive lung adenocarcinoma cases, including adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), along with tumor-normal samples from 99 invasive lung adenocarcinoma cases.

From these data, the researchers focused in on one progression-related alteration in particular: an arm-level deletion affecting the 4q12 locus on chromosome 4. With the help of wound healing, migration, and cell migration assays, they found that the deletion, in turn, coincided with lower-than-usual expression levels of the mitophagy-related gene SPATA18, along with reduced levels of lysosome-like organelle markers.

"The deletion of chr4q12 contributes to the progression from pre-invasive to invasive adenocarcinoma by downregulating SPATA18," the authors reported, "thus suppressing mitophagy and promoting cell invasion."

Along with analyses focused on proteomics-based lung adenocarcinoma subtypes turning up at different stages of tumor progression, the team highlighted a handful of multiomics-based clusters corresponding to the immune cell types and immune responses found in relation to the lung tumors.

"Taken together, our findings provide insights into the proteomic characterization of pre-neoplasia of lung cancer and pave the way for future studies of lung cancer carcinogenesis," the study authors explained, adding that "data from this project serve as a valuable resource for the scientific community to explore the tumorigenesis and progression of lung adenocarcinoma, guiding the way to a deeper understanding of this lethal disease."

In a related paper published in Cell on Thursday, meanwhile, researchers from Tongji University and other centers in China and the US presented findings from a proteogenomic profiling and prognostic biomarker study of small cell lung cancer (SCLC), an aggressive form of lung cancer involving neuroendocrine carcinomas.

"Although targeted therapies and immunotherapies have tremendously improved the outcomes of NSCLC patients for molecularly defined subtypes, progress in the treatment of SCLC has been slow," senior and co-corresponding author Peng Zhang, a researcher with Tongji University's Shanghai Pulmonary Hospital, and colleagues wrote, noting that "[p]atient survival has not significantly improved over the last few decades, and SCLC still remains outside the realm of precision medicine."

The researchers used exome sequencing, RNA sequencing, and isobaric tandem mass tag labeling-based mass spectrometry on matched tumor and tumor-adjacent lung tissue samples from 112 treatment-naïve SCLC patients from China who were receiving surgical intervention. Based on those results, they built tumor mutation, copy number, expression, proteomic, and phosphoproteomic profiles that pointed to four SCLC molecular subtypes and offered a look at functional and prognostic insights into the tumors.

"Our comprehensive proteogenomic study explored the functional consequences of genomic aberrations, catalogued SCLC-associated molecular characteristics, identified actionable prognostic biomarkers, and provided a better understanding of patient stratification with personalized therapeutic strategies," the study authors explained.

In particular, the team delved into somatic gene mutations, deletions, and chromosomal alterations in the tumors, along with their biological, prognostic, and immune microenvironment consequences.

While enhanced expression of the HMGB3 gene coincided with increased SCLC cell migration and reduced patient survival, for example, the investigators linked ZFHX3 mutations to immune "hot" forms of SCLC marked by an enhanced tumor mutational burden, high cytotoxic immune cell and immune inhibitory cell activity, and increased potential response to immune checkpoint blockade therapy.

"Altogether, this work extends the understanding of SCLC cancer biology that could not be captured by genomic analysis and generates subtypes that may guide precision therapeutics," the authors wrote. "We hope that these findings will contribute to more effective SCLC clinical treatment in addition to providing a valuable resource for basic and clinical researchers."