Researchers employ proteogenomics, a combination of proteomics and genomics, to gain a deeper understanding of the molecular workings of lung adenocarcinoma
Lung cancer is the leading cause of cancer-related death in men, and the second leading cause in women just behind breast cancer. Lung adenocarcinoma (LUAD), a form of non-small cell lung cancer, accounts for about 40 percent of all lung cancers. LUAD is also the most common form of lung cancer in younger women and in Asian populations.
Like many other forms of lung cancer, there is a higher risk of developing LUAD in individuals who are cigarette smokers. However, LUAD is the most common type of lung cancer seen in non-smokers and women. While the adenocarcinoma grows relatively slowly compares to other types of lung cancer, metastasis tends to occur at earlier stages, making treatment more difficult by the time LUAD is diagnosed in patients.
The pathogenesis of LUAD is known to involve gene mutations and copy number alterations, as well as chromosomal rearrangements. These are believed to be linked to smoking as a mutagenic agent, thereby affecting the expression and activity of many cancer-related genes or causing chromosomal alterations that disrupt normal patterns of gene expression. However, much remains to be discovered about the details of genetic mutations and how they cause LUAD.
A new collaborative study between researchers from the Clinical Proteomic Tumour Analysis Consortium (CPTAC) and the International Cancer Proteogenome Consortium (ICPC) aims to fill the gaps in knowledge on how various gene mutations could result in the development of LUAD. This was achieved by applying comprehensive proteomics to genomics, in a field of study known as proteogenomics.
The CPTAC-led study investigated tumour tissue and healthy tissue from 110 LUAD patients, who were categorised based on proteomic features, key driver mutations, countries of origin, and their gender. Differences in protein signalling and tumour responses between these groups were found, along with the discovery of a fourth tumour subgroup. By comparing the tissue profiles of these groups, the researchers identified the rho guanine nucleotide exchanger factor 5 (ARHGEF5) protein as a potential target involved in LUAD development in non-smokers.
The proteomics analysis also demonstrated that high levels of activation were present for key proteins in tumour development, as well as anaplastic lymphoma kinase (ALK) fusion – a predictive biomarker that influences treatment decisions in lung cancer – and mutations of the epidermal growth factor receptor (EGFR) and KRAS genes. These mutations in turn affect the activity of several downstream cancer-related genes, making ALK, EGFR and KRAS potential targets for treatment development.
With relation to the above findings on gene activation, the researchers drew attention to the phosphorylation of the protein tyrosine phosphatase non-receptor type 11 (PTPN11), which was observed across ALK fusion- and EGFR mutation-driven tumours, suggesting that further research into targeting PTPN11 for cancer treatment may be worthwhile.
By examining the tumour immune micro-environment, the team also uncovered new immunosuppressive mechanisms, and observed alterations in white blood cells in tumours with specific mutations.
A team from Taiwan led by ICPC and including scientists from Academia Sinica, National Taiwan University, and Taipei Medical University in cooperation with the Institute of Cancer Research from the UK also investigated early stage LUAD in East Asian patients, specifically from Taiwan. By comparing matched tumour and normal tissue samples, the team found strong associations between mutagenesis of members of the apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) family of proteins, and carcinogenesis. APOBEC was also identified as a potential biomarker for early-stage diagnosis of LUAD and treatment development. The team also found links suggesting that reducing carcinogen exposure due to air pollution and food preservatives could be key to preventing lung cancer.
Proteomic characterisation of patients into five distinct categories also revealed a novel subtype of LUAD with aggressive clinical features. This new subtype was observed in patients with specific genetic mutations that were distinct from other known mutations. This discovery could be used for diagnosis and treatment determination.
According to Dr Pan-Chyr Yang from ICPC, “[proteogenomics] has provided new insights on the management of early stage never-smokers with LUAD”, allowing scientists to learn more about early-stage LUAD and therefore contributing to the development of new strategies for diagnosis and cancer management.
These methods could even be applied to the study of other forms of cancer, according to Dr. Henry Rodriguez, Director of the United States National Cancer Institute’s Office of Cancer Clinical Proteomics Research, who says: “The collective findings of these studies are a result of using proteogenomics in research to produce an additional dimension to cancer biology and organisations working together to take on cancer, with a focus on patients as cancer knows no borders.”