| dc.description.abstract | In Ireland, lung cancer represents the third most common cancer, after breast and
prostate cancer. Major improvements have been made in treating this disease with the
advent of targeted therapies and immunotherapy. These treatments have superior
outcomes compared to conventional chemotherapies and have less associated toxicities.
However, survival remains low with a 5 year overall survival of 24%. This is much lower
when comparing to other common cancers such as breast, prostate, and colorectal
cancer at 91%, 97%, and 65%, respectively. This is mainly due to the late stage of
diagnosis – the majority of patients, 57%, are diagnosed with distant disease where 5
year survival is 4.7% compared to a 5 year survival of 56.3% when diagnosed with
localised disease. Additionally, a substantial number of patients, up to 40%, lack a
targetable mutation, and those that do, inevitably develop resistance. Therefore,
identification of biomarkers, both diagnostic and predictive, remains crucial.
In this study, we describe two biomarkers, USO1 and Acyl-CoA oxidase 2 (ACOX2), which
may have potential predictive and diagnostic utility in non-small cell lung cancer
(NSCLC). KRAS mutations, the most commonly found mutation in NSCLC, demonstrates
genetic variation across populations. They also have been reported to represent a
distinct subtype of NSCLC. There is minimal data available regarding KRAS mutated
NSCLCs in Ireland and therefore this study also investigated the rates and histological
features of these carcinomas in an Irish cohort.
USO1 is a protein involved in Golgi transport (1) and ACOX2 is an enzyme involved in
peroxisomal bile acid synthesis and b-oxidation (2). These genes have been implicated in
many cancers, however, few studies exist in relation to NSCLC. Therefore, this study
aimed to investigate these genes as potential diagnostic and predictive biomarkers in
NSCLC.
Lung tissue from an Irish cohort, both fresh frozen, and FFPE samples were used to
investigate the expression and prognosis of these genes at the mRNA and protein levels,
respectively. In silico analysis was used to support these results, and to further
investigate the role of these biomarkers in NSCLC tumorigenesis.
In this study ACOX2 and USO1 were both altered in NSCLC compared to adjacent normal
lung, and both were prognostic.
USO1 was significantly overexpressed in NSCLC and this overexpression was seen in
early stage (Stage I) lung adenocarcinoma (LUAD) and lung squamous cell carcinoma
(LUSC). Therefore, USO1 may have a potential role as a diagnostic biomarker as well as a
target in these cancers.
ACOX2 expression was significantly decreased in NSCLC. Using in silico analysis, ACOX2
expression in LUSC was associated with an immunomodulatory role, switching from fatty
acid metabolism to an inflammatory role. Additionally, a significantly increased immune
infiltration with CD4+ T cells, macrophages, neutrophils, and dendritic cells was seen.
These changes may suggest ACOX2 switches its functional role in LUSC and may act as a
predictive biomarker for immunotherapy, however, validation of these results should be
undertaken.
Finally, KRAS G12C mutations were significantly associated with PD-L1 positivity (TPS
≥1%) in our Irish cohort compared to non-G12C and wild type NSCLCs. This finding
suggests these tumours may also derive superior response to immunotherapies.
The results from this study suggests USO1 and ACOX2 may have potential utility as
predictive biomarkers and could provide the basis for further investigative work into
potential treatment strategies. It could also provide the basis for development of
diagnostic biomarkers for early stage lung cancer in at risk individuals. | en |
