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Lipidomic Profiling of Lung Pleural Effusion Identifies Unique Metabotype for EGFR-Mutants in Non-Small Cell Lung Cancer

From left: Nurhidayah Basri, Dr Ho Ying Swan and Dr Yip Lian Yee


Ying Swan Ho1,*, Lian Yee Yip1,*, Nurhidayah Basri1, Vivian Su Hui Chong1, Chin Chye Teo1, Eddy Tan1, Kah Ling Lim2, Gek San Tan2, Xulei Yang3, Si Yong Yeo3, Mariko Si Yue Koh4, Anantham Devenand4, Angela Takano4, Daniel Shao Weng Tan5,6, Tony Kiat Hon Lim2,6

1 Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), Singapore
2 Department of Pathology, Singapore General Hospital, Singapore
3 Institute of High Performance Computing, Agency for Science, Technology and Research (A*STAR), Singapore
4 Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore
5 National Cancer Centre, Singapore
6 Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

Published in Scientific Reports 2017 6: 35110 (Online Version)



Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) being the predominant form of the disease, accounting for ~85–90% of all cases. Currently, small biopsy and cytological examination of malignant cells forms a cornerstone in the diagnosis of lung cancer. However, obtaining sufficient tumour cells from liquid biopsies remains a challenge with significant false-negative rate being a problem in the event of insufficient cell specimens. Pleural effusion (PE) is an abnormal accumulation of fluids in the pleural cavity surrounding the lungs. It occurs in 7–30% of all lung cancer cases and also in benign inflammatory conditions including pneumonia, tuberculosis and pulmonary disorders. As large amount of PE can lead to breathing difficulties and chest pain, doctors may drain the effusion as part of the treatment. To identify a cell/tissue-free diagnostic strategy for NSCLC, we investigated the global lipid profiles (lipidomes) of PE for unique metabolic signatures and novel diagnostic markers that can discriminate between benign and malignant PE. Univariate and multivariate analyses of 30 benign and 36 malignant cases with and without EGFR mutation revealed distinctive differences between the lipidomes of benign and malignant PE as well as between malignant EGFR and non-EGFR mutant subtypes. Polyunsaturated fatty acids (PUFAs) such as docosapentaenoic acid and docosahexaenoic acid gave superior sensitivity and specificity for detecting NSCLC when used singly. Additionally, several 20- and 22- carbon PUFAs and phospholipid species were significantly elevated in the EGFR compared to non-EGFR mutant subtype. A 7-lipid panel showed great promise in the stratification of EGFR from non-EGFR malignant PE. Collectively, our data demonstrated the clinical usefulness of PE-derived lipid species to stratify the presence of malignancy and mutational subtypes of NSCLC. Our identified panel can serve as a complementary approach to conventionalmethods of diagnosis, particularly in cases whentumour cells and tissues are limited or unavailable.

Figure 1. Principal component analysis scores plots for (A) benign (n=30) and malignant lung PE (n=36), and the PE of (B) EGFR mutant (n=19) and non-EGFR mutant (n=17) collected from the malignant patients. Green, blue and red circles represent the benign, malignant non-EGFR mutant and malignant EGFR mutant PE respectively. (C) Heat map of differential lipid metabolites derived from individual pairwise comparisons between benign, non-EGFR mutant and EGFR mutant PE samples. All represented species are statistically significant (VIP>1, p-value<0.05, fold change (FC)≥1.5) for at least one of the pairwise comparisons. Metabolites are grouped according to their lipid classes.


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