Blood-based lung cancer biomarkers identified through proteomic discovery in cancer tissues, cell lines and conditioned medium

Abstract

BackgroundSupport for early detection of lung cancer has emerged from the National Lung Screening Trial (NLST), in which low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20 % relative to chest x-ray. The US Preventive Services Task Force (USPSTF) recently recommended annual screening for the high-risk population, concluding that the benefits (life years gained) outweighed harms (false positive findings, abortive biopsy/surgery, radiation exposure). In making their recommendation, the USPSTF noted that the moderate net benefit of screening was dependent on the resolution of most false-positive results without invasive procedures. Circulating biomarkers may serve as a valuable adjunctive tool to imaging.ResultsWe developed a broad-based proteomics discovery program, integrating liquid chromatography/mass spectrometry (LC/MS) analyses of freshly resected lung tumor specimens (n = 13), lung cancer cell lines (n = 17), and conditioned media collected from tumor cell lines (n = 7). To enrich for biomarkers likely to be found at elevated levels in the peripheral circulation of lung cancer patients, proteins were prioritized based on predicted subcellular localization (secreted, cell-membrane associated) and differential expression in disease samples. 179 candidate biomarkers were identified. Several markers selected for further validation showed elevated levels in serum collected from subjects with stage I NSCLC (n = 94), relative to healthy smoker controls (n = 189). An 8-marker model was developed (TFPI, MDK, OPN, MMP2, TIMP1, CEA, CYFRA 21–1, SCC) which accurately distinguished subjects with lung cancer (n = 50) from high risk smokers (n = 50) in an independent validation study (AUC = 0.775).ConclusionsIntegrating biomarker discovery from multiple sample types (fresh tissue, cell lines and conditioned medium) has resulted in a diverse repertoire of candidate biomarkers. This unique collection of biomarkers may have clinical utility in lung cancer detection and diagnoses.Electronic supplementary materialThe online version of this article (doi:10.1186/s12014-015-9090-9) contains supplementary material, which is available to authorized users.

Identification and Characterization of Potential Biomarkers by Quantitative Tissue Proteomics of Primary Lung Adenocarcinoma

“…Many researchers have applied quantitative proteomic approaches or combined proteomic and genomic analyses for the systematic discovery of potential lung cancer biomarkers (13,14,(22)(23)(24)(25). We compared the 133 potential lung cancer biomarkers identified in the current study with six lung cancer biomarker-related proteome data sets.…”

“…Birse et al identified 179 candidate lung cancer biomarkers across three discovery platforms (lung cancer cell lines, conditioned medium, and fresh resected tissue) (23), and one protein (THY1) was identified in our list of candidates. Clark et al found 62 proteins that were commonly increased in abundance in NSCLC exosomes compared with HBE4 exosomes (24), and one protein (MUC5B) was found in our tissue proteome data set.…”

“…An alternative strategy for biomarker discovery is the use of tissue specimens, which may both reflect the progression of cancers in vivo and serve as prognostic markers. Several groups have successfully used tissue proteomic technologies to identify potential biomarkers in lung cancer (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Recently, Kikuchi et al performed an in-depth proteomic analysis of 3621 proteins from squamous cell carcinoma and ADC tissues using label-free quantitative proteomic approaches (14).…”

Probability of cancer in high‐risk patients predicted by the protein‐based lung cancer biomarker panel in China: LCBP study

“…21 These malignant tumors are difficult to differentiate from the benign ones due to the limitations of current diagnostic methods, 22 especially for solitary pulmonary nodules measuring <8 mm in diameter. However, only 1.1% to 12.0% of these solitary nodules are found to be malignant.…”

“…23,24 Currently in China, the procedures for the early diagnosis of lung cancer are primarily localized in general hospitals. 21 Our previous preliminary single-center study demonstrated that a panel of 4 biomarkers can improve the efficacy of CT scanning in identifying patients with lung cancer. 21 Our previous preliminary single-center study demonstrated that a panel of 4 biomarkers can improve the efficacy of CT scanning in identifying patients with lung cancer.…”