Diagnostic Marker For Lung Cancer Research Articles

Inhibition of proteinase-activated receptor 2 (PAR2) decreased the malignant progression of lung cancer cells and increased the sensitivity to chemotherapy

ObjectivesThis study aimed to study the effect of protease-activated receptor 2 (PAR2) on the proliferation, invasion, and clone formation of lung cancer cells. It also aimed to evaluate the inhibitory effect of melittin on PAR2 and the anti-lung cancer effect of melittin combined with gefitinib.MethodsThe correlation between the co-expression of PAR2 and epithelial–mesenchymal transition (EMT) markers was analyzed. PAR2 in A549 and NCI-H1299 cells was knocked down using siRNA. MTT assay, Transwell assay, and colony formation assay were used to detect the effects of PAR2 on cell proliferation, invasion, and clone formation. The anti-cancer effect of PAR2 knockdown on gefitinib treatment was analyzed. The synergistic effect of melittin on gefitinib treatment by inhibiting PAR2 and the underlying molecular mechanism were further analyzed and tested.ResultsThe expression of PAR2 was upregulated in lung cancer, which was associated with the poor prognosis of lung cancer. PAR2 knockdown inhibited the stemness and EMT of lung cancer cells. It also inhibited the proliferation, invasion, and colony formation of A549 and NCI-H1299 cells. Moreover, PAR2 knockdown increased the chemotherapeutic sensitivity of gefitinib in lung cancer. Melittin inhibited PAR2 and the malignant progression of lung cancer cells. Melittin increased the chemotherapeutic sensitivity of gefitinib in lung cancer by inhibiting PAR2.ConclusionPAR2 may promote the proliferation, invasion, and colony formation of lung cancer cells by promoting EMT. Patients with a high expression of PAR2 have a poor prognosis. Inhibition of PAR2 increased the chemotherapeutic sensitivity of gefitinib. PAR2 may be a potential therapeutic target and diagnostic marker for lung cancer.

Screening of plasma IL-6 and IL-17 in Bangladeshi lung cancer patients

Lung cancer is responsible for causing one of the highest numbers of cancer deaths. In Bangladesh, both men and women are affected by lung cancer, and environmental contaminants are believed to be one of the main risk factors apart from smoking. The diagnosis of lung cancer is difficult due to the delicate structure and complexity of the lungs. Diagnosis in later stages results in a poor prognosis of the disease. Tissue biopsy is the most reliable way of identifying lung cancer, but it is invasive and requires identification of the primary neoplasm within the lungs. As inflammation is involved in carcinogenesis, circulating levels of cytokines might be elevated in patients during the early stages of cancer. Increased IL-6 levels have been associated with the promotion of tumor growth, and IL-17 is believed to aid metastasis of lung cancer. In this study, the use of IL-6 and IL-17 was investigated as diagnostic markers for lung cancer. IL-6 and IL-17 levels were compared between 35 lung cancer patients and 19 healthy individuals. IL-6 levels were markedly elevated (7.417 pg/mL) in lung cancer cases compared to the controls (0.970 pg/mL), indicating a positive correlation (p < 0.05). IL-17 levels were only slightly higher in lung cancer patients (9.400 pg/mL) compared to healthy individuals (8.922 pg/mL). Both IL-6 and IL-17 levels were higher in patients with adenocarcinoma compared with other subtypes of lung cancer. Treatment with chemotherapy and radiotherapy did not significantly affect IL-6 levels. However, IL-17 levels were reduced due to cancer treatment. Further studies with larger sample sizes assessing the IL-6 and IL-17 in lung cancer patients are needed to establish the diagnostic role of the two cytokines.

Thyroid hormones as biomarkers of lung cancer: a retrospective study

Background Thyroid hormones are key regulators of several physiological processes, including differentiation, embryonic development, proliferation, and metabolism. Several prospective studies have shown a relationship between hyperthyroidism and cancer incidence; however, since the association between thyroid hormone levels and lung cancer remains controversial, this study aimed to determine the correlation between the same. Methods We retrospectively analyzed 289 patients, who were diagnosed with lung cancer at the Huzhou Central Hospital between January 2016 and January 2021, and 238 healthy subjects. The baseline clinical data of two groups were collected. The concentrations of thyroid hormones, tumor CEA, CYF, SCC, and NSE in both the lung cancer patient and healthy volunteer groups were analyzed. Student’s t-test or Mann–Whitney test was used to compare continuous variables. A chi-square test was adopted to estimate the relationship between serum thyroid hormones level and clinical characteristics of lung cancer cases. ROC curve analyses were used to determine the characteristics of thyroid hormones for recognizing lung cancer. Results The results showed that serum thyroid stimulating hormone (TSH), total thyroxine, total triiodothyronine, and free triiodothyronine (FT3) levels were significantly decreased, while free thyroxine (FT4) levels were increased in patients with lung cancer. In addition, FT3 was identified as a potential diagnostic biomarker of stage I–IV lung cancer with the area under the curve values of 0.807. What’s more, FT3 and FT4 were used in combination with CEA and were identified as potential diagnostic biomarkers of stage 0 lung cancer (Tis) with the area under the curve values of 0.774. Conclusions Our study highlights the possibility of using thyroid hormones as innovative diagnostic markers for lung cancer.

Value of human epididymis secretory protein 4 in differentiating malignant from benign pleural effusion: an analysis of two cohorts.

Lung cancer is the most common cause of malignant pleural effusion (MPE). Serum human epididymis secretory protein 4 (HE4) is a useful diagnostic marker for lung cancer. This study aimed to evaluate the diagnostic accuracy of pleural fluid HE4 for MPE. A prospective, double-blind diagnostic test accuracy study. Patients with undiagnosed pleural effusion were enrolled in two cohorts (Hohhot and Changshu). Electrochemiluminescence immunoassay was used to detect pleural fluid HE4. The diagnostic accuracy of HE4 was evaluated by a receiver operating characteristic (ROC) curve, and the net benefit of HE4 was assessed by a decision curve analysis (DCA). A total of 66 MPEs and 86 benign pleural effusions (BPEs) were enrolled in the Hohhot cohort. In the Changshu cohort, 26 MPEs and 32 BPEs were enrolled. In both cohorts, MPEs had significantly higher pleural fluid HE4 than BPEs. The area under the ROC curve (AUC) of HE4 was 0.73 (95% CI: 0.64-0.81) in the Hohhot cohort and 0.79 (95% CI: 0.67-0.91) in the Changshu cohort. At a threshold of 1300 pmol/L, HE4 had sensitivities of 0.44 (95% CI: 0.33-0.56) in the Hohhot cohort and 0.54 (95% CI: 0.35-0.73) in the Changshu cohort. The corresponding specificities were 0.90 (95% CI: 0.83-0.95) in the Hohhot cohort and 0.94 (95% CI: 0.84-1.00) in the Changshu cohort. In subgroup analyses, HE4 had an AUC (95% CI) of 0.78 (0.71-0.85) in exudates and an AUC of 0.69 (0.57-0.81) in patients with negative effusion cytology. The DCA revealed that HE4 determination had a net benefit in both cohorts. Pleural fluid HE4 has moderate diagnostic accuracy for MPE and has net benefit in pleural effusion patients with unknown etiology.

Differential expression of long non-coding RNAs as diagnostic markers for lung cancer and other malignant tumors.

Due to advances in chip and sequencing technology, several types and numbers of long non-coding RNAs (lncRNAs) have been identified. LncRNAs are defined as non-protein-coding RNA molecules longer than 200 nucleotides, and are now thought as a new frontier in the study of human malignant diseases including NSCLC. Diagnosis of numerous malignant tumors has been closely linked to the differential expression of certain lncRNAs. LncRNAs are involved in gene expression regulation at multiple levels of epigenetics, transcriptional regulation, and post-transcriptional regulation. Mutations, deletions, or abnormal expression levels lead to physiological abnormalities, disease occurrence and are closely associated with human tumor diseases. LncRNAs play a crucial role in cancerous processes as either oncogenes or tumor suppressor genes. The expression of lncRNAs can regulate tumor cell in the proliferation, migration, apoptosis, cycle, invasion, and metastasis. As such, lncRNAs are potential diagnostic and treatment targets for cancer. And that, tumor biomarkers need to be detectable in easily accessible body samples, should be characterized by high specificity and sufficient sensitivity. Herein, it is significant clinical importance to screen and supplement new biomarkers for early diagnosis of lung cancer. This study aimed at systematically describing lncRNAs from five aspects based on recent studies: concepts, classification, structure, molecular mechanism, signal pathway, as well as review lncRNA implications in malignant tumor.

Is Methionyl-tRNA Synthetase Applicable as a Diagnostic Marker for Lung Cancer in Bronchial Ultrasound-Guided Brushing Cells?

Background and objective: Methionyl-tRNA synthetase (MARS) and A variant of Aminoacyl-tRNA synthetase interacting multifunctional protein 2 (AIMP2) with an exon 2 deletion (AIMP2-DX2) are known to be overexpressed in lung cancer. However, their role as diagnostic markers in lung cancer has not been well established. Thus, we evaluated their diagnostic performance in brushed cells obtained from nodular lung lesions suspected of lung cancer. Methods: Samples obtained by radial endobronchial ultrasound-guided brushing were processed for cytological examination with Papanicolaou (Pap) staining. Then, double IF staining with MARS and AIMP2-DX2 antibodies was measured in the cytology samples for peripheral lung nodules. The diagnostic performance was compared against biomarkers. Results: MARS IF staining was the only independent staining method used for the prediction of malignant cells. The area under the curve (AUC) of conventional cytology, MARS IF, and MARS IF plus cytology was 0.64, 0.68, and 0.69, respectively. The diagnostic accuracy was increased in MARS IF plus conventional cytology compared with cytology alone (71% vs. 47%). Conclusions: The combination of MARS staining with conventional cytology showed increases in the diagnostic accuracy for diagnosing lung nodules suspected of lung cancer on chest-computed tomography scans.

The Association Between Matrix Metalloproteinases-9-1562 C/T Polymorphism and Lung Cancer Susceptibility: A Systematic Review and Meta-Analysis

Introduction: Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinase. Several studies have reported the association between the single nucleotide polymorphisms(C/T) -1562 in the MMP-9 promoter and the risk of cancer. In this study, we decided to carry out a comprehensive meta-analysis to obtain a reasonable result about the association between this polymorphism and the risk of lung cancer. Materials and Methods: A complete literature review was conducted within the databases of ISI Web of Knowledge, google scholar, and PubMed for studies on lung cancer published from 2002 to 2018. A meta-analysis was conducted which included more than 3000 case and control subjects. The pooled Odds Ratio (OR) and 95% Confidence Intervals ( CI) were used for dominant, recessive, and co-dominant MMP-9 genotypes to assess the strength of the association. Results: Analysis indicated no significant association between MMP-9-1562C/T polymorphism and the risk of lung cancer, dominant model; [CT+TT/CC]: OR = 0.972, 95% CI = 0.811–1.164, recessive model [CC+CT/TT] OR= 1.027, 95% CI = 0.651–1.618 and co-dominant model [TT/CC] OR = 0.983, 95% CI = 0.550–1.755. Conclusions: No association was observed between the MMP9 -1562 C/T polymorphism and the incidence of lung cancer. The meta-analysis demonstrated that this polymorphism can't serve as a diagnostic marker for lung cancer.

Expression and Clinical Significance of Lipocalin-2 in the Serum of Lung Cancer Patients

背景与目的肺癌是全球发病率最高的癌症类型，严重威胁着人类健康。肺癌的早期诊断、早期治疗对于肺癌患者的生存尤为重要。血清中的肿瘤标志物作为肿瘤早期诊断的一种重要方法已被广泛应用。然而，肺癌的早期诊断标志物还很少。本研究旨在探讨Lipocalin-2在肺癌患者血清中的表达水平及其临床意义。方法采用酶联免疫吸附法（enzyme linked immunosorbent assay, ELISA）检测Lipocalin-2在60例肺癌患者与63例健康人群外周血血清中的浓度，并分析Lipocalin-2表达水平与肺癌临床特征之间的关系。结果Lipocalin-2在肺癌患者外周血血清中的表达水平明显高于健康人群，差异具有明显统计学意义（P < 0.001）。Lipocalin-2在肺癌患者中的表达与病理组织的分化、分期及淋巴结转移相关，差异具有明显统计学意义（P < 0.05）。Lipocalin-2在病理分化差的肺癌患者血清中的表达高于分化良好患者；在发生淋巴结转移的肺癌患者血清中的表达高于没有发生淋巴结转移患者；在临床Ⅲ期+Ⅳ期肺癌患者中的表达水平显著高于临床Ⅰ期Ⅱ期患者；差异均具有统计学意义（P < 0.05）。结论Lipocalin-2在肺癌患者血清水平中高表达，与病理组织的分化、分期及淋巴结转移相关，有望成为一种潜在的用于临床诊断的新型肺癌肿瘤标志物。

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Blood to Distinguish Lung Cancer Patients from Healthy Subjects.

Objective Inflammation-driven markers play a crucial role in tumorigenesis and tumor progression. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in blood are systemic inflammatory response markers. Some reports have showed that NLR and PLR are related to a poor prognosis in patients with lung cancer. However, little studies have reported whether NLR and PLR can be diagnostic markers for lung cancer. The aim of the current study is to investigate the roles of NLR and PLR in diagnosing lung cancer. Methods This study analyzed data from lung cancer patients and healthy individuals in Wuxi People's Hospital Affiliated with Nanjing Medical University. The Mann–Whitney U test was performed to compare differences between the lung cancer group and the control group. Based on white blood cell (WBC) counts, both lung cancer patients and healthy individuals were divided into the low-level group, moderate-level group, and high-level group. The Kruskal-Wallis test was applied to compare differences of NLR and PLR among those groups with different WBC counts. Spearman correlation analysis was used to assess correlations. Receiver operating characteristic (ROC) curves were performed to determine diagnostic accuracy. Results 210 patients diagnosed with lung cancer and 261 healthy subjects were enrolled in this study. Levels of NLR and PLR increased in the lung cancer group compared with the control group (P < 0.001). For the lung cancer group, NLR levels could rise with the increasing of WBC levels (P < 0.001) while PLR levels had no significant variation with the increasing of WBC levels (P = 0.206). For the control group, NLR levels could rise with the increasing of WBC levels (P < 0.001) while PLR levels would decline with the increasing of WBC levels (P < 0.001). In the lung cancer group, both NLR and PLR had no significant correlations with aspartate transaminase, urea, and glucose. The area under the curve (AUC) with 95% confidence interval (95% CI) of NLR and PLR to distinguish lung cancer patients from healthy subjects was, respectively, 0.684 (0.634-0.735) and 0.623 (0.571-0.674). When NLR and PLR were combined, AUC (95% CI) increased to 0.691 (0.642-0.740). Conclusions NLR and PLR alone have moderate ability to distinguish lung cancer patients from healthy subjects. Furthermore, combination forms of NLR and PLR can improve diagnostic ability.

Verification of expression of LINC00648 in the serum of lung cancer patients by TCGA database

TCGA data were used to verify the expression of LINC00648 in lung cancer patients to provide a reference for clinical practice. Lung cancer transcriptome data were downloaded by the TCGA database and LINC00648 data were extracted for analysis. Fifty-two patients with lung cancer diagnosed in our hospital from May 2014 to March 2016 were collected as the patient group and 30 normal people as the control group. RT-qPCR was used to detect the expression of LINC00648 in serum, follow up of patients was carried out, and bioinformatics was used to analyze the potential mechanism of LINC00648. LINC00648 was highly expressed in lung cancer. Lymphatic metastasis and probability of low differentiation were significantly increased, and the overall survival rate of highly expressed patients with lung cancer was reduced and the prognosis was poor. LINC00648 had 17 potential miR-targeted and 78 miR-targeted mRNAs. LINC00648 was found to have participated in SMAD binding, transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific DNA binding, PDZ domain binding, cytokine binding, activin binding, RNA polymerase II activating transcription factor binding, transforming growth factor-beta receptor binding, etc. LINC00648 participated in the signal pathways of the Hippo signaling pathway, Transcriptional misregulation in cancer, MAPK signaling pathway, Proteoglycans in cancer. There were 55 co-expression pairs in PPI protein co-expression analysis, of which KIF11 was the most common. High expression of LINC00648 in lung cancer patients indicates poor prognosis of patients and is expected to become a potential diagnostic marker for lung cancer.

Genomic characterization and outcome evaluation of kinome fusions in a large non-small cell lung cancer population.

9620 Background: Lung cancer is the leading cause of cancer death worldwide. Kinase fusion represents an important type of somatic alterations which promote oncogenesis and serve as a diagnostic marker in lung cancer. This study aims to identify the landscape of kinase fusions in lung cancer and expand our understanding of druggable fusions, together providing valuable information for therapeutics decision making. Methods: We performed genomic profiling of tumor/plasma biopsies of a total of 18,839 Chinese lung cancer patients using next generation sequencing (NGS) by targeting 425 cancer-relevant genes. Patients’ clinical characteristics and treatment history were retrospectively studied. Results: A total of 1,048 patients (5.56%, 1,048/18,839) were identified with kinase fusions, including 815 adenocarcinomas (ADCs) and 34 squamous cell carcinomas (SCCs). Briefly, a total of 198 unique gene fusion events have been observed, including 37 recurrent fusions and 114 novel fusions which have previously not been documented. ADC patients with kinase fusions were relatively younger than SCC patients (median: 53 vs 61 years old, p&lt; 0.01). The most frequently observed fusion was EML4-ALK for both ADCs (50.0%) and SCCs (32.4%), followed by FGFR3-TACC3 (29.4%) in SCCs and KIF5B-RET (11.8%), CD74-ROS1 (9.2%), CCDC6-RET (3.9%) and SLC34A2-ROS1 (2.3%) in ADCs, retrospectively. A total of 14 recurrent fusions including FN1-ALK, MEMO1-ALK, CUX1-ALK, KIF13A-RET and PHF20-NTRK1 were also identified at low frequencies. Of note, EML4- or STRN- ALK fusion events mainly rearranged in the intron 19 of ALK, but the breakpoints of VCL-ALK were mostly located upstream of ALK exon 18. Meanwhile, CD74-, SLC34A2- and TPM3- ROS1 rearrangement mainly occurred in the ROS1 introns 31, 33 and 34. In addition, among patients with novel fusions, RORB- ALK and AFF2-RET may potentially function as oncogenic drivers in lung cancer and have demonstrated clinical benefit from crizotinib treatment. Conclusions: Our data have depicted a comprehensive overview of the landscape of kinase fusions in lung cancer, which helps recognize potentially druggable fusions and translate into therapeutic applications.

Absolute Neutrophil Count and Mean Platelet Volume in the Blood as Biomarkers to Detect Lung Cancer.

Objective Inflammation plays an extremely considerable role in the development and progression of malignancies. Absolute neutrophil count (ANC) and mean platelet volume (MPV) in blood are associated with various inflammatory conditions and resulted in independent prognostic factors for lung cancer. However, whether ANC and MPV can be diagnostic markers for lung cancer remains unknown. This retrospective study investigated the roles of ANC and MPV, either alone or combined, in diagnosing lung cancer. Methods This study analyzed data from lung cancer patients and healthy individuals in Wuxi People's Hospital Affiliated with Nanjing Medical University. The Mann–Whitney U-test was performed to compare differences between lung cancer patients and healthy individuals. Spearman's correlation analysis was used to assess correlations. Receiver operating characteristic (ROC) curves were performed to determine diagnostic accuracy. Results 209 patients diagnosed with lung cancer and 236 healthy subjects were enrolled in this study. Levels of ANC and MPV increased in lung cancer patients compared with healthy individuals (P < 0.001). ANC had statistically significant negative weak correlation with albumin concentrations (r = ‐0.154, P = 0.026), and MPV had statistically significant negative weak correlation with total protein concentrations (r = ‐0.153, P = 0.027) in lung cancer patients. ANC and neutrophil-to-lymphocyte ratio had statistically significant positive correlation in both lung cancer patients (r = 0.756, P < 0.001) and healthy subjects (r = 0.639, P < 0.001). MPV and platelet-to-lymphocyte ratio had statistically significant negative weak correlation in both lung cancer patients (r = ‐0.242, P < 0.001) and healthy subjects (r = ‐0.325, P < 0.001). ANC had sensitivity (SEN) and specificity (SPE) of 0.512 and 0.809, respectively, and the area under the curve (AUC) with 95% confidence interval (95% CI) was 0.656 (0.603-0.710). SEN and SPE of MPV were 0.928 and 0.708, respectively, and the AUC (95% CI) was 0.913 (0.889-0.938). When ANC and MPV were combined, SEN and SPE became 0.842 and 0.835, respectively, and the AUC (95% CI) became 0.919 (0.895-0.943). Conclusions Compared with ANC or MPV alone, the combination of ANC and MPV can improve diagnostic ability to distinguish lung cancer patients from healthy subjects.

Vitamin B12 and its binding proteins in patients with non-small cell lung cancer referred to fast-track diagnostic work-up for lung cancer

High cobalamin levels have previously been associated with short-term cancer risk, including lung cancer. We explored whether levels of cobalamin and/or its binding proteins are useful as a diagnostic tool in patients suspected of non-small cell lung cancer. We included 889 patients referred for fast-track diagnosis of lung cancer to Aarhus University Hospital, Denmark. We analyzed plasma concentrations of cobalamin, transcobalamin, holotranscobalamin and haptocorrin. Information on lung cancer diagnosis was retrieved from a national database. The study cohort showed levels above reference intervals for cobalamin 12%, holotranscobalamin 25%, transcobalamin 9% and haptocorrin 36% (all p-values <.05). We observed no difference in cobalamin or holotranscobalamin levels when comparing patients diagnosed with non-small cell lung cancer (n = 161, 18%) to patients without lung cancer (n = 742, 80%), while transcobalamin showed minor differences. Haptocorrin was significantly higher in those with cancer, mainly among patients with adenocarcinoma (n = 94). A comparison of patients with the highest vs. lowest quartile levels of haptocorrin yielded an adjusted odds ratio for adenocarcinoma of 2.39 (95% confidence interval: 1.26–4.55). However, ROC curve analyzes showed haptocorrin (AUC = 0.55) and total transcobalamin (AUC = 0.56) to be poor diagnostic markers for lung cancer. A high proportion of patients suspected for non-small cell lung cancer showed increased levels of cobalamin-binding proteins. We thereby confirm the association between non-small cell lung cancer and high cobalamin levels and found that haptocorrin was the major underlying factor causing high cobalamin levels. However, none of these biomarkers were of diagnostic use among patients referred for suspected lung cancer.

Characterization of Protein Profiling and mRNA Expression of LLC Exosomes.

Circulating exosomes are promising biomarker source in various diseases. Exosomal constituents can stably exist in the circulating plasma and serum thus making them ideal biomarkers for a number of clinical applications. Exosomes can also mediate the occurrence of many types of diseases, including distal cancerous metastasis and tumour enlargement, through encapsulated proteins or RNAs, which regulate interactions among tissues. While performing these actions, exosomes show tissue specificity. However, the mechanism for such selection is not clear. For non-small cell lung cancer (NSCLC), molecular diagnostic markers and mechanisms of exosome-mediated tumour metastasis are not well understood. Therefore, in this study, we characterized LLC exosomal proteins and mRNAs by analysing their molecular profiles, laying a foundation for exploring diagnostic markers of lung cancer. Furthermore, the interactions between exosomal membrane proteins and their target proteins were analysed and revealed a possible tissue propensity of LLC cell-derived exosomes. These findings provide a theoretical basis for studying exosome-mediated tissue targeting and distal lung cancer metastasis.

Detection of Lung Cancer by Analysis of Exhaled Gas Utilizing Extractive Electrospray Ionization-Mass Spectroscopy.

In this study, extractive electrospray ionization and mass spectrometry (EESI-MS) was used to evaluate whether volatile organic compounds (VOCs) in exhaled gases can serve as specific diagnostic markers of lung cancer. The patients with lung cancer were diagnosed by chest CT or chest X-ray exam and confirmed by histopathology and cytology. Patients with pulmonary infections were identified by imaging, pathological diagnosis, or improvement of symptoms after antiinflammatory treatment. The control group had no lung abnormalities in imaging. Exhaled gases were collected using a Tedlar sampling bag and were detected using electrospray ionization mass spectrometry. By combining statistical and analytical chemistry, characteristic volatile organic compounds were screened. The results show that butadiene, orotic acid, tetrahydrobiopterin, and N-phenylacetylglutamine in lung cancer patients are significantly different from those in the control and lung infection groups.

Clinical significance of the expression of miRNA-21, miRNA-31 and miRNA-let7 in patients with lung cancer.

ObjectiveTo explore the expression differences of miRNA-21, miRNA-31 and miRNA-let7 between lung cancer patient and healthy people, thereby providing reference for early diagnosis of lung cancer.MethodReal-time PCR was employed to determine the expression difference between lung cancer patients (50 cases) and healthy people (24 cases). The clinical data of lung cancer patients were analyzed to explore the correlation between clinicopathological characteristics and expression level of miRNA-21, miRNA-31, miRNA-let7.ResultsThe relative expression levels of miRNA-21 and miRNA-31 in lung cancer group were obviously higher than those in healthy control group, and the relative expression level of miRNA-let7 in lung cancer group was slightly higher than that in healthy control group. Lung cancer patients with lymph node metastasis had higher expression level than those without lymph node metastasis. The ROC curve showed that the three miRNAs had clinical diagnosis efficiency for lung cancer, and the combined detection of the three miRNAs were more efficient in diagnosing lung cancer. Survival curve analysis suggested that the median survival times of patients in the miRNA-21 and miRNA-31 high expression groups were shorter than those in the low expression groups, and the median survival time of patients in miRNA-let7 high expression group was longer than that in the low expression group.ConclusionPlasma miRNA-21, miRNA-31 and miRNA-let7 may be diagnostic marker for lung cancer.

Abstract A22: Establishing a deep cfDNA methylation sequencing-based signature for noninvasive early-stage lung cancer diagnosis

Abstract Although mortality rate has been greatly reduced by low-dose computed tomography (LDCT) screening of high-risk patients, the benefit is compromised by the high false-positive rate, thus necessitating the development of biomarkers differentiating benign and malignant nodules. The role of aberrant DNA methylation in the process of tumorigenesis both at individual genes and a genome-wide scale has been well elucidated. It occurs very early in cancer development, and thus is capable of serving as a diagnostic biomarker. In this prospective study, we evaluated the feasibility and performance of assessing cfDNA methylation status as an early diagnostic marker for lung cancer. We developed a novel targeted bisulfite sequencing assay called ELSA and designed a methylation panel based on TCGA data on 838 lung cancer patients and 74 normal controls. We then interrogated the methylation status of 7,572 regions consisting of about 100,000 CpG sites from plasma samples of 163 newly recruited Chinese patients with early-stage NSCLC and 41 with benign nodules using our panel. A region-based methylation statistic was used in the classification model. We constructed diagnostic classification models using elastic net and random forest based on 3,000 DMRs selected by logistic regression between benign and malignant nodules using FFPE samples. Within this cohort, 54 patients had malignant tumor (39 stage I, 6 stage II and 9 stage IIIa) and 30 patients had benign nodules. We performed 5-fold cross-validation with 20 time repeats to gain a robust estimation of model performance, achieving a sensitivity of 92.6%, specificity of 100% and AUC of 98.1%. We further refined the DMRs selected above using 68 healthy baseline plasmas, and subsequently constructed a weighting decision tree model for plasma samples obtained from a separate cohort consisting of 163 patients with malignant tumor (127 stage I, 36 stage II and above) and 41 patients with hamartoma, chronic inflammation, granuloma, or other lung benign lesions, achieving a sensitivity of 84.0%, specificity of 85.7% and AUC of 90.7% based on 170 markers. We further analyzed PPVs according to stage and tumor size. PPVs for patients with stage I, II, and III diseases are 82.4%, 84.6%, and 94.4%, respectively; and for tumor diameter less than 1 cm, between 1-2 cm, and greater than 2 cm are 78.5%, 87.1%, and 88.2%, respectively. Citation Format: Zhihong Zhang, Naixin Liang, Wanglong Deng, Chenyang Wang, Tao Zheng, Wenjun Li, Jian Hu, Jinh Su, Han Han-Zhang, Bingsi Li, Hao Liu, Shanqing Li. Establishing a deep cfDNA methylation sequencing-based signature for noninvasive early-stage lung cancer diagnosis [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A22.

COX-2 rs5275 and rs689466 polymorphism and risk of lung cancer: A PRISMA-compliant meta-analysis.

Background:Cyclooxygenase-2 (COX-2) is an inducible enzyme that mediates the synthesis of prostaglandin, which plays an important role in the inflammation response. The overexpression of COX-2 in lung cancer has been found in several studies, suggesting that COX-2 contributes to carcinogenesis. There are many previous case-control studies focused on the association between COX-2 polymorphism and lung cancer risk, however, the conclusion remained controversial.Objectives:We performed this meta-analysis to evaluate the association between COX-2 rs5275 and rs689466 polymorphism and susceptibility to lung cancer.Methods:A systematic literature research was conducted on PubMed, Embase, Cochrane Library, OVID, Web of Science, and Google Scholar up to November 30, 2017. The quality of studies was assessed by Newcastle–Ottawa scale. We combined odds ratios (ORs) and 95% confidence intervals (CIs) in 5 different genetic models for evaluation under a fixed-effect model or random-effect model. Subgroup analysis was performed according to source of control, ethnicity, pathological types, and smoking status. Sensitivity analysis and publication bias were also conducted.Results:Eventually, 14 eligible studies were included in our meta-analysis. We found rs5275 gene polymorphism decreased the risk of lung cancer under heterozygote model (OR: 0.91, 95% CI: 0.84–0.98, P = .02). COX-2 rs689466 gene polymorphism was also related to a significantly reduced risk under allele (OR: 0.88, 95% CI: 0.82–0.95, P = .001), homozygote (OR: 0.81, 95% CI: 0.68–0.95, P = .01), heterozygote (OR: 0.81, 95% CI: 0.72–0.91, P < .001), and dominant model (OR: 0.81, 95% CI: 0.72–0.91, P < .001), except for recessive model. Subgroup analysis suggested a similar association in Asians, but not in Caucasians. Polymorphism of rs5275 was strongly associated with a reduced risk of lung adenocarcinoma according to stratified analysis by pathological types. Egger test identified no significant publication bias.Conclusions:Our meta-analysis demonstrated that COX-2 rs5275 and rs689466 polymorphism significantly decrease the risk of lung cancer in Asians but not in Caucasians, indicating COX-2 could serve as a potential diagnostic marker for lung cancer.

Body Fluids-Derived Exosomes: Paving the Novel Road to Lung Cancer Diagnosis and Therapy.

Lung cancer is a major human malignancy. Nowadays, the lack of specific diagnostic markers of lung cancer restricts the early diagnosis and therapy of patients. Exosomes, as spherical 30-100 nm microvesicles, are released by normal and cancer cells in both physiological and pathological circumstances. Exosomes carry various molecular cargos such as miRNA, proteins, mRNA, DNA and lipids. Therefore, analysis of the molecular profiles of exosomes may provide beneficial biomarkers for disease diagnosis. Exosomes can be transported by body fluids. The molecules (miRNAs and proteins) detected in body fluid exosomes may contribute to lung cancer diagnosis. In this review, we summarize typical molecules (miRNAs and proteins) in body fluids-derived exosomes to reveal the potential biomarkers in lung cancer. Besides, the role and the application of exosomes in chemotherapy and radiotherapy of lung cancer patients have also been discussed in this review.

Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) promotes lung tumorigenesis via attenuating p53 stability.

Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3/IMP3/KOC), initially identified as an RNA-binding protein, is highly expressed in embryonic tissues and a variety of cancers. Previously, our group reported that IGF2BP3 may serve as a potential diagnostic marker for lung cancer. However, little is known about the function of IGF2BP3 in lung cancer development. Here we demonstrate that IGF2BP3 expression was markedly increased in lung cancer tissues compared to normal tissues at both mRNA and protein levels. Overexpression of IGF2BP3 in lung cancer cells promoted cell proliferation, tumor migration and invasion in vitro and in vivo, whereas knockdown of IGF2BP3 exhibited opposite effects. Notably IGF2BP3 was directly associated with a deubiquitinase Ubiquitin specific peptidase 10 (USP10) and attenuated its function in stabilizing p53 protein. Silencing IGF2BP3 expression in lung cancer cells consistently increased the half-life and protein level of p53 and induced G0/G1 arrest. Thus, our data together demonstrate that IGF2BP3 promotes lung tumorigenesis via attenuating p53 protein stability.