Lung cancer is the leading cause of cancer-related deaths worldwide. Despite growing efforts for its early detection by screening populations at risk, the majority of lung cancer patients are still diagnosed in an advanced stage. The management of lung cancer has dramatically improved in the last decade and is no longer based on the “one-fits-all” paradigm or the general histological classification of non-small cell versus small cell lung cancer. Emerging options of targeted therapies and immunotherapies have shifted the management of lung cancer to a more personalized treatment approach, significantly influencing the clinical course and outcome of the disease. Molecular biomarkers have emerged as valuable tools in the prognosis and prediction of therapy response. In this review, we discuss the relevant biomarkers used in the clinical management of lung tumors, from diagnosis to prognosis. We also discuss promising new biomarkers, focusing on non-small cell lung cancer as the most abundant type of lung cancer.
BackgroundThe neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were analyzed in various carcinomas and their potential prognostic significance was determined. The objective of present study was to determine the correlation between these parameters and the survival of patients with small cell lung cancer (SCLC), since very few studies have been published on this type of carcinoma.Patients and methodsOne hundred and forty patients diagnosed with SCLC at University Hospital Center Zagreb, between 2012 and 2016 were retrospectively analyzed. Extensive-stage disease (ED) was verified in 80 patients and limited-stage disease (LD) in 60 patients. We analyzed the potential prognostic significance of various laboratory parameters, including NLR, PLR, and LMR, measured before the start of treatment.ResultsDisease extension, response to therapy, chest irradiation and prophylactic cranial irradiation (PCI), as well as hemoglobin, monocyte count, C-reactive protein (CRP), and lactate dehydrogenase (LDH) showed a prognostic significance in all patients. When we analyzed the patients separately, depending on the disease extension, we found that only skin metastases as well as LDH and NLR values, regardless of the cut-off value, had a prognostic significance in ED. Meanwhile, the ECOG performance status, chest irradiation, PCI, and hemoglobin and creatinine values had a prognostic significance in LD.ConclusionsNLR calculated before the start of the treatment had a prognostic significance for ED, while PLR and LMR had no prognostic significance in any of the analyzed groups of patients.
Chronic obstructive pulmonary disease (COPD) is a chronic disease characterized by a progressive decline in lung function due to airflow limitation, mainly related to IL-1β-induced inflammation. We have hypothesized that single nucleotide polymorphisms (SNPs) in NLRP genes, coding for key regulators of IL-1β, are associated with pathogenesis and clinical phenotypes of COPD. We recruited 704 COPD individuals and 1238 healthy controls for this study. Twenty non-synonymous SNPs in 10 different NLRP genes were genotyped. Genetic associations were estimated using logistic regression, adjusting for age, gender, and smoking history. The impact of genotypes on patients’ overall survival was analyzed with the Kaplan–Meier method with the log-rank test. Serum IL-1β concentration was determined by high sensitivity assay and expression analysis was done by RT-PCR. Decreased lung function, measured by a forced expiratory volume in 1 s (FEV1% predicted), was significantly associated with the minor allele genotypes (AT + TT) of NLRP1 rs12150220 (p = 0.0002). The same rs12150220 genotypes exhibited a higher level of serum IL-1β compared to the AA genotype (p = 0.027) in COPD patients. NLRP8 rs306481 minor allele genotypes (AG + AA) were more common in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition of group A (p = 0.0083). Polymorphisms in NLRP1 (rs12150220; OR = 0.55, p = 0.03) and NLRP4 (rs12462372; OR = 0.36, p = 0.03) were only nominally associated with COPD risk. In conclusion, coding polymorphisms in NLRP1 rs12150220 show an association with COPD disease severity, indicating that the fine-tuning of the NLRP1 inflammasome could be important in maintaining lung tissue integrity and treating the chronic inflammation of airways.
Background: Lung cancer is the leading cause of cancer-related death worldwide, with 5-year overall survival less than 15%. Therefore, it is essential to find biomarkers for early detection and prognosis.Aberrant DNA methylation is a common feature of human cancers and its utility is already recognized in cancer management. The aim of this study was to explore the diagnostic and prognostic value of the promoter methylation status of the ASC/TMS1/PYCARD and MyD88 genes, key adaptor molecules in the activation of the innate immune response and apoptosis pathways. Methods: A total of 50 non-small cell lung cancer (NSCLC) patients were enrolled in the study. Methylation of bisulphite converted DNA was quantified by pyrosequencing in fresh frozen malignant tissues and adjacent non-malignant tissues. Associations between methylation and lung function, tumor grade and overall survival were evaluated using receiver-operating characteristics (ROC) analysis and statistical tests of hypothesis. Results: Methylation level of tested genes is generally low but significantly decreased in tumor tissues (ASC/ TMS1/PYCARD, P<0.0001; MyD88, P<0.0002), which correlates with increased protein expression. Three CpG sites were identified as promising diagnostic marker candidates; CpG11 (-63 position) in ASC/TMS1/ PYCARD and CpG1 (-253 position) and 2 (-265 position) in MyD88. The association study showed that the methylation status of the ASC/TMS1 CpG4 site (-34 position) in malignant and non-malignant tissues is associated with the overall survival (P=0.019) and the methylation status of CpG8 site (-92 position) is associated with TNM-stage (P=0.011). Conclusions:The methylation status of the ASC/TMS1/PYCARD and MyD88 promoters are promising prognostic biomarker candidates. However, presented results should be considered as a preliminary and should be confirmed on the larger number of the samples.
Chronic obstructive pulmonary disease (COPD) is considered as the strongest independent risk factor for lung cancer (LC) development, suggesting an overlapping genetic background in both diseases. A common feature of both diseases is aberrant immunity in respiratory epithelia that is mainly regulated by Toll-like receptors (TLRs), key regulators of innate immunity. The function of the flagellin-sensing TLR5 in airway epithelia and pathophysiology of COPD and LC has remained elusive. We performed case–control genetic association and functional studies on the importance of TLR5 in COPD and LC development, comparing Caucasian COPD/LC patients (n = 974) and healthy donors (n = 1283). Association analysis of three single nucleotide polymorphisms (SNPs) (rs725084, rs2072493_N592S, and rs5744174_F616L) indicated the minor allele of rs2072493_N592S to be associated with increased risk for COPD (OR = 4.41, p < 0.0001) and NSCLC (OR = 5.17, p < 0.0001) development and non-small cell LC risk in the presence of COPD (OR = 1.75, p = 0.0031). The presence of minor alleles (rs5744174 and rs725084) in a co-dominant model was associated with overall survival in squamous cell LC patients. Functional analysis indicated that overexpression of the rs2072493_N592S allele affected the activation of NF-κB and AP-1, which could be attributed to impaired phosphorylation of p38 and ERK. Overexpression of TLR5N592S was associated with increased chemosensitivity in the H1299 cell line. Finally, genome-wide transcriptomic analysis on WI-38 and H1299 cells overexpressing TLR5WT or TLR5N592S, respectively, indicated the existence of different transcription profiles affecting several cellular pathways potentially associated with a dysregulated immune response. Our results suggest that TLR5 could be recognized as a potential biomarker for COPD and LC development with functional relevance.
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