Early studies have shown how aberrantly expressed microRNAs are a hallmark of several diseases like cancer. MicroRNA expression profiling was shown to be associated with tumour development, progression and response to therapy, suggesting their possible use as diagnostic, prognostic and predictive biomarkers. Moreover, based on the increasing number of studies demonstrating that microRNAs can function as potential oncogenes or oncosuppressor genes, with the goal to improve disease response and increase cure rates, miRNA-based anticancer therapies have recently been exploited, either alone or in combination with current targeted therapies. The advantage of using microRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. Here, we review our current knowledge about the involvement of microRNAs in cancer, and their potential as diagnostic, prognostic and therapeutic tools.

https://www.embopress.org/doi/pdf/10.1002/emmm.201100209

MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review

Although most lung cancers are a result of smoking, approximately 25% of lung cancer cases worldwide are not attributable to tobacco use, accounting for over 300,000 deaths each year. Striking differences in the epidemiological, clinical and molecular characteristics of lung cancers arising in never smokers versus smokers have been identified, suggesting that they are separate entities. This Review summarizes our current knowledge of this unique and poorly understood disease.

Lung Cancer in Never Smokers - Different Disease

Efficient patient management relies on early diagnosis of disease and monitoring of treatment. In this regard, much effort has been made to find informative, blood-based biomarkers for patients with cancer. Owing to their attributes-which are specifically modulated by the tumour-circulating cell-free microRNAs found in the peripheral blood of patients with cancer may provide insights into the biology of the tumour and the effects of therapeutic interventions. Moreover, the role of microRNAs in the regulation of different cellular processes points to their clinical utility as blood-based biomarkers and future therapeutic targets. MicroRNAs are optimal biomarkers owing to high stability under storage and handling conditions and their presence in blood, urine and other body fluids. In particular, detection of levels of microRNAs in blood plasma and serum has the potential for an earlier cancer diagnosis and to predict prognosis and response to therapy. This Review article considers the latest developments in the use of circulating microRNAs as prognostic and predictive biomarkers and discusses their utility in personalized medicine.

Clinical relevance of circulating cell-free microRNAs in cancer

The efficacy of computed tomography (CT) screening for early lung cancer detection in heavy smokers is currently being tested by a number of randomized trials. Critical issues remain the frequency of unnecessary treatments and impact on mortality, indicating the need for biomarkers of aggressive disease. We explored microRNA (miRNA) expression profiles of lung tumors, normal lung tissues and plasma samples from cases with variable prognosis identified in a completed spiral-CT screening trial with extensive follow-up. miRNA expression patterns significantly distinguished: (i) tumors from normal lung tissues, (ii) tumor histology and growth rate, (iii) clinical outcome, and (iv) year of lung cancer CT detection. Interestingly, miRNA profiles in normal lung tissues also displayed remarkable associations with clinical features, suggesting the influence of a permissive microenvironment for tumor development. miRNA expression analyses in plasma samples collected 1–2 y before the onset of disease, at the time of CT detection and in disease-free smokers enrolled in the screening trial, resulted in the generation of miRNA signatures with strong predictive, diagnostic, and prognostic potential (area under the ROC curve ≥ 0.85). These signatures were validated in an independent cohort from a second randomized spiral-CT trial. These results indicate a role for miRNAs in lung tissues and plasma as molecular predictors of lung cancer development and aggressiveness and have theoretical and clinical implication for lung cancer management.

/pdf/microrna-signatures-in-tissues-and-plasma-predict-4jwernp4fq.pdf

MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer

Epidemiology of Lung Cancer : Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Plasma microRNAs as potential biomarkers for non-small-cell lung cancer

Adenocarcinoma is the most common type of lung cancer, the leading cause of cancer deaths in the world. Early detection is the key to improve the survival of lung adenocarcinoma patients. We have previously shown that microRNAs (miRNAs) were stably present in sputum and could be applied to diagnosis of lung cancer. The aim of our study was to develop a panel of miRNAs that can be used as highly sensitive and specific sputum markers for early detection of lung adenocarcinoma. Our study contained 3 phases: (i) marker discovery using miRNA profiling on paired normal and tumor lung tissues from 20 patients with lung adenocarcinoma; (ii) marker optimization by real-time reverse transcription-quantitative polymerase chain reaction on sputum of a case-control cohort consisting of 36 cancer patients and 36 health individuals and (iii) validation on an independent set of 64 lung cancer patients and 58 cancer-free subjects. From the surgical tissues, 7 miRNAs with significantly altered expression were identified, of which "4" were overexpressed and "3" were underexpressed in all 20 tumors. On the sputum samples of the case-control cohort, 4 (miR-21, miR-486, miR-375 and miR-200b) of the 7 miRNAs were selected, which in combination produced the best prediction in distinguishing lung adenocarcinoma patients from normal subjects with 80.6% sensitivity and 91.7% specificity. Validation of the marker panel in the independent populations confirmed the sensitivity and specificity that provided a significant improvement over any single one alone. The sputum markers demonstrated the potential of translation to laboratory settings for improving the early detection of lung adenocarcinoma.

/pdf/early-detection-of-lung-adenocarcinoma-in-sputum-by-a-panel-16ue2a6fxd.pdf

Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers

Background
Making a definitive preoperative diagnosis of solitary pulmonary nodules (SPNs) found by CT has been a clinical challenge. We previously demonstrated that microRNAs (miRNAs) could be used as biomarkers for lung cancer diagnosis. Here we investigate whether plasma microRNAs are useful in identifying lung cancer among individuals with CT-detected SPNs.

/pdf/diagnosis-of-lung-cancer-in-individuals-with-solitary-1vludmokkf.pdf

Diagnosis of lung cancer in individuals with solitary pulmonary nodules by plasma microRNA biomarkers

Purpose: The early detection of lung cancer in heavy smokers by low-dose CT (LDCT) can reduce the mortality. However, LDCT screening increases the number of indeterminate solitary pulmonary nodules (SPN) in asymptomatic individuals, leading to overdiagnosis. Making a definitive preoperative diagnosis of malignant SPNs has been a clinical challenge. We have demonstrated that sputum miRNAs could provide potential biomarkers for lung cancer. Here, we aimed to develop sputum miRNA biomarkers for diagnosis of malignant SPNs. Experimental Design: Using quantitative RT-PCR, we evaluated expressions of 13 sputum miRNAs, previously identified sputum miRNA signatures of lung cancer, in a training set of 122 patients with either malignant ( n = 60) or benign SPNs ( n = 62) to define a panel of biomarkers. We then validated the biomarker panel in an internal testing set of 136 patients with either malignant ( n = 67) or benign SPNs ( n = 69), and an external testing cohort of 155 patients with either malignant ( n = 76) or benign SPNs ( n = 79). Results: In the training set, a panel of three miRNA biomarkers (miRs21, 31, and 210) was developed, producing 82.93% sensitivity and 87.84% specificity for identifying malignant SPNs. The sensitivity and specificity of the biomarkers in the two independent testing cohorts were 82.09% and 88.41%, 80.52% and 86.08%, respectively, confirming the diagnostic value. Conclusions: Sputum miRNA biomarkers may improve LDCT screening for lung cancer in heavy smokers by preoperatively diagnosing malignant SPNs. Nevertheless, a prospective study in a large population to validate the biomarkers is needed. Clin Cancer Res; 21(2); 484–9. ©2015 AACR .

/pdf/sputum-microrna-biomarkers-for-identifying-lung-cancer-in-4uqtm3jvv2.pdf

Sputum microRNA biomarkers for identifying lung cancer in indeterminate solitary pulmonary nodules.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death. Early detection of NSCLC will improve its outcome. We previously identified genetic signatures whose genomic copy number aberrations were associated with early stage NSCLC. Here, we aimed to develop a panel of genes that could be detected in sputum for NSCLC early detection. We first optimized a panel of genes by using an in situ minichip for measuring changes of the signatures in sputum of a case-control cohort of 49 NSCLC patients, 49 patients with chronic obstructive pulmonary disease (COPD), and 49 healthy smokers. We then validated the genes in an independent cohort of 69 NSCLC patients and 65 noncancer subjects. The results were compared with those of sputum cytology. Fifteen genes showed significant differences of their copy number changes in sputum between NSCLC and both COPD and healthy subjects. A logistic regression model with the best prediction was built on the basis of 6 genes, ENO1, FHIT, HYAL2, SKP2, p16, and 14-3-3zeta. The composite of the 6 genes produced 86.7% sensitivity and 93.9% specificity in distinguishing stage I NSCLC patients from the noncancer individuals. Furthermore, the genes had higher sensitivity (86.9%) in identification of squamous cell carcinoma (SCC) than in adenocarcinoma of the lungs (80.8%; P < 0.05). Validation of the genes in the independent cohort confirmed their diagnostic power that also showed higher accuracy for lung SCCs than for sputum cytology. The gene panel could provide sputum-based markers that have the potential to improve early detection of lung SCCs.

https://cancerpreventionresearch.aacrjournals.org/content/canprevres/3/12/1571.full.pdf

Howard Zhang

Papers

Plasma microRNAs as potential biomarkers for non-small-cell lung cancer

Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers

Diagnosis of lung cancer in individuals with solitary pulmonary nodules by plasma microRNA biomarkers

Sputum microRNA biomarkers for identifying lung cancer in indeterminate solitary pulmonary nodules.

A panel of sputum-based genomic marker for early detection of lung cancer.