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

Abstract

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.circulating biomarkers | risk prediction | miRNA ratios D espite recent advances in the management of resected lung cancer and the use of molecular targeted agents in specific clinical settings, the cure rate of non-small-cell lung cancer (NSCLC) remains low due to drug-refractory recurrent and metastatic disease.Early detection studies using chest X-rays (1) and, more recently, spiral-computed tomography (CT; refs. 2 and 3), have reported a significant increase in the number of lung cancer diagnoses, without apparent major decrease in advanced cancers or reduction of mortality in smokers (4). A recent press release (http://www.cancer.gov) reporting the findings of the largest randomized trial comparing spiral-CT to chest X-rays showed a 6.9% reduction in all-cause mortality (−20.3% lung cancer mortality), but a full report of the results of this trial is not yet available. A likely explanation of the limited impact of CT screening on mortality is that perhaps not all aggressive lung tumors arise from identifiable slow-growing precursors, suggesting a possible paradigm shift in our understanding of the natural history of lung cancer (5, 6). In this respect, the identification of biologic and molecular features of indolent and aggressive disease would be critical to define clinically useful predictors of high-risk lesions. microRNAs (miRNAs) are small RNA molecules with regulatory function and marked tissue specificity that can modulate multiple targets belonging to several pathways. They are fr...

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

“…A negative result was found in 810 out of the 1067 (76%) individuals without lung cancer and in 10 of the 48 (21%) individuals with lung cancer, and the authors suggested that the miRNA test could be used as a first-line screening tool in high-risk individuals. However, the usefulness of miRNAs extends beyond the early detection of NSCLC [89,90]. miRNA panels offer the possibility to differentiate NSCLC from benign lesions and to determine the histological tumour type from a tissue sample [87,91], with sensitivities and specificities within the range of 60-100%.…”

“…miRNA panels offer the possibility to differentiate NSCLC from benign lesions and to determine the histological tumour type from a tissue sample [87,91], with sensitivities and specificities within the range of 60-100%. In their analysis, Boeri et al [89] suggested that specific miRNAs detectable in plasma samples collected from healthy smokers with an average exposure of 40 pack-years allowed the identification of those with NSCLC 1-2 years before the first symptoms of lung cancer became evident and allowed determination of their prognoses. Cazzoli et al [92] screened 742 miRNAs isolated from circulating exosomes and identified four miRNAs (miR-378a, miR-379, miR-139-5p and miR-200b-5p) as screening markers to segregate lung adenocarcinoma and granuloma patients, from healthy former smokers (AUC = 0.908; P < 0.001).…”

Circulating Serum Exosomal miRNAs As Potential Biomarkers for Esophageal Adenocarcinoma

“…The ratio method used in our study was the same as that utilized by Boeri et al to develop diagnostic and prognostic miRNA signatures for lung cancer [17]. Boeri et al recently validated their miRNA signature in a large cohort of individuals with lung cancer [26], highlighting the potential for application in other cancers.…”

“…MiRNA expression data values were then derived for all possible permutations of miRNA ratios within each individual. This ratio method was identical to that utilized by Boeri et al [17] in an analysis of data from individuals with lung cancer. Altogether 9900 miRNA ratios were obtained.…”

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

“…Another example is the involvement of microvesicle-contained serum miRNAs which mediate the signalling of angiogenesis and thus promote uncontrolled cell proliferation in glioblastoma [42]. Additionally, serum miRNAs are promising non-invasive biomarkers for diverse diagnostic applications such as for multiple sclerosis [43] or for cancers [44][45][46][47]. It has been proposed that different subtypes of glioblastoma can be distinguished by their unique serum miRNA signatures [48].…”