miRNA markers for subtyping of non-small cell lung cancer : a data-adaptive analysis of expression profiles

Background: Within the group of non-small cell lung cancers (NSCLC), the number of clinically relevant subtypes is increasing. At the same time, diagnostic tissue is more often sampled through minimally invasive procedures, making accurate subtyping difficult. microRNA (miRNA) molecules may be able to satisfy the need for molecular markers in NSCLC subtyping. Rationale: This study aims to identify miRNA markers for NSCLC subtyping. It is necessary to differentiate adenocarcinoma (Adeno) and squamous cell carcinoma (SqCC) because several therapeutics agents are only admitted for Adeno, not for SqCC. For his purpose, miRNA markers may provide diagnostic support. miRNA markers may also help to distinguish typical carcinoid (TC) and atypical carcinoid (AC), as the therapeutic approach is more aggressive for AC than for TC. Methods: In 33 NSCLC samples (ten Adeno, seven SqCC, eight TC, eight AC), the expression of 800 miRNA was quantified through the nCounter technology from NanoString. The data were quality-controlled, normalized and the removal of artefacts reduced the panel size to 543 miRNA. Through cluster calculations, the data were explored. The subsequent analysis was designed as a data-adaptive approach: Each miRNA was examined for its distributional properties through the Shapiro-Wilk test (for normality) and Levene’s test (for equal distribution) and accordingly categorized. Statistical testing for differences between all four groups was performed through one-way analysis of variance (ANOVA), Welch’s ANOVA, the Kruskal-Wallis test, and Welch’s ANOVA on ranks (all at α= 0.05). The significances were examined for differences in the two comparisons of interest through student’s t-test, Welch’s t-test, the Wilcoxon rank-sum test, and Welch’s ttest on ranks (all at α= 0.05). The false discovery rate was controlled, and the results had to pass a final quality control. Results and conclusion: Three miRNA markers were identified for Adeno/SqCC: miR.1246, miR.218.5p and miR.375, which fit into current knowledge of their biological role in lung cancers. For TC/AC subtyping, six markers were identified: miR.1202, miR.549a, miR.141.3p, miR.137, miR.1253 and miR.128. They are the first miRNA markers investigated specifically for differentiating the pulmonary carcinoids.

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