miR375-3p Distinguishes Low-Grade Neuroendocrine From Non-neuroendocrine Lung Tumors in FFPE Samples

Abstract

Lung cancer is still one of the leading cause of death worldwide. The clinical variability of lung cancer is high and drives treatment decision. In this context, correct discrimination of pulmonary neuroendocrine tumors is still of critical relevance. The spectrum of neuroendocrine tumors is various, and each type has molecular and phenotypical differences. In order to advance in the discrimination of neuroendocrine from non-neuroendocrine lung tumors, we tested a series of 95 surgically resected and formalin-fixed paraffin embedded lung cancer tissues, and we analyzed the expression of miR205-5p and miR375-3p via TaqMan RT-qPCR. Via a robust mathematical approach, we excluded technical outliers increasing the data reproducibility. We found that miR375-3p levels are higher in low-grade neuroendocrine lung tumor samples compared to non-neuroendocrine lung tumors. However, miR375-3p is not able to distinguish among different types of neuroendocrine lung tumors. In this work, we provide a new molecular marker for distinguishing non-neuroendocrine from low-grade neuroendocrine lung tumors samples establishing an easy miRNA score to be used in clinical settings, enabling the pathologist to classify more accurately lung tumors biopsies, which may be ambiguously cataloged in routine examination.

MiRNA Expression in Neuroendocrine Neoplasms of Frequent Localizations

“…Small intestine miRNA-375 [24] miRNA-375 miRNA-21 miRNA-143 [25] miRNA-204-5p miRNA-7-5p miRNA-1 miRNA-143 [6] miRNA-186 [26] miRNA-133a [27] miRNA-182 miRNA-196a miRNA-200a miRNA-31 miRNA-129-5p miRNA-133a [28] miRNA-21 miRNA-1290 miRNA-137 miRNA-204-5p miRNA-486-5p miRNA-30c [24] miRNA-95 miRNA-210 miRNA-378a-3p [29] miRNA-150-5p [30] miRNA-885-5p [28] [21,39,40] miRNA-150 miRNA-886-3p [38] miRNA-92a2 miRNA-7 miRNA-150 miRNA-886-3p [8,10] miRNA-34a miRNA-21 [41] miRNA-92a-2 miRNA-147 miRNA-574-5p [42] miRNA-150 miRNA-886-3p [43] miRNA-7 [44] miRNA-192 miRNA-200c miRNA-205 [45] miRNA-409-3p miRNA-409-5p miRNA-431-5p [8,10] Unlike a number of other malignant diseases, miRNA expression in patients diagnosed with NENs is not well understood. One of the reasons for this is the low prevalence of this disease.…”

“…An increased level of the expression of miRNA-21 and miRNA-34a was shown in different types of lung NEN [41]. In an investigation of miRNA-205-5p and miRNA-375-3p expression in NENs and other malignant lung tumors, it has been shown that miRNA-205-5p does not have discriminatory properties, in contrast to miRNA-375-3p [39].…”

“…MiRNA-7-5p and miRNA-96-5p are characteristic of both NENs of the stomach and NENs of the intestine [10,19]. MiRNA-137, miRNA-196a and miRNA-1290 are characteristic of NENs of the intestine and pancreas [8,24,28]; miRNA-1 and miRNA-143 are characteristic of NENs of the intestine and lung [6,21,39,40]; miRNA-222 is characteristics of NENs of the lung and stomach [32] and miRNA-155 and miRNA-224 are characteristic of NENs of the lung and pancreas [35,38,47]. It should be noted that the largest number of miRNAs expressed in more than one type of NEN is expressed in intestinal NENs (75% expressed in different types of NEN), followed by the lung NENs.…”

“…Distinguishes low-grade neuroendocrine lung tumors from non-neuroendocrine lung tumors with 92.6% of sensitivity and 90.4% of specificity qRT-PCR [39] miRNA-21, miRNA-155…”

Measurements Methods for the Development of MicroRNA-Based Tests for Cancer Diagnosis

“…In 2019 miR-223 was validated as a reproducible, effective serum biomarker of early-stage non-small-cell lung cancer using ddPCR technology [ 75 ]. A recent study from Detassis and colleagues demonstrated that miR375-3p distinguishes low-grade neuroendocrine from non-neuroendocrine lung tumors in FFPE samples [ 76 ].…”