Small Non-Coding RNA Profiling in Plasma Extracellular Vesicles of Bladder Cancer Patients by Next-Generation Sequencing: Expression Levels of miR-126-3p and piR-5936 Increase with Higher Histologic Grades.

Alexandru A Sabo,Serena Aneli,Marco Oderda,Carlotta Sacerdote,Mihnea P Dragomir,Paolo Vineis,Alessio Naccarati,Giovanni Birolo,Barbara Pardini,Marco Allasia,Paolo Gontero,Giuseppe Matullo,Alessandra Allione

doi:10.3390/cancers12061507

Abstract

Bladder cancer (BC) is the tenth most frequent cancer worldwide. Due to the need for recurrent cystoscopies and the lack of non-invasive biomarkers, BC is associated with a high management burden. In this respect, small non-coding RNAs (sncRNAs) have been investigated in urine as possible biomarkers for BC, but in plasma their potential has not yet been defined. The expression levels of sncRNAs contained in plasma extracellular vesicles (EVs) from 47 men with BC and 46 healthy controls were assessed by next-generation sequencing. The sncRNA profiles were compared with urinary profiles from the same subjects. miR-4508 resulted downregulated in plasma EVs of muscle-invasive BC patients, compared to controls (adj-p = 0.04). In World Health Organization (WHO) grade 3 (G3) BC, miR-126-3p was upregulated both in plasma EVs and urine, when compared to controls (for both, adj-p < 0.05). Interestingly, two sncRNAs were associated with the risk class: miR-4508 with a downward trend going from controls to high risk BC, and piR-hsa-5936 with an upward trend (adj-p = 0.04 and adj-p = 0.05, respectively). Additionally, BC cases with low expression of miR-185-5p and miR-106a-5p or high expression of miR-10b-5p showed shorter survival (adj-p = 0.0013, adj-p = 0.039 and adj-p = 0.047, respectively). SncRNAs from plasma EVs could be diagnostic biomarkers for BC, especially in advanced grade.

Highlights

Bladder cancer (BC) ranks as the tenth most frequent diagnosed human cancer worldwide, with549,393 new cases and 199,922 related deaths being reported in 2018, according to the GLOBOCAN statistics [1].BC has a marked male predominance, with a 3:1 male-to-female ratio [2]
We created a count matrix composed by 93 samples and 2408 small non-coding RNAs (sncRNAs) having at least one read in one sample
We investigated by high throughput sequencing technology the sncRNA profiles in plasma derived extracellular vesicles (EVs) in all stages of BC and matched controls, with the aim to find non-invasive biomarkers that could be a valid alternative to cystoscopy

Summary

Introduction

Bladder cancer (BC) ranks as the tenth most frequent diagnosed human cancer worldwide, with549,393 new cases and 199,922 related deaths being reported in 2018, according to the GLOBOCAN statistics [1].BC has a marked male predominance, with a 3:1 male-to-female ratio [2]. Bladder cancer (BC) ranks as the tenth most frequent diagnosed human cancer worldwide, with. 549,393 new cases and 199,922 related deaths being reported in 2018, according to the GLOBOCAN statistics [1]. BC has a marked male predominance, with a 3:1 male-to-female ratio [2]. BC incidence peaks at an older age (5th to 7th decade) and is strongly connected to the habit of smoking. Occupational and environmental carcinogens are additional contributing risk factors. BC is more prevalent in countries with a high human development index [2,3]. In some world regions, like Northern and sub-Saharan Africa, higher prevalence is attributed to the Schistosoma haematobium infection [4]

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