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Cancers (Basel). 2019 Jan 10;11(1). pii: E70. doi: 10.3390/cancers11010070.

The Circulating Transcriptome as a Source of Biomarkers for Melanoma.

Author information

1
Molecular Oncology group, Biodonostia Research Institute, San Sebastián 20012, Spain. carla.sole@biodonostia.org.
2
Department of Oncology, University of Oxford, Oxford OX3 9DU, UK. dtramonti@hotmail.com.
3
Molecular Oncology group, Biodonostia Research Institute, San Sebastián 20012, Spain. m.schramm02@googlemail.com.
4
Faculty of Biosciences, University of Heidelberg, Heidelberg 69120, Germany. m.schramm02@googlemail.com.
5
Molecular Oncology group, Biodonostia Research Institute, San Sebastián 20012, Spain. ibai.goicoechea@biodonostia.org.
6
Molecular Oncology group, Biodonostia Research Institute, San Sebastián 20012, Spain. maria.armesto@biodonostia.org.
7
Molecular Oncology group, Biodonostia Research Institute, San Sebastián 20012, Spain. luiza.hernandez@liu.se.
8
Molecular Oncology group, Biodonostia Research Institute, San Sebastián 20012, Spain. lorea.manterola@biodonostia.org.
9
Molecular Oncology group, Biodonostia Research Institute, San Sebastián 20012, Spain. marta.fernandez@biodonostia.org.
10
Onkologikoa-Oncology Institute Gipuzkoa, Gipuzkoa 20012, Spain. kmujika@onkologikoa.org.
11
Department of Dermatology, Hospital Universitario de Donostia, San Sebastian 20012, Spain. annadonosti@gmail.com.
12
Department of Dermatology, Hospital Universitario de Donostia, San Sebastian 20012, Spain. iratzia@hotmail.com.
13
Molecular Oncology group, Biodonostia Research Institute, San Sebastián 20012, Spain. maitena.tellaeche@biodonostia.org.
14
Genomics and Disease group, Centre for Genomic Regulation (CRG), Barcelona 08003, Spain. marc.friedlander@scilifelab.se.
15
Universitat Pompeu Fabra (UPF), Barcelona 08002, Spain. marc.friedlander@scilifelab.se.
16
Centro de Investigación Biomédica en Red Epidemiología y Salud Pública (CIBERESP), Barcelona 08002, Spain. marc.friedlander@scilifelab.se.
17
Hospital del Mar Research Institute (IMIM), Barcelona 08003, Spain. marc.friedlander@scilifelab.se.
18
Science for Life Laboratory, The Wenner-Gren Institute, Stockholm University, Stockholm SE-106 9, Sweden. marc.friedlander@scilifelab.se.
19
Genomics and Disease group, Centre for Genomic Regulation (CRG), Barcelona 08003, Spain. xavier.estivill@crg.es.
20
Universitat Pompeu Fabra (UPF), Barcelona 08002, Spain. xavier.estivill@crg.es.
21
Centro de Investigación Biomédica en Red Epidemiología y Salud Pública (CIBERESP), Barcelona 08002, Spain. xavier.estivill@crg.es.
22
Hospital del Mar Research Institute (IMIM), Barcelona 08003, Spain. xavier.estivill@crg.es.
23
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. p.piazza@imperial.ac.uk.
24
Imperial BRC Genomics Facility, Imperial College London, London SW7 2AZ, UK. p.piazza@imperial.ac.uk.
25
Department of Dermatology, 12 de Octubre Hospital, Madrid 28041, Spain. pablo.ortiz@salud.madrid.org.
26
Medical School, Universidad Complutense, Institute i+12, Centro de Investigación Biomédica en Red en Oncologia (CIBERONC), Madrid 28040, Spain. pablo.ortiz@salud.madrid.org.
27
Department of Oncology, University of Oxford, Oxford OX3 9DU, UK. mark.middleton@oncology.ox.ac.uk.
28
Molecular Oncology group, Biodonostia Research Institute, San Sebastián 20012, Spain. charles.lawrie@biodonostia.org.
29
Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK. charles.lawrie@biodonostia.org.
30
IKERBASQUE, Basque Foundation for Science, Bilbao 48013, Spain. charles.lawrie@biodonostia.org.

Abstract

The circulating transcriptome is a valuable source of cancer biomarkers, which, with the exception of microRNAs (miRNAs), remains relatively unexplored. To elucidate which RNAs are present in plasma from melanoma patients and which could be used to distinguish cancer patients from healthy individuals, we used next generation sequencing (NGS), and validation was carried out by qPCR and/or ddPCR. We identified 442 different microRNAs in samples, eleven of which were differentially expressed (p < 0.05). Levels of miR-134-5p and miR-320a-3p were significantly down-regulated (p < 0.001) in melanoma samples (n = 96) compared to healthy controls (n = 28). Differentially expressed protein-encoding mRNA 5'-fragments were enriched for the angiopoietin, p21-activated kinase (PAK), and EIF2 pathways. Levels of ATM1, AMFR, SOS1, and CD109 gene fragments were up-regulated (p < 0.001) in melanoma samples (n = 144) compared to healthy controls (n = 41) (AUC = 0.825). Over 40% of mapped reads were YRNAs, a class of non-coding RNAs that to date has been little explored. Expression levels of RNY3P1, RNY4P1, and RNY4P25 were significantly higher in patients with stage 0 disease than either healthy controls or more advanced stage disease (p < 0.001). In conclusion, we have identified a number of novel RNA biomarkers, which, most importantly, we validated in multi-center retrospective and prospective cohorts, suggesting potential diagnostic use of these RNA species.

KEYWORDS:

RNA species; YRNA; biomarker; liquid biopsy; mRNA; melanoma; miRNA; plasma

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