title: MiR expression profiles of paired primary colorectal cancer and metastases by next-generation sequencing.
abstract: MicroRNAs (miRs) have been recognized as promising biomarkers. It is unknown to what extent tumor-derived miRs are differentially expressed between primary colorectal cancers (pCRCs) and metastatic lesions, and to what extent the expression profiles of tumor tissue differ from the surrounding normal tissue. Next-generation sequencing (NGS) of 220 fresh-frozen samples, including paired primary and metastatic tumor tissue and non-tumorous tissue from 38 patients, revealed expression of 2245 known unique mature miRs and 515 novel candidate miRs. Unsupervised clustering of miR expression profiles of pCRC tissue with paired metastases did not separate the two entities, whereas unsupervised clustering of miR expression profiles of pCRC with normal colorectal mucosa demonstrated complete separation of the tumor samples from their paired normal mucosa. Two hundred and twenty-two miRs differentiated both pCRC and metastases from normal tissue samples (false discovery rate (FDR) <0.05). The highest expressed tumor-specific miRs were miR-21 and miR-92a, both previously described to be involved in CRC with potential as circulating biomarker for early detection. Only eight miRs, 0.5% of the analysed miR transcriptome, were differentially expressed between pCRC and the corresponding metastases (FDR <0.1), consisting of five known miRs (miR-320b, miR-320d, miR-3117, miR-1246 and miR-663b) and three novel candidate miRs (chr 1-2552-5p, chr 8-20656-5p and chr 10-25333-3p). These results indicate that previously unrecognized candidate miRs expressed in advanced CRC were identified using NGS. In addition, miR expression profiles of pCRC and metastatic lesions are highly comparable and may be of similar predictive value for prognosis or response to treatment in patients with advanced CRC.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: M
authors.identifier: http://orcid.org/0000-0002-0146-9375
authors.initials: M
authors.lastname: Neerincx
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: D L S
authors.initials: DL
authors.lastname: Sie
authors.affiliation: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.|Department of Mathematics, VU University, Amsterdam, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: van de Wiel
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: N C T
authors.initials: NC
authors.lastname: van Grieken
authors.affiliation: Department of Pathology, Spaarne Hospital, Hoofddorp, The Netherlands.
authors.forename: J D
authors.initials: JD
authors.lastname: Burggraaf
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Dekker
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: P P
authors.initials: PP
authors.lastname: Eijk
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Ylstra
authors.affiliation: Department of Surgical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Verhoef
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: G A
authors.initials: GA
authors.lastname: Meijer
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: T E
authors.initials: TE
authors.lastname: Buffart
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: H M W
authors.initials: HM
authors.lastname: Verheul