title: In-depth characterization of the microRNA transcriptome in normal thyroid and papillary thyroid carcinoma.
abstract: BACKGROUND
  A single microRNA gene may give rise to several mature products that differ in length, called isomiRs. IsomiRs are known to be tissue specific and functionally relevant. The microRNA sequence heterogeneity of the thyroid gland has yet to be determined.
  
  
  OBJECTIVE
  The objective of the study was to provide a comprehensive view of the microRNA transcriptome in normal thyroid and papillary thyroid carcinoma (PTC).
  
  
  METHODS
  We used next-generation deep sequencing to analyze microRNA length heterogeneity and expression profiles of PTC tumors (n = 14), unaffected tissue adjacent to tumors (n = 14), and control, noncancerous thyroid tissue (n = 14). The results were validated with a microarray on an additional set of 9 PTC tumor/normal tissue pairs.
  
  
  RESULTS
  Eighty-nine microRNAs were significantly deregulated in PTC compared with normal thyroid tissue (false discovery rate < 0.05, fold change 0.13-20.7). Top deregulated miRNAs included miR-146b-5p, miR-221-3p, miR-7-3p, miR-551b-3p, miR-486-3p, and miR-144-3p, confirming previous microarray profiling. The expression of miRNAs did not depend on the BRAF mutation status. Interestingly, 85% of the most abundant microRNAs consisted of isoforms that differed from the standard reference sequence deposited in miRBase. Moreover, the reference microRNAs were completely absent in 42.4% and 35.9% of the microRNAs expressed in normal thyroid and PTC tumors, respectively. Numerous isomiRs had altered seed sequences, which led to a different set of target genes. For highly deregulated miR-146b-5p, we detected 6 isoforms (tumor/normal fold change 14.4-28.7, false discovery rate < 0.002) that varied at their 5' ends with a 1-nt difference that created 2 alternative seeds. The target genes for those 2 seeds overlapped in only 13.1% of genes.
  
  
  CONCLUSIONS
  Almost all microRNAs exhibit isoforms of variable length and potentially distinct function in thyroid tumorigenesis.
authors.affiliation: Laboratory of Genomic Medicine, Department of General, Transplant, and Liver Surgery, Medical University of Warsaw, Warsaw 02-097, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Swierniak
authors.forename: Anna
authors.initials: A
authors.lastname: Wojcicka
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Czetwertynska
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Stachlewska
authors.forename: Monika
authors.initials: M
authors.lastname: Maciag
authors.forename: Wieslaw
authors.initials: W
authors.lastname: Wiechno
authors.forename: Barbara
authors.initials: B
authors.lastname: Gornicka
authors.forename: Magdalena
authors.initials: M
authors.lastname: Bogdanska
authors.forename: Lukasz
authors.initials: L
authors.lastname: Koperski
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
authors.forename: Krystian
authors.initials: K
authors.lastname: Jazdzewski
mesh_terms: D002277:Carcinoma / Q000209:etiology / Q000235:genetics*; D002291:Carcinoma, Papillary; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000209:etiology / Q000235:genetics*; D059467:Transcriptome
chemical_list: D035683:MicroRNAs; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf