title: Differential gene expression of medullary thyroid carcinoma reveals specific markers associated with genetic conditions.
abstract: Medullary thyroid carcinoma accounts for 2% to 5% of thyroid malignancies, of which 75% are sporadic and the remaining 25% are hereditary and related to multiple endocrine neoplasia type 2 syndrome. Despite a genotype-phenotype correlation with specific germline RET mutations, knowledge of pathways specifically associated with each mutation and with non-RET-mutated sporadic MTC remains lacking. Gene expression patterns have provided a tool for identifying molecular events related to specific tumor types and to different clinical features that could help identify novel therapeutic targets. Using transcriptional profiling of 49 frozen MTC specimens classified as RET mutation, we identified PROM1, LOXL2, GFRA1, and DKK4 as related to RET(M918T) and GAL as related to RET(634) mutation. An independent series of 19 frozen and 23 formalin-fixed, paraffin-embedded (FFPE) MTCs was used for validation by RT-qPCR. Two tissue microarrays containing 69 MTCs were available for IHC assays. According to pathway enrichment analysis and gene ontology biological processes, genes associated with the MTC(M918T) group were involved mainly in proliferative, cell adhesion, and general malignant metastatic effects and with Wnt, Notch, NFκB, JAK/Stat, and MAPK signaling pathways. Assays based on silencing of PROM1 by siRNAs performed in the MZ-CRC-1 cell line, harboring RET(M918T), caused an increase in apoptotic nuclei, suggesting that PROM1 is necessary for survival of these cells. This is the first report of PROM1 overexpression among primary tumors.
authors.affiliation: Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Center CNIO, Madrid, Spain.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Maliszewska
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Leandro-Garcia
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Castelblanco
authors.forename: Anna
authors.initials: A
authors.lastname: Macià
authors.forename: Aguirre
authors.initials: A
authors.lastname: de Cubas
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Goméz-López
authors.forename: Lucía
authors.initials: L
authors.lastname: Inglada-Pérez
authors.forename: Cristina
authors.initials: C
authors.lastname: Álvarez-Escolá
authors.forename: Leticia
authors.initials: L
authors.lastname: De la Vega
authors.forename: Rocío
authors.initials: R
authors.lastname: Letón
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Gómez-Graña
authors.forename: Iñigo
authors.initials: I
authors.lastname: Landa
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascón
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Antona
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.forename: Mariangela
authors.initials: M
authors.lastname: Zane
authors.forename: Francesca
authors.initials: F
authors.lastname: Schiavi
authors.forename: Isabella
authors.initials: I
authors.lastname: Merante-Boschin
authors.forename: Maria R
authors.initials: MR
authors.lastname: Pelizzo
authors.forename: David G
authors.initials: DG
authors.lastname: Pisano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.forename: Mario
authors.initials: M
authors.lastname: Encinas
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D018278:Carcinoma, Neuroendocrine; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D040582:Inheritance Patterns / Q000235:genetics; D010455:Peptides / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D014408:Biomarkers, Tumor; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D034741:RNA, Small Interfering