TY - JOUR T1 - Molecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information JF - Oncogene Y1 - 2008 A1 - Montero-Conde, C. A1 - Martin-Campos, J. M. A1 - Lerma, E. A1 - Gimenez, G. A1 - Martinez-Guitarte, J. L. A1 - Combalia, N. A1 - Montaner, D. A1 - Matias-Guiu, X. A1 - Dopazo, J. A1 - de Leiva, A. A1 - M. Robledo A1 - Mauricio, D. KW - Adenoma/genetics/metabolism/pathology Adolescent Adult Aged Carcinoma/genetics/metabolism/pathology Carcinoma KW - Biological/*genetics/metabolism KW - Neoplasm/genetics/metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Thyroid Neoplasms/classification/*genetics/metabolism Tumor Markers KW - Neoplastic Humans Male Middle Aged *Oligonucleotide Array Sequence Analysis Prognosis RNA KW - Papillary/genetics/metabolism/pathology Cell Differentiation Female *Gene Expression Profiling *Gene Expression Regulation AB -

Undifferentiated and poorly differentiated thyroid tumors are responsible for more than half of thyroid cancer patient deaths in spite of their low incidence. Conventional treatments do not obtain substantial benefits, and the lack of alternative approaches limits patient survival. Additionally, the absence of prognostic markers for well-differentiated tumors complicates patient-specific treatments and favors the progression of recurrent forms. In order to recognize the molecular basis involved in tumor dedifferentiation and identify potential markers for thyroid cancer prognosis prediction, we analysed the expression profile of 44 thyroid primary tumors with different degrees of dedifferentiation and aggressiveness using cDNA microarrays. Transcriptome comparison of dedifferentiated and well-differentiated thyroid tumors identified 1031 genes with >2-fold difference in absolute values and false discovery rate of <0.15. According to known molecular interaction and reaction networks, the products of these genes were mainly clustered in the MAPkinase signaling pathway, the TGF-beta signaling pathway, focal adhesion and cell motility, activation of actin polymerization and cell cycle. An exhaustive search in several databases allowed us to identify various members of the matrix metalloproteinase, melanoma antigen A and collagen gene families within the upregulated gene set. We also identified a prognosis classifier comprising just 30 transcripts with an overall accuracy of 95%. These findings may clarify the molecular mechanisms involved in thyroid tumor dedifferentiation and provide a potential prognosis predictor as well as targets for new therapies.

VL - 27 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17873908 N1 -

Montero-Conde, C Martin-Campos, J M Lerma, E Gimenez, G Martinez-Guitarte, J L Combalia, N Montaner, D Matias-Guiu, X Dopazo, J de Leiva, A Robledo, M Mauricio, D Research Support, Non-U.S. Gov’t England Oncogene Oncogene. 2008 Mar 6;27(11):1554-61. Epub 2007 Sep 17.

ER - TY - JOUR T1 - Association study of 69 genes in the ret pathway identifies low-penetrance loci in sporadic medullary thyroid carcinoma JF - Cancer Res Y1 - 2007 A1 - Ruiz-Llorente, S. A1 - Montero-Conde, C. A1 - Milne, R. L. A1 - Moya, C. M. A1 - Cebrian, A. A1 - Leton, R. A1 - Cascon, A. A1 - Mercadillo, F. A1 - Landa, I. A1 - Borrego, S. A1 - Perez de Nanclares, G. A1 - Alvarez-Escola, C. A1 - Diaz-Perez, J. A. A1 - Carracedo, A. A1 - Urioste, M. A1 - Gonzalez-Neira, A. A1 - Benitez, J. A1 - Santisteban, P. A1 - Dopazo, J. A1 - Ponder, B. A. A1 - M. Robledo KW - 80 and over Carcinoma KW - Adolescent Adult Aged Aged KW - Genetic KW - Genetic Proto-Oncogene Proteins c-ret/*genetics/metabolism Signal Transduction Thyroid Neoplasms/*genetics/metabolism Transcription KW - Medullary/*genetics/metabolism Case-Control Studies Cyclin-Dependent Kinase Inhibitor p15/biosynthesis/genetics Female Genetic Predisposition to Disease Germ-Line Mutation Haplotypes Humans Male Middle Aged Penetrance Polymorphism KW - Single Nucleotide Promoter Regions AB - To date, few association studies have been done to better understand the genetic basis for the development of sporadic medullary thyroid carcinoma (sMTC). To identify additional low-penetrance genes, we have done a two-stage case-control study in two European populations using high-throughput genotyping. We selected 417 single nucleotide polymorphisms (SNP) belonging to 69 genes either related to RET signaling pathway/functions or involved in key processes for cancer development. TagSNPs and functional variants were included where possible. These SNPs were initially studied in the largest known series of sMTC cases (n = 266) and controls (n = 422), all of Spanish origin. In stage II, an independent British series of 155 sMTC patients and 531 controls was included to validate the previous results. Associations were assessed by an exhaustive analysis of individual SNPs but also considering gene- and linkage disequilibrium-based haplotypes. This strategy allowed us to identify seven low-penetrance genes, six of them (STAT1, AURKA, BCL2, CDKN2B, CDK6, and COMT) consistently associated with sMTC risk in the two case-control series and a seventh (HRAS) with individual SNPs and haplotypes associated with sMTC in the Spanish data set. The potential role of CDKN2B was confirmed by a functional assay showing a role of a SNP (rs7044859) in the promoter region in altering the binding of the transcription factor HNF1. These results highlight the utility of association studies using homogeneous series of cases for better understanding complex diseases. VL - 67 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17909067 N1 - Ruiz-Llorente, Sergio Montero-Conde, Cristina Milne, Roger L Moya, Christian M Cebrian, Arancha Leton, Rocio Cascon, Alberto Mercadillo, Fatima Landa, Inigo Borrego, Salud Perez de Nanclares, Guiomar Alvarez-Escola, Cristina Diaz-Perez, Jose Angel Carracedo, Angel Urioste, Miguel Gonzalez-Neira, Anna Benitez, Javier Santisteban, Pilar Dopazo, Joaquin Ponder, Bruce A Robledo, Mercedes Medullary Thyroid Carcinoma Clinical Group Research Support, Non-U.S. Gov’t United States Cancer research Cancer Res. 2007 Oct 1;67(19):9561-7. ER - TY - JOUR T1 - A novel candidate region linked to development of both pheochromocytoma and head/neck paraganglioma JF - Genes Chromosomes Cancer Y1 - 2005 A1 - Cascon, A. A1 - Ruiz-Llorente, S. A1 - Rodriguez-Perales, S. A1 - Honrado, E. A1 - Martinez-Ramirez, A. A1 - Leton, R. A1 - Montero-Conde, C. A1 - Benitez, J. A1 - Dopazo, J. A1 - Cigudosa, J. C. A1 - M. Robledo KW - 80 and over Child Chromosomes KW - Adolescent Adrenal Gland Neoplasms/*genetics Adult Aged Aged KW - Biological/*genetics KW - Human KW - Pair 1/genetics Chromosomes KW - Pair 11/genetics Chromosomes KW - Pair 3/genetics Chromosomes KW - Pair 8/genetics Female Gene Deletion Head and Neck Neoplasms/*genetics Humans Male Middle Aged Nucleic Acid Hybridization Paraganglioma/*genetics Pheochromocytoma/*genetics Tumor Markers AB - Although the histologic distinction between pheochromocytomas and head and neck paragangliomas is clear, little is known about the genetic differences between them. To date, various sets of genes have been found to be involved in inherited susceptibility to developing both tumor types, but the genes involved in sporadic pathogenesis are still unknown. To define new candidate regions, we performed CGH analysis on 29 pheochromocytomas and on 24 paragangliomas mainly of head and neck origin (20 of 24), which allowed us to differentiate between the two tumor types. Loss of 3q was significantly more frequent in pheochromocytomas, and loss of 1q appeared only in paragangliomas. We also found gain of 11q13 to be a significantly frequent alteration in malignant cases of both types. In addition, recurrent loss of 8p22-23 was found in 62% of pheochromocytomas (including all malignant cases) versus in 33% of paragangliomas, suggesting that this region contains candidate genes involved in the pathogenesis of this abnormality. Using FISH analysis on tissue microarrays, we confirmed genomic deletion of this region in 55% of pheochromocytomas compared to 12% of paragangliomas. Loss of 8p22-23 appears to be an important event in the sporadic development of these tumors, and additional molecular studies are necessary to identify candidate genes in this chromosomal region. VL - 42 UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15609347 N1 - Cascon, Alberto Ruiz-Llorente, Sergio Rodriguez-Perales, Sandra Honrado, Emiliano Martinez-Ramirez, Angel Leton, Rocio Montero-Conde, Cristina Benitez, Javier Dopazo, Joaquin Cigudosa, Juan C Robledo, Mercedes Research Support, Non-U.S. Gov’t United States Genes, chromosomes & cancer Genes Chromosomes Cancer. 2005 Mar;42(3):260-8. ER -