%0 Journal Article %J Cancer Res %D 2007 %T Association study of 69 genes in the ret pathway identifies low-penetrance loci in sporadic medullary thyroid carcinoma %A Ruiz-Llorente, S. %A Montero-Conde, C. %A Milne, R. L. %A Moya, C. M. %A Cebrian, A. %A Leton, R. %A Cascon, A. %A Mercadillo, F. %A Landa, I. %A Borrego, S. %A Perez de Nanclares, G. %A Alvarez-Escola, C. %A Diaz-Perez, J. A. %A Carracedo, A. %A Urioste, M. %A Gonzalez-Neira, A. %A Benitez, J. %A Santisteban, P. %A Dopazo, J. %A Ponder, B. A. %A M. Robledo %K 80 and over Carcinoma %K Adolescent Adult Aged Aged %K Genetic %K Genetic Proto-Oncogene Proteins c-ret/*genetics/metabolism Signal Transduction Thyroid Neoplasms/*genetics/metabolism Transcription %K 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 %K Single Nucleotide Promoter Regions %X 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. %B Cancer Res %V 67 %P 9561-7 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17909067 %0 Journal Article %J Genes Chromosomes Cancer %D 2005 %T A novel candidate region linked to development of both pheochromocytoma and head/neck paraganglioma %A Cascon, A. %A Ruiz-Llorente, S. %A Rodriguez-Perales, S. %A Honrado, E. %A Martinez-Ramirez, A. %A Leton, R. %A Montero-Conde, C. %A Benitez, J. %A Dopazo, J. %A Cigudosa, J. C. %A M. Robledo %K 80 and over Child Chromosomes %K Adolescent Adrenal Gland Neoplasms/*genetics Adult Aged Aged %K Biological/*genetics %K Human %K Pair 1/genetics Chromosomes %K Pair 11/genetics Chromosomes %K Pair 3/genetics Chromosomes %K Pair 8/genetics Female Gene Deletion Head and Neck Neoplasms/*genetics Humans Male Middle Aged Nucleic Acid Hybridization Paraganglioma/*genetics Pheochromocytoma/*genetics Tumor Markers %X 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. %B Genes Chromosomes Cancer %V 42 %P 260-8 %G eng %U http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15609347