03226nas a2200433   4500008004100000245012400041210006900165300001100234490000700245520156900252653002601821653003101847653001201878653013601890653023502026653003902261100002202300700002202322700001802344700001702362700001602379700001402395700001502409700001902424700001402443700001602457700002402473700002302497700002302520700001802543700001602561700002302577700001602600700002002616700001502636700001902651700001602670856010602686       2007                        eng d00aAssociation study of 69 genes in the ret pathway identifies low-penetrance loci in sporadic medullary thyroid carcinoma0 aAssociation study of 69 genes in the ret pathway identifies lowp  a9561-70 v673 aTo 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.10a80 and over Carcinoma10aAdolescent Adult Aged Aged10aGenetic10aGenetic Proto-Oncogene Proteins c-ret/*genetics/metabolism Signal Transduction Thyroid Neoplasms/*genetics/metabolism Transcription10aMedullary/*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 Polymorphism10aSingle Nucleotide Promoter Regions1 aRuiz-Llorente, S.1 aMontero-Conde, C.1 aMilne, R., L.1 aMoya, C., M.1 aCebrian, A.1 aLeton, R.1 aCascon, A.1 aMercadillo, F.1 aLanda, I.1 aBorrego, S.1 ade Nanclares, Perez1 aAlvarez-Escola, C.1 aDiaz-Perez, J., A.1 aCarracedo, A.1 aUrioste, M.1 aGonzalez-Neira, A.1 aBenitez, J.1 aSantisteban, P.1 aDopazo, J.1 aPonder, B., A.1 aRobledo, M.  uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1790906702830nas a2200277   4500008004100000245011000041210006900151300001100220490000700231520162300238653016301861653002002024653018602044653004602230100001802276700001402294700002302308700001802331700001402349700001702363700001502380700001902395700001602414700001602430856010602446       2006                        eng d00aERCC4 associated with breast cancer risk: a two-stage case-control study using high-throughput genotyping0 aERCC4 associated with breast cancer risk a twostage casecontrol   a9420-70 v663 aThe failure of linkage studies to identify further high-penetrance susceptibility genes for breast cancer points to a polygenic model, with more common variants having modest effects on risk, as the most likely candidate. We have carried out a two-stage case-control study in two European populations to identify low-penetrance genes for breast cancer using high-throughput genotyping. Single-nucleotide polymorphisms (SNPs) were selected across preselected cancer-related genes, choosing tagSNPs and functional variants where possible. In stage 1, genotype frequencies for 640 SNPs in 111 genes were compared between 864 breast cancer cases and 845 controls from the Spanish population. In stage 2, candidate SNPs identified in stage 1 (nominal P < 0.01) were tested in a Finnish series of 884 cases and 1,104 controls. Of the 10 candidate SNPs in seven genes identified in stage 1, one (rs744154) on intron 1 of ERCC4, a gene belonging to the nucleotide excision repair pathway, was associated with recessive protection from breast cancer after adjustment for multiple testing in stage 2 (odds ratio, 0.57; Bonferroni-adjusted P = 0.04). After considering potential functional SNPs in the region of high linkage disequilibrium that extends across the entire gene and upstream into the promoter region, we concluded that rs744154 itself could be causal. Although intronic, it is located on the first intron, in a region that is highly conserved across species, and could therefore be functionally important. This study suggests that common intronic variation in ERCC4 is associated with protection from breast cancer.10a80 and over Breast Neoplasms/epidemiology/*genetics/pathology Case-Control Studies DNA-Binding Proteins/genetics/*physiology Female Finland/epidemiology Genes10aAdult Aged Aged10aRecessive Genetic Predisposition to Disease Genotype Humans Introns/genetics Linkage Disequilibrium Middle Aged Neoplasm Proteins/genetics/*physiology Neoplasm Staging *Polymorphism10aSingle Nucleotide Risk Spain/epidemiology1 aMilne, R., L.1 aRibas, G.1 aGonzalez-Neira, A.1 aFagerholm, R.1 aSalas, A.1 aGonzalez, E.1 aDopazo, J.1 aNevanlinna, H.1 aRobledo, M.1 aBenitez, J.  uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1701859602687nas a2200337   4500008004100000245010400041210006900145300001000214490000700224520138200231653003401613653006501647653002501712653001001737653003201747653003301779653003201812653019101844100001502035700002202050700002602072700001602098700002502114700001402139700002202153700001602175700001502191700002102206700001602227856010602243       2005                        eng d00aA novel candidate region linked to development of both pheochromocytoma and head/neck paraganglioma0 anovel candidate region linked to development of both pheochromoc  a260-80 v423 aAlthough 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.10a80 and over Child Chromosomes10aAdolescent Adrenal Gland Neoplasms/*genetics Adult Aged Aged10aBiological/*genetics10aHuman10aPair 1/genetics Chromosomes10aPair 11/genetics Chromosomes10aPair 3/genetics Chromosomes10aPair 8/genetics Female Gene Deletion Head and Neck Neoplasms/*genetics Humans Male Middle Aged Nucleic Acid Hybridization Paraganglioma/*genetics Pheochromocytoma/*genetics Tumor Markers1 aCascon, A.1 aRuiz-Llorente, S.1 aRodriguez-Perales, S.1 aHonrado, E.1 aMartinez-Ramirez, A.1 aLeton, R.1 aMontero-Conde, C.1 aBenitez, J.1 aDopazo, J.1 aCigudosa, J., C.1 aRobledo, M.  uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1560934702968nas a2200337   4500008004100000245012900041210006900170300000900239490000700248520175600255653010902011653003502120653001702155653006002172653007102232100001702303700001602320700001502336700001602351700001502367700001602382700001802398700002102416700001302437700001502450700001402465700001502479700001402494700001602508856010602524       2005                        eng d00aPhenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers0 aPhenotypic characterization of BRCA1 and BRCA2 tumors based in a  a5-140 v903 aFamilial breast cancers that are associated with BRCA1 or BRCA2 germline mutations differ in both their morphological and immunohistochemical characteristics. To further characterize the molecular difference between genotypes, the authors evaluated the expression of 37 immunohistochemical markers in a tissue microarray (TMA) containing cores from 20 BRCA1, 14 BRCA2, and 59 sporadic age-matched breast carcinomas. Markers analyzed included, amog others, common markers in breast cancer, such as hormone receptors, p53 and HER2, along with 15 molecules involved in cell cycle regulation, such as cyclins, cyclin dependent kinases (CDK) and CDK inhibitors (CDKI), apoptosis markers, such as BCL2 and active caspase 3, and two basal/myoepithelial markers (CK 5/6 and P-cadherin). In addition, we analyzed the amplification of CCND1, CCNE, HER2 and MYC by FISH.Unsupervised cluster data analysis of both hereditary and sporadic cases using the complete set of immunohistochemical markers demonstrated that most BRCA1-associated carcinomas grouped in a branch of ER-, HER2-negative tumors that expressed basal cell markers and/or p53 and had higher expression of activated caspase 3. The cell cycle proteins associated with these tumors were E2F6, cyclins A, B1 and E, SKP2 and Topo IIalpha. In contrast, most BRCA2-associated carcinomas grouped in a branch composed by ER/PR/BCL2-positive tumors with a higher expression of the cell cycle proteins cyclin D1, cyclin D3, p27, p16, p21, CDK4, CDK2 and CDK1. In conclusion, our study in hereditary breast cancer tumors analyzing 37 immunohistochemical markers, define the molecular differences between BRCA1 and BRCA2 tumors with respect to hormonal receptors, cell cycle, apoptosis and basal cell markers.10aAdult Apoptosis Breast Neoplasms/*genetics/*pathology Cell Cycle Proteins Cluster Analysis Female *Genes10aBiological/genetics/metabolism10aBRCA1 *Genes10aBRCA2 Humans Immunohistochemistry In Situ Hybridization10aFluorescence Phenotype Spain *Tissue Array Analysis *Tumor Markers1 aPalacios, J.1 aHonrado, E.1 aOsorio, A.1 aCazorla, A.1 aSarrio, D.1 aBarroso, A.1 aRodriguez, S.1 aCigudosa, J., C.1 aDiez, O.1 aAlonso, C.1 aLerma, E.1 aDopazo, J.1 aRivas, C.1 aBenitez, J.  uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1577052102881nas a2200397   4500008004100000245016800041210006900209300001200278490000700290520143600297653010101733653002201834653001001856653008301866653003301949653003301982653003302015653003202048653005102080100001602131700002102147700001502168700001602183700001602199700001602215700001602231700001802247700001602265700001402281700001302295700002102308700001502329700001702344700001602361856010602377       2005                        eng d00aA predictor based on the somatic genomic changes of the BRCA1/BRCA2 breast cancer tumors identifies the non-BRCA1/BRCA2 tumors with BRCA1 promoter hypermethylation0 apredictor based on the somatic genomic changes of the BRCA1BRCA2  a1146-530 v113 aThe genetic changes underlying in the development and progression of familial breast cancer are poorly understood. To identify a somatic genetic signature of tumor progression for each familial group, BRCA1, BRCA2, and non-BRCA1/BRCA2 (BRCAX) tumors, by high-resolution comparative genomic hybridization, we have analyzed 77 tumors previously characterized for BRCA1 and BRCA2 germ line mutations. Based on a combination of the somatic genetic changes observed at the six most different chromosomal regions and the status of the estrogen receptor, we developed using random forests a molecular classifier, which assigns to a given tumor a probability to belong either to the BRCA1 or to the BRCA2 class. Because 76.5% (26 of 34) of the BRCAX cases were classified with our predictor to the BRCA1 class with a probability of >50%, we analyzed the BRCA1 promoter region for aberrant methylation in all the BRCAX cases. We found that 15 of the 34 BRCAX analyzed tumors had hypermethylation of the BRCA1 gene. When we considered the predictor, we observed that all the cases with this epigenetic event were assigned to the BRCA1 class with a probability of >50%. Interestingly, 84.6% of the cases (11 of 13) assigned to the BRCA1 class with a probability >80% had an aberrant methylation of the BRCA1 promoter. This fact suggests that somatic BRCA1 inactivation could modify the profile of tumor progression in most of the BRCAX cases.10aBRCA1 Protein/*genetics BRCA2 Protein/*genetics Breast Neoplasms/*genetics/pathology Chromosomes10aGenetic/*genetics10aHuman10aHuman Humans Male Mutation Nucleic Acid Hybridization/methods Promoter Regions10aPair 12/genetics Chromosomes10aPair 15/genetics Chromosomes10aPair 18/genetics Chromosomes10aPair 2/genetics Chromosomes10aPair 8/genetics *DNA Methylation Female Genome1 aAlvarez, S.1 aDiaz-Uriarte, R.1 aOsorio, A.1 aBarroso, A.1 aMelchor, L.1 aPaz, M., F.1 aHonrado, E.1 aRodriguez, R.1 aUrioste, M.1 aValle, L.1 aDiez, O.1 aCigudosa, J., C.1 aDopazo, J.1 aEsteller, M.1 aBenitez, J.  uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1570918202990nas a2200325   4500008004100000245013600041210006900177300001100246490000700257520176100264653001602025653002602041653001002067653003402077653003402111653011302145653008802258100001702346700002102363700001602384700002502400700002702425700001502452700002102467700001402488700001502502700002502517700001602542856010602558       2004                        eng d00aGene expression analysis of chromosomal regions with gain or loss of genetic material detected by comparative genomic hybridization0 aGene expression analysis of chromosomal regions with gain or los  a353-650 v413 aComparative genomic hybridization (CGH) has been widely used to detect copy number alterations in cancer and to identify regions containing candidate tumor-responsible genes; however, gene expression changes have been described only in highly amplified regions (amplicons). To study the overall impact of slight copy number changes on gene expression, we analyzed 16 T-cell lymphomas by using CGH and a custom-designed cDNA microarray containing 7,657 genes and expressed sequence tags related to tumorigenesis. We evaluated mean gene expression and variability within CGH-altered regions and explored the relationship between the effects of the gene and its position within these regions. Minimally overlapping CGH candidate areas (6q25, 13q21-q22, and 19q13.1) revealed a weak relationship between altered genomic content and gene expression. However, some candidate genes showed modified expression within these regions in the majority of tumors; these candidate genes were evaluated and confirmed in another independent series of 23 T-cell lymphomas by use of the same cDNA microarray and by FISH on a tissue microarray. When all the CGH regions detected for each tumor were considered, we found a significant increase or decrease in the mean expression of the genes contained in gained or lost regions, respectively. In addition, we found that the expression of a gene was dependent not only on its position within an altered region but also on its own mechanism of regulation: genes in the same altered region responded very differently to the gain or loss of genetic material. Supplementary material for this article can be found on the Genes, Chromosomes, and Cancer website at http://www.interscience.wiley.com/jpages/1045-2257/suppmat/index.html.10aChromosomes10aFluorescence Lymphoma10aHuman10aPair 13/*genetics Chromosomes10aPair 19/*genetics Chromosomes10aPair 6/*genetics Expressed Sequence Tags *Gene Dosage Gene Expression Profiling Humans In Situ Hybridization10aT-Cell/*genetics Nucleic Acid Hybridization Oligonucleotide Array Sequence Analysis1 aMelendez, B.1 aDiaz-Uriarte, R.1 aCuadros, M.1 aMartinez-Ramirez, A.1 aFernandez-Piqueras, J.1 aDopazo, A.1 aCigudosa, J., C.1 aRivas, C.1 aDopazo, J.1 aMartinez-Delgado, B.1 aBenitez, J.  uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15382261