title: Association study of 69 genes in the ret pathway identifies low-penetrance loci in sporadic medullary thyroid carcinoma.
abstract: 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.
authors.affiliation: Hereditary Endocrine Cancer Group, Human Genetics Group, Biomedical Research Institute, CSIC, UAM, Madrid, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Ruiz-Llorente
authors.forename: Cristina
authors.initials: C
authors.lastname: Montero-Conde
authors.forename: Roger L
authors.initials: RL
authors.lastname: Milne
authors.forename: Christian M
authors.initials: CM
authors.lastname: Moya
authors.forename: Arancha
authors.initials: A
authors.lastname: Cebrián
authors.forename: Rocío
authors.initials: R
authors.lastname: Letón
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascón
authors.forename: Fátima
authors.initials: F
authors.lastname: Mercadillo
authors.forename: Iñigo
authors.initials: I
authors.lastname: Landa
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.forename: Guiomar
authors.initials: G
authors.lastname: Pérez de Nanclares
authors.forename: Cristina
authors.initials: C
authors.lastname: Alvarez-Escolá
authors.forename: José Angel
authors.initials: JA
authors.lastname: Díaz-Pérez
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.forename: Pilar
authors.initials: P
authors.lastname: Santisteban
authors.forename: Joaquín
authors.initials: J
authors.lastname: Dopazo
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ponder
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human