title: Association of a let-7 miRNA binding region of TGFBR1 with hereditary mismatch repair proficient colorectal cancer (MSS HNPCC).
abstract: The purpose of this study was to identify novel colorectal cancer (CRC)-causing alleles in unexplained familial CRC cases. In order to do so, coding regions in five candidate genes (MGMT, AXIN2, CTNNB1, TGFBR1 and TGFBR2) were sequenced in 11 unrelated microsatellite-stable hereditary non-polyposis CRC (MSS HNPCC) cases. Selected genetic variants were genotyped in a discovery set of 27 MSS HNPCC cases and 85 controls. One genetic variant, rs67687202, in TGFBR1 emerged as significant (P = 0.002), and it was genotyped in a replication set of 87 additional MSS HNPCC-like cases and 338 controls where it was also significantly associated with MSS HNPCC cases (P = 0.041). In the combined genotype data, rs67687202 was associated with a moderate increase in CRC risk (OR = 1.68; 95% CI = 1.13-2.50; P = 0.010). We tested a highly correlated SNP rs868 in 723 non-familial CRC cases compared with 629 controls, and it was not significantly associated with CRC risk (P = 0.370). rs868 is contained in a let-7 miRNA binding site in the 3'UTR of TGFBR1, which might provide a functional basis for the association in MSS HNPCC. In luciferase assays, the risk-associated allele for rs868 was associated with half the luciferase expression in the presence of miRNA let-7b-5p compared with protective allele, suggesting more binding of let-7b-5p and less TGFBR1 expression. Thus, rs868 potentially is a CRC risk-causing allele. Our results support the concept that rs868 is associated with lower TGFBR1 expression thereby increasing CRC risk.
authors.affiliation: Department of Medicine and Cancer Center, Yale University, New Haven, CT, USA.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Xicola
authors.affiliation: Department of Medicine and Cancer Center, Yale University, New Haven, CT, USA.
authors.forename: Sneha
authors.initials: S
authors.lastname: Bontu
authors.affiliation: Department of Medicine and Cancer Center, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Doyle
authors.affiliation: Department of Medicine and Cancer Center, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rawson
authors.affiliation: Laboratorio de Oncología Molecular, Hospital Clinico San Carlos, IdISSC , Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Garre
authors.affiliation: Department of Medicine and Cancer Center, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Lee
authors.affiliation: Laboratorio de Oncología Molecular, Hospital Clinico San Carlos, IdISSC , Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: de la Hoya
authors.affiliation: Department of Gastroenterology, Hospital del Mar, Barcelona, Catalonia, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bessa
authors.affiliation: Department of Gastroenterology, Hospital de Sagunto, Sagunto, Valencia, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Clofent
authors.affiliation: Department of Gastroenterology, Hospital Donostia/Instituto Biodonostia, CIBERehd, Universidad del País Vasco (UPV/EHU), San Sebastian, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Bujanda
authors.affiliation: Department of Gastroenterology, Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Balaguer
authors.affiliation: Department of Gastroenterology, Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Castellví-Bel
authors.affiliation: Department of Gastroenterology and Department of Pathology, Hospital General Universitario de Alicante, Alicante, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Alenda
authors.affiliation: Department of Gastroenterology and Department of Pathology, Hospital General Universitario de Alicante, Alicante, Spain.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jover
authors.affiliation: Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, Grupo de Medicina Xenómica, IDIS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERer), Santiago de Compostela, Galiza, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Ruiz-Ponte
authors.affiliation: Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Sapna
authors.initials: S
authors.lastname: Syngal
authors.affiliation: Department of Gastroenterology, Hospital del Mar, Barcelona, Catalonia, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Andreu
authors.affiliation: Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, Grupo de Medicina Xenómica, IDIS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERer), Santiago de Compostela, Galiza, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: Department of Gastroenterology, Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Noralane
authors.initials: N
authors.lastname: Lindor
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Epidemiology, University of Washington, Seattle, WA, USA Centre for Public Health Research, Wellington, New Zealand.
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.affiliation: Department of Biostatistics and Epidemiology, Dartmouth College, Lebanon, NH, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Ellis
authors.affiliation: Laboratorio de Oncología Molecular, Hospital Clinico San Carlos, IdISSC , Madrid, Spain xavier.llor@yale.edu trinidad.caldes@salud.madrid.org.
authors.forename: Trinidad
authors.initials: T
authors.lastname: Caldes
authors.affiliation: Department of Medicine and Cancer Center, Yale University, New Haven, CT, USA xavier.llor@yale.edu.
authors.forename: Xavier
authors.initials: X
authors.lastname: LLor
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D060466:Axin Protein / Q000235:genetics; D001665:Binding Sites; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair / Q000235:genetics*; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: C491761:AXIN2 protein, human; D060466:Axin Protein; C495270:CTNNB1 protein, human; D018125:Receptors, Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human; D045643:DNA Repair Enzymes