Association of a let-7 miRNA binding region of TGFBR1 with hereditary mismatch repair proficient colorectal cancer (MSS HNPCC)
| Autor: | Sneha Bontu, Esther Lee, Francesc Balaguer, Pilar Garre, Brian J. Doyle, John A. Baron, Xavier Bessa, Nathan A. Ellis, Luis Bujanda, Jamie Rawson, Sergi Castellví-Bel, Miguel de la Hoya, Trinidad Caldés, Montserrat Andreu, Polly A. Newcomb, Joan Clofent, Xavier Llor, John D. Potter, Sapna Syngal, Clara Ruiz-Ponte, Antoni Castells, Rosa M. Xicola, Angel Carracedo, Cristina Alenda, Noralane M. Lindor, Rodrigo Jover |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Cancer Research Candidate gene Genotype Colorectal cancer Receptor Transforming Growth Factor-beta Type I Original Manuscript Single-nucleotide polymorphism MiRNA binding Protein Serine-Threonine Kinases Biology DNA Mismatch Repair 03 medical and health sciences 0302 clinical medicine Axin Protein medicine Humans SNP DNA Modification Methylases neoplasms Alleles beta Catenin Aged Genetics Binding Sites Tumor Suppressor Proteins Receptor Transforming Growth Factor-beta Type II Microsatellite instability General Medicine Middle Aged Protein-Serine-Threonine Kinases medicine.disease Colorectal Neoplasms Hereditary Nonpolyposis digestive system diseases Gene Expression Regulation Neoplastic DNA Repair Enzymes 030104 developmental biology 030220 oncology & carcinogenesis Female Microsatellite Instability DNA mismatch repair Receptors Transforming Growth Factor beta |
| Zdroj: | CARCINOGENESIS r-FISABIO. Repositorio Institucional de Producción Científica instname r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante r-FISABIO: Repositorio Institucional de Producción Científica Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid |
| ISSN: | 6768-7202 0143-3334 |
| Popis: | We describe an association between TGFBR1 polymorphism rs868 and mismatch repair proficient hereditary colorectal cancers. This polymorphism results in more binding of TGFBR1 to let-7b-5p miRNA, which would result in lower expression of TGFBR1 and thus higher colorectal cancer risk.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. |
| Databáze: | OpenAIRE |
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