TGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer
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Título: | TGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer |
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Autor/es: | Martínez-Cantó, Ana | Catillejo, Adela | Mata Balaguer, Trinidad | Castillejo, María Isabel | Hernández Illán, Eva | Irles, Esperanza | Barberá, Víctor Manuel | Egoavil, Cecilia | Guarinos, Carla | Alenda, Cristina | Ochoa, Enrique | Lázaro, Rafael | Fajardo, Silvia | Lacueva, Javier | Calpena, Rafael | Soto, José Luis |
Grupo/s de investigación o GITE: | Biotecnología | Transducción de Señales en Bacterias |
Centro, Departamento o Servicio: | Universidad de Alicante. Departamento de Biotecnología |
Palabras clave: | Colorectal cancer | Risk factor | TGFBR1 intralocus |
Área/s de conocimiento: | Biología Celular |
Fecha de publicación: | 23-ene-2012 |
Editor: | Public Library of Science (PLoS) |
Cita bibliográfica: | Martinez-Canto A, Castillejo A, Mata-Balaguer T, Castillejo M-I, Hernandez-Illan E, et al. (2012) TGFBR1 Intralocus Epistatic Interaction as a Risk Factor for Colorectal Cancer. PLoS ONE 7(1): e30812. doi:10.1371/journal.pone.0030812 |
Resumen: | In colorectal cancer (CRC), an inherited susceptibility risk affects about 35% of patients, whereas high-penetrance germline mutations account for <6% of cases. A considerable proportion of sporadic tumors could be explained by the coinheritance of multiple low-penetrance variants, some of which are common. We assessed the susceptibility to CRC conferred by genetic variants at the TGFBR1 locus. We analyzed 14 polymorphisms and the allele-specific expression (ASE) of TGFBR1 in 1025 individuals from the Spanish population. A case-control study was undertaken with 504 controls and 521 patients with sporadic CRC. Fourteen polymorphisms located at the TGFBR1 locus were genotyped with the iPLEX Gold (MassARRAY-Sequenom) technology. Descriptive analyses of the polymorphisms and haplotypes and association studies were performed with the SNPator workpackage. No relevant associations were detected between individual polymorphisms or haplotypes and the risk of CRC. The TGFBR1*9A/6A polymorphism was used for the ASE analysis. Heterozygous individuals were analyzed for ASE by fragment analysis using cDNA from normal tissue. The relative level of allelic expression was extrapolated from a standard curve. The cutoff value was calculated with Youden's index. ASE was found in 25.4% of patients and 16.4% of controls. Considering both bimodal and continuous types of distribution, no significant differences between the ASE values of patients and controls were identified. Interestingly, a combined analysis of the polymorphisms and ASE for the association with CRC occurrence revealed that ASE-positive individuals carrying one of the most common haplotypes (H2: 20.7%) showed remarkable susceptibility to CRC (RR: 5.25; 95% CI: 2.547–5.250; p<0.001) with a synergy factor of 3.7. In our study, 54.1% of sporadic CRC cases were attributable to the coinheritance of the H2 haplotype and TGFBR1 ASE. These results support the hypothesis that the allelic architecture of cancer genes, rather than individual polymorphisms, more accurately defines the CRC risk. |
Patrocinador/es: | This action has been supported in part by grants from the Generalitat Valenciana in Spain (AP140/08) and the Biomedical Research Foundation from the Hospital of Elche, Spain (FIBElx0902). AM-C, CE, and CG are recipients of fellowships from the Fundacion Juan Peran-Pikolinos; Fundacion Carolina-BBVA and Conselleria de Educación (Generalitat Valenciana), respectivelly. |
URI: | http://hdl.handle.net/10045/34253 |
ISSN: | 1932-6203 |
DOI: | 10.1371/journal.pone.0030812 |
Idioma: | eng |
Tipo: | info:eu-repo/semantics/article |
Derechos: | © 2012 Martinez-Canto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
Revisión científica: | si |
Versión del editor: | http://dx.doi.org/10.1371/journal.pone.0030812 |
Aparece en las colecciones: | INV - TSB - Artículos de Revistas INV - GIDBT - Artículos de Revistas |
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