TGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer.

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...

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Autores principales: Ana Martinez-Canto, Adela Castillejo, Trinidad Mata-Balaguer, Maria-Isabel Castillejo, Eva Hernandez-Illan, Esperanza Irles, Victor Manuel Barbera, Cecilia Egoavil, Carla Guarinos, Cristina Alenda, Enrique Ochoa, Rafael Lazaro, Silvia Fajardo, Javier Lacueva, Rafael Calpena, Jose Luis Soto
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Publicado: Public Library of Science (PLoS) 2012
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spelling oai:doaj.org-article:d2f8a9a836814a7ea970a57da17059022021-11-18T07:29:33ZTGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer.1932-620310.1371/journal.pone.0030812https://doaj.org/article/d2f8a9a836814a7ea970a57da17059022012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22292045/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203In 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.Ana Martinez-CantoAdela CastillejoTrinidad Mata-BalaguerMaria-Isabel CastillejoEva Hernandez-IllanEsperanza IrlesVictor Manuel BarberaCecilia EgoavilCarla GuarinosCristina AlendaEnrique OchoaRafael LazaroSilvia FajardoJavier LacuevaRafael CalpenaJose Luis SotoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 1, p e30812 (2012)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Ana Martinez-Canto
Adela Castillejo
Trinidad Mata-Balaguer
Maria-Isabel Castillejo
Eva Hernandez-Illan
Esperanza Irles
Victor Manuel Barbera
Cecilia Egoavil
Carla Guarinos
Cristina Alenda
Enrique Ochoa
Rafael Lazaro
Silvia Fajardo
Javier Lacueva
Rafael Calpena
Jose Luis Soto
TGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer.
description 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.
format article
author Ana Martinez-Canto
Adela Castillejo
Trinidad Mata-Balaguer
Maria-Isabel Castillejo
Eva Hernandez-Illan
Esperanza Irles
Victor Manuel Barbera
Cecilia Egoavil
Carla Guarinos
Cristina Alenda
Enrique Ochoa
Rafael Lazaro
Silvia Fajardo
Javier Lacueva
Rafael Calpena
Jose Luis Soto
author_facet Ana Martinez-Canto
Adela Castillejo
Trinidad Mata-Balaguer
Maria-Isabel Castillejo
Eva Hernandez-Illan
Esperanza Irles
Victor Manuel Barbera
Cecilia Egoavil
Carla Guarinos
Cristina Alenda
Enrique Ochoa
Rafael Lazaro
Silvia Fajardo
Javier Lacueva
Rafael Calpena
Jose Luis Soto
author_sort Ana Martinez-Canto
title TGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer.
title_short TGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer.
title_full TGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer.
title_fullStr TGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer.
title_full_unstemmed TGFBR1 intralocus epistatic interaction as a risk factor for colorectal cancer.
title_sort tgfbr1 intralocus epistatic interaction as a risk factor for colorectal cancer.
publisher Public Library of Science (PLoS)
publishDate 2012
url https://doaj.org/article/d2f8a9a836814a7ea970a57da1705902
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