Susceptibility Genetic Variants Associated With Colorectal Cancer Risk Correlate With Cancer Phenotype

Susceptibility Genetic Variants Associated With Colorectal Cancer Risk Correlate With Cancer Phenotype
Anna Abulí

, Gastrointestinal Oncology Group of the Spanish Gastroenterological Association
Received 14 January 2010; accepted 17 May 2010. published online 02 June 2010.

Abstract
Ten common low-penetrant genetic variants have been consistently associated with colorectal cancer (CRC) risk; little is known about the correlation between these variants and CRC phenotype. Characterization of such a correlation would improve CRC management and prevention programs. We assessed the association between these genetic variants and CRC phenotype in patients and modeled pairwise combinations to detect epistasis.

Methods
The validation population corresponded to a prospective, multicenter, population-based cohort (EPICOLON I) of 1096 patients with newly diagnosed CRC. The replication set was an independent, prospective, multicenter Spanish cohort (EPICOLON II) of 895 patients with newly diagnosed CRC. For individual single nucleotide polymorphism (SNP) association analyses, a multivariate method using logistic regression was applied in EPICOLON I and subsequently prospectively validated in EPICOLON II. Interactions between SNPs were assessed using the likelihood ratio test.

Results
Validated results confirmed that the C allele on 8q23.3 (rs16892766) was significantly associated with advanced-stage tumors (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.15–1.90; P value = 4.9 × 10−3). The G allele on 8q24.21 (rs6983267) was more common in patients with a familial history of CRC (OR, 2.02; 95% CI, 1.35–3.03; P value = 3.9 × 10−4). The combination of rs6983267 on 8q24.21 and rs9929218 on 16q22.2 was associated with a history of colorectal adenoma (carriers of GG and AA, respectively; OR, 2.28; 95% CI, 1.32–3.93; P = 5.0 × 10−4).

Conclusions
CRC susceptibility variants at 8q23.3, 8q24.21, and 16q22.2 appear to be associated with cancer phenotype. These findings might be used to develop screening and surveillance strategies.

Keywords: Colon Cancer, Genetic Susceptibility, Low Penetrance, Genotype-Phenotype Correlation

Abbreviations used in this paper: CI, confidence interval, CRC, colorectal cancer, GWAS, genome-wide association studies, HNPCC, hereditary nonpolyposis colorectal cancer, OR, odds ratio, SNP, single nucleotide polymorphism

Gastroenterology, Volume 139, Issue 3 , Pages 788-796.e6, (September 2010); doi:10.1053/j.gastro.2010.05.072
http://www.gastrojournal.org/article/S0016-5085(10)00833-4/abstract



APARATO DIGESTIVO
Identifican la variabilidad genética con el cáncer colorrectal
JANO.es · 07 Septiembre 2010 09:16

La investigación pretende mejorar la detección de este tipo de cáncer en familias, mediante la identificación de las personas con mayor susceptibilidad de desarrollarlo.

Un estudio multicéntrico desarrollado al mismo tiempo en 25 hospitales españoles, y liderado por el Hospital del Mar y el Hospital Clínic de Barcelona, ha identificado la correlación entre las variantes genéticas de susceptibilidad y las diferentes características clínicas y familiares de pacientes afectados de cáncer colorrectal.

La investigación, que publica la revista Gastroenterology pretende mejorar la detección del cáncer colorrectal familiar, mediante la identificación de las personas con mayor susceptibilidad de desarrollar este tipo de tumor.

Hasta la fecha se han identificado, mediante estudios de asociación, hasta 10 variantes genéticas comunes de estos enfermos que, aunque no presentan una relación directa, "sí proporcionan cierta susceptibilidad", ha señalado la jefa de Gastroenterología del Hospital del Mar, Montserrat Andreu.

El estudio español, se ha basado en establecer la correlación entre estos polimorfismos genéticos -ya identificados en estudios previos- y las características personales de cada enfermo. Esta práctica "podrá aumentar la precisión en la estratificación del riesgo poblacional y las políticas de cribado", ha señalado Andreu.

La investigación ha sido liderada por el Servicio de Digestivo del Hospital del Mar, el Instituto de Investigación del mismo centro (IMIM), el Centro de Investigación en Epidemiología Ambiental (CREAL), el Servicio de Gastroenterología del Hospital Clínic de Barcelona y el Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS).


Gastroenterology, Volume 139, Issue 3 , Pages 788-796.e6, (September 2010); doi:10.1053/j.gastro.2010.05.072
http://www.gastrojournal.org/article/S0016-5085(10)00833-4/abstract

CREAL
http://www.creal.cat/

Gastroenterology
http://www.gastrojournal.org/home



Affiliations
Department of Gastroenterology, Hospital del Mar, Institut Municipal d'Investigació Mèdica, Pompeu Fabra University, Barcelona, Catalonia, Spain
, Xavier Bessa

Affiliations
Department of Gastroenterology, Hospital del Mar, Institut Municipal d'Investigació Mèdica, Pompeu Fabra University, Barcelona, Catalonia, Spain
, Juan Ramón González
Affiliations

Centre for Research in Environmental Epidemiology, Institut Municipal d'Investigació Mèdica, Barcelona, Catalonia, Spain
, Clara Ruiz–Ponte

Affiliations
Fundación Pública Galega de Medicina Xenómica, CIBERER, Genomic Medicine Group - University of Santiago de Compostela, Santiago de Compostela, Galicia, Spain
, Alejandro Cáceres

Affiliations
Centre for Research in Environmental Epidemiology, Institut Municipal d'Investigació Mèdica, Barcelona, Catalonia, Spain
, Jenifer Muñoz

Affiliations
Department of Gastroenterology, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Catalonia, Spain
, Victoria Gonzalo

Affiliations
Department of Gastroenterology, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Catalonia, Spain
, Francesc Balaguer

Affiliations
Department of Gastroenterology, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Catalonia, Spain
, Ceres Fernández–Rozadilla

Affiliations
Fundación Pública Galega de Medicina Xenómica, CIBERER, Genomic Medicine Group - University of Santiago de Compostela, Santiago de Compostela, Galicia, Spain
, Dolors González

Affiliations
Department of Gastroenterology, Hospital Sant Pau, Barcelona, Catalonia, Spain
, Luisa de Castro

Affiliations
Department of Gastroenterology, Hospital Meixoeiro, Vigo, Spain
, Juan Clofent

Affiliations
Department of Gastroenterology, Hospital Meixoeiro, Vigo, Spain
, Luís Bujanda

Affiliations
Department of Gastroenterology, Hospital de Donostia, CIBERehd, University of Basque Country, San Sebastian, Spain
, Joaquín Cubiella

Affiliations
Department of Gastroenterology, Hospital de Ourense, Galicia, Spain
, Josep Ma Reñé

Affiliations
Department of Gastroenterology, Hospital Universitari Arnau de Vilanova, Lleida, Catalonia, Spain
, Juan Diego Morillas

Affiliations
Department of Gastroenterology, Hospital 12 de Octubre, Madrid, Spain
, Ángel Lanas

Affiliations
Department of Gastroenterology, Hospital Clínico Universitario, CIBERehd, Zaragoza, Zaragoza, Spain
, Joaquim Rigau

Affiliations
Department of Medicine, Hospital General de Granollers, Barcelona, Catalonia, Spain
, Ana Ma García

Affiliations
Fundación para la Formación e Investigación Sanitaria, Murcia, Spain
, Mercedes Latorre

Affiliations
Department of Gastroenterology, Hospital General Universitario de Valencia, Valencia, Spain
, Joan Saló

Affiliations
Department of Gastroenterology, Hospital General de Vic, Barcelona, Catalonia, Spain
, Fernando Fernández Bañares

Affiliations
Department of Gastroenterology, Hospital Mutua de Terrassa, Barcelona, Catalonia, Spain
, Lídia Argüello

Affiliations
Department of Gastroenterology, Hospital Universitario La Fe, Valencia, Valencia, Spain
, Elena Peña

Affiliations
Department of Gastroenterology, Hospital Royo Villanova, Zaragoza, Spain
, Àngels Vilella

Affiliations
Department of Medicine, Hospital Son Llatzer, Palma de Mallorca, Balearic Islands, Spain
, Sabino Riestra

Affiliations
Department of Gastroenterology, Hospital Central de Asturias, Oviedo, Asturias, Spain
, Ramiro Carreño

Affiliations
Department of Gastroenterology, Fundación Hospitalaria de Calahorra, Navarre, Spain
, Artemio Paya

Affiliations
Department of Pathology and Gastroenterology, Hospital General d'Alacant, Alicante, Spain
, Cristina Alenda

Affiliations
Department of Pathology and Gastroenterology, Hospital General d'Alacant, Alicante, Spain
, Rosa M. Xicola

Affiliations
Digestive Diseases and Nutrition Section, University of Illinois at Chicago, Chicago, Illinois
, Brian J. Doyle

Affiliations
Digestive Diseases and Nutrition Section, University of Illinois at Chicago, Chicago, Illinois
, Rodrigo Jover

Affiliations
Department of Pathology and Gastroenterology, Hospital General d'Alacant, Alicante, Spain
, Xavier Llor

Affiliations
Digestive Diseases and Nutrition Section, University of Illinois at Chicago, Chicago, Illinois
, Angel Carracedo

Affiliations
Fundación Pública Galega de Medicina Xenómica, CIBERER, Genomic Medicine Group - University of Santiago de Compostela, Santiago de Compostela, Galicia, Spain
, Antoni Castells

Affiliations
Department of Gastroenterology, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Catalonia, Spain
, Sergi Castellví–Bel

Affiliations
Department of Gastroenterology, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Catalonia, Spain
Reprint requests Address requests for reprints to: Sergi Castellví-Bel, PhD, Gastroenterology Department, Hospital Clínic, Villarroel 170, 08036 Barcelona, Catalonia, Spain
, Montserrat Andreu

Affiliations
Department of Gastroenterology, Hospital del Mar, Institut Municipal d'Investigació Mèdica, Pompeu Fabra University, Barcelona, Catalonia, Spain
Montserrat Andreu, MD, Gastroenterology Department, Hospital del Mar, Passeig Maritim 25-29, 08003 Barcelona, Catalonia, Spain