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Carcinogenesis Advance Access originally published online on April 21, 2007
Carcinogenesis 2007 28(8):1687-1691; doi:10.1093/carcin/bgm098
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Association of the ARLTS1 Cys148Arg variant with sporadic and familial colorectal cancer

Sergi Castellví-Bel*, Antoni Castells, Rafael de Cid1, Jenifer Muñoz, Francesc Balaguer, Victoria Gonzalo, Clara Ruiz-Ponte2, Montserrat Andreu3, Xavier Llor4,7, Rodrigo Jover5, Xavier Bessa3, Rosa M. Xicola4,7, Elisenda Pons4, Cristina Alenda6, Artemio Payá6, Angel Carracedo2, Josep M. Piqué for the Gastrointestinal Oncology Group of the Spanish Gastroenterological Association{dagger}

Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, CIBER-EHD, IDIBAPS, Villarroel 170, 08036 Barcelona, Catalonia, Spain
1 Gene and Disease Program, Centre for Genomic Regulation, UPF, Barcelona, Catalonia, Spain
2 Grupo de Medicina Xenomica–USC, Fundacion Publica Galega de Medicina Xenomica-CHUS, Santiago de Compostela, Galicia, Spain
3 Department of Gastroenterology, Hospital del Mar, Barcelona, Catalonia, Spain
4 Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain
5 Department of Gastroenterology, Hospital General Universitario de Alicante, Alicante, Spain
6 Department of Pathology, Hospital General Universitario de Alicante, Alicante, Spain
7 Present address: Digestive Disease and Nutrition Department, University of Illinois at Chicago, Chicago, IL, USA

* To whom correspondence should be addressed. Tel: +34 93 227 54 18; Fax: +34 93 227 93 87;Email: sbel{at}clinic.ub.es


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 
ARLTS1 was recently identified in chromosome 13q14 as a tumor suppressor gene of the ADP-ribosylation factor family with pro-apoptotic characteristics. Additionally, one of its genetic variants (W149X) was hypothesized to be a polymorphism associated with familial cancer. We performed a large case–control association study within the EPICOLON project aimed at evaluating the sporadic and familial colorectal cancer (CRC) risk associated with ARLTS1 genetic variants. Whereas P131L and W149X did not seem to affect CRC risk, C148R did show, for the first time in CRC, statistically significant differences between cases and controls [odds ratio (OR) = 1.45, 95% confidence interval (95% CI) = 1.13–1.86, P = 0.003], sporadic cases and controls (OR = 1.59, 95% CI = 1.13–2.23, P = 0.007) and familial cases and controls (OR = 1.55, 95% CI = 1.10–2.19, P = 0.01) in agreement with a hypothetical moderate increase of the cancer risk linked to the C148R ARLTS1 variant, both in sporadic and familial CRC cases.

Abbreviations: CRC, colorectal cancer; 95% CI, 95% confidence interval; OR, odds ratio; SNP, single-nucleotide polymorphism


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Appendix
 References
 
Colorectal cancer (CRC) stands as the second more common tumor and the second more frequent cause of death related to cancer in Spain after lung cancer (1). CRC lifetime risk is ~5% in the general population, although this figure rises exponentially with age, and it is much higher for individuals with a family history of CRC, especially for those belonging to families affected with Mendelian CRC forms, such as familial adenomatous polyposis and hereditary nonpolyposis CRC (Lynch syndrome) (2). The high-penetrance genes responsible for the hereditary CRC forms were identified in the last 15 years (APC, MLH1, MSH2, MSH6, PMS2 and MUTYH) but they only correspond to a small fraction of the total CRC genetic susceptibility (3). Some unidentified rare high-penetrance genes and a majority of low-penetrance common genetic components are likely to explain the rest of familial CRC genetics (4).

Recently, ARLTS1, also known as ARL11, was identified in chromosome 13q14 as a tumor suppressor gene of the ADP-ribosylation factor family with pro-apoptotic characteristics (5). Moreover, one of its genetic variants (W149X) was hypothesized to be a polymorphism associated with familial cancer, and it has been evaluated so far for melanoma, chronic lymphocytic leukemia, breast cancer, colon cancer, prostate cancer, thyroid papillary cancer and laryngeal cancer with controversial results (5–12).

Other genetic variants have been identified in the ARLTS1 gene and its putative association with sporadic and familial cancer has been also evaluated (7–9,11,12), including the C148R variant, apparently damaging by in silico prediction. Regarding CRC, a previous report studied the influence of ARLTS1 variants on CRC risk, although their limited study sample size yielded inconclusive results warranting a new evaluation of this hypothetical association (8).

Here, we present a large case–control association study performed within the EPICOLON project aimed at evaluating the sporadic and familial CRC risk associated with ARLTS1 genetic variants.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Appendix
 References
 
Study population
Between November 2000 and October 2001, all patients with newly diagnosed CRC in 25 hospitals were included in the EPICOLON project, a clinical epidemiology survey aimed at establishing the incidence and characteristics of hereditary and familial CRC forms in Spain (13,14). Patients with familial adenomatous polyposis, or personal history of inflammatory bowel disease, and those who refused to participate in the study were excluded. The study was approved by the Institutional Ethics Committee of each participating hospital, and written informed consent was obtained from all patients.

Demographic, clinical and tumor-related characteristics of probands, as well as a detailed family history were obtained. Pedigrees were traced backward and laterally as far as possible, or at least up to second-degree relatives, regarding cancer history. Age at cancer diagnosis, type, location and tumor stage of the neoplasm and current status were registered for each affected family member.

Tissue samples from tumor and normal colonic mucosa were obtained from each patient, immediately frozen in liquid nitrogen and stored at –70°C until use. Genomic DNA from these samples was isolated using the QiaAmp® Tissue Kit (Qiagen, Courtaboeuf, France). As part of the EPICOLON project, microsatellite instability testing and immunostaining for DNA mismatch repair proteins were performed in all patients and those found to have tumors with microsatellite instability and/or lack of protein expression underwent germ line genetic testing for MSH2 and MLH1. All sporadic or familial cases with microsatellite instability and/or lack of DNA mismatch repair protein expression were excluded in the present study, leaving 329 sporadic CRC cases and 187 familial CRC cases to be evaluated. Familial cases had at least one first- or second-degree relative with CRC or related neoplasms (endometrial, gastric, ovarian, hepatobiliary, small bowel, renal pelvis and urethra).

Control subjects matched by age, gender and center were recruited among individuals with no personal or familial history of cancer (n = 515) at the time of ascertainment from a large cohort of individuals attended in the outpatient clinics of orthopedic surgery department of participating institutions. Genomic DNA was obtained from peripheral blood samples using the QiaAmp® DNA Blood Mini Kit (Qiagen).

ARLTS1 genotyping
Genomic DNA extracted from normal colonic mucosa of the CRC cases was used for the present study, as well as genomic DNA extracted from peripheral blood of the case-matched controls.

Genotyping of four ARLTS1 variants (P131L, L132L, C148R and W149X) was performed by the same PCR amplification of 278 bp using primers ARLTS1-F (5'-GCTGGACAGCACAGATGAAG-3') and ARLTS1-R (5'-ACATGCAGCTGCGAGATTT-3'), followed by PCR purification and sequencing in forward and reverse orientations using the BigDye terminator v3.1. cycle sequencing kit (Applied Biosystems, Foster City, CA). Genotyping was scored manually and blindly by two independent operators to avoid errors. Sequencing was repeated in any case of doubt in genotype assignment.

In silico analysis of ARLTS1 variants
The putative phenotypic effect of amino acid changes on the ARLTS1 protein was checked using the web-based tools PolyPhen (http://genetics.bwh.harvard.edu/cgi-bin/pph/polyphen.cgi) and SNPs3D (http://www.snps3d.org) (15,16).

Statistical analysis
Allelic frequency description and Hardy–Weinberg equilibrium test were performed using SNPator, a web-based tool offered by the Bioinformatics division of the Centro Nacional de Genotipado (http://bioinformatica.cegen.upf.es). Genetic effect of the single-nucleotide polymorphisms (SNPs) was assessed by univariate and multivariate methods based on logistic regression analyses. Inter-group comparisons of genotype frequency differences were performed by regression analysis for dominant, recessive, overdominant and log-additive models of inheritance. We estimated the crude odds ratio (OR) and their 95% confidence intervals (95% CIs). We then estimated the OR adjusted by those clinical variables that were selected in the general linear model analysis with a logistic regression stepwise procedure. The best genetic or inheritance model was selected using the Akaike information criteria.

The selected clinical variables to be evaluated were sex, age (dichotomized by 50 years old), previous adenoma, left/right location of CRC, tumor, node, metastasis tumor stage, degree of differentiation, lymphocytic infiltration, previous CRC, synchronous CRC, number of synchronous polyps, synchronous adenoma, any relative with CRC, first-degree relative with CRC, endometrial cancer or other hereditary nonpolyposis CRC-related neoplasms, first-degree relative with CRC or hereditary nonpolyposis CRC-related neoplasm before 50 years old, fulfillment of modified or revised Bethesda guidelines (17).

Regarding haplotype analysis, linkage disequilibrium measures were estimated from inferred haplotypes using the Haploview 3.2 software (18). Haplotype frequencies were estimated using the expectation maximization algorithm using the function haplo.glm implemented in haplo.stats in the R programming language (19). Genotype and haplotype analyses were carried out using the SNPassoc R library (20).

Multiple testing problem was assessed calculating the effective number of independent marker loci (Meff) with the SNP Spectral Decomposition approach (SNPSpD) using all fully genotyped subjects for all four markers (Meff = 1) (21). Since there is a high SNP correlation, experiment-wide significance threshold required to keep type I error rate at 5% was set at a P = 0.012 accounting only for multiple inheritance models tested.

Genetic power was estimated using Genetic Power Calculator software (http://pngu.mgh.harvard.edu/~purcell) assuming low prevalence for CRC (5%), SNP marker frequency of 0.5, equal number of cases (n = 515) and controls, selected controls and adjusting for a type I error rate {alpha} = 0.05. Under this assumptions, our sample set has enough power (90%) to detect moderate high-risk alleles (RR = 2) but limited (60%) for moderate low-risk alleles (RR = 1.5).


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Appendix
 References
 
Genotyping of the four ARLTS1 analyzed variants (P131L, L132L, C148R and W149X) was successful for all tested samples (Figure 1) and the resulting allelic and genotype distributions are shown in Table I. The genotype frequencies of the four ARLTS1 variants in the control population fitted the Hardy–Weinberg equilibrium, supporting absence of confounding population stratification in the tested samples. After calculations using Genetic Power Calculator software, our sample set was estimated to have enough genetic power (90%) to detect moderate high-risk alleles (RR = 2) but limited (60%) for moderate low-risk alleles (RR = 1.5). The L132L variant was not selected for further analyses due to its low frequency.


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  		Table I. Allele and genotype frequencies of the ARLTS1 P131L, L132L, C148R and W149X variants in sporadic–familial CRC cases and controls

 


Figure 1
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  		Fig. 1. Sequence pictograms for the ARLTS1 variants. (a) Heterozygote DNA sample for P131L and C148R and (b) heterozygote DNA sample for C148R and W149X. Sequences are in forward orientation.

 
Influence of the P131L, C148R and W149X variants on CRC risk was evaluated confronting all CRC cases versus controls, sporadic CRC cases versus controls, familial CRC cases versus controls and familial CRC cases versus sporadic CRC cases, as it is detailed in Table II. We observed no significant differences between all confronted groups for P131L and W149X. On the contrary, C148R showed significant differences between cases and controls (TT versus TC + CC, OR = 1.47, 95% CI = 1.10–1.98, P = 0.009; TT + CC versus TC, OR = 1.45, 95% CI = 1.13–1.86, P = 0.003), sporadic cases and controls (TT versus TC + CC, OR = 1.59, 95% CI = 1.13–2.23, P = 0.007; TT + CC versus TC, OR = 1.40, 95% CI = 1.06–1.85, P = 0.018) and familial cases and controls (TT + CC versus TC, OR = 1.55, 95% CI = 1.10–2.19, P = 0.01). These associations were present after Bonferroni correction for multiple models testing, even after adjusting for gender and age differences. However, no significant differences were found between familial and sporadic CRC cases for the C148R variant (Table II).


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  		Table II. ORs with 95% CIs and respective P values for the ARLTS1 P131L, C148R and W149X variants in sporadic–familial CRC cases and controls

 
A putative phenotypic effect could be hypothesized for both amino acid changes P131L and C148R on the ARLTS1 protein after checking the web-based tools PolyPhen and SNPs3D.

Concerning haplotype analyses of the P131L/C148R/W149X variants, linkage disequilibrium measures calculated from inferred haplotypes showed P131L to be strongly linked to C148R, as well as C148R to W149X. Four different haplotypes were inferred, corresponding to two major haplotypes [CTG (48.6%) and CCG (48.6%)] and two minor haplotypes [CTA (1.1%) and TTG (1.7%)]. No haplotype association was observed either in the crude analysis or in the analysis adjusted by sex and age, showing again no statistically significant differences between familial and sporadic CRC cases.

Regarding the most parsimonious model of inheritance for the ARLTS1 C148R variant, the overdominant or dominant models seemed to be the most likely, as suggested by Akaike information criteria for all group comparisons (Table III).


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  		Table III. ORs with 95% CIs and respective P values related to different inheritance models for the ARLTS1 C148R variant (rs3803185) in sporadic–familial CRC cases and controls

 
In order to identify confounding factors related to the familial–sporadic CRC comparison, a multivariate approach by means of a general linear model analysis with a stepwise procedure was used. Presence of synchronous CRC, age at diagnosis and sex were selected as independent covariates. Adjusted genotype and haplotype analyses for these variables did not reveal any statistically significant result comparing familial and sporadic CRC cases. Since colorectal adenomas are regarded as the initial presentation of the CRC malignancy, we also investigated the correlation between the ARLTS1 variants and the presence of these neoplastic lesions. After determination of the confounding variables, no statistically significant difference was observed between the familial and sporadic CRC groups.


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Appendix
 References
 
After evaluating the results of our large case–control association study for each ARLTS1 variant individually, P131L and W149X did not seem to affect CRC risk, whereas C148R did show, for the first time in CRC, statistically significant differences between cases and controls (OR = 1.45, 95% CI = 1.13–1.86, P = 0.003), sporadic cases and controls (OR = 1.59, 95% CI = 1.13–2.23, P = 0.007) and familial cases and controls (OR = 1.55, 95% CI = 1.10–2.19, P = 0.01) in agreement with a hypothetical moderate increase of the cancer risk linked to the C148R ARLTS1 variant, both in sporadic and familial CRC cases. It is important to emphasize that these correlation results were statistically significant after correction for multiple testing, reinforcing the strength of this C148R-associated risk for CRC.

In contrast, haplotype evaluation of the three ARLTS1 variants showed P131L to be strongly linked to C148R as shown previously (7,11), as well as C148R to W149X (11), but it failed to yield any other statistically significant result, neither in the crude analysis nor in the analysis adjusted by sex and age. Additionally, our comparison regarding the ARLTS1 variants between sporadic and familial CRC, as an effort to identify any difference between these two CRC groups in terms of the CRC risk associated with the ARLTS1 variants, also failed to detect statistically significant differences in the individual genotype or the haplotype analyses.

Regarding the putative phenotypic effect of the ARLTS1 variants, whereas the W149X variant causes the C-terminal loss of 25 highly conserved amino acids of the ARLTS1 protein and, thus, it is very likely to be pathogenic (5), P131L and C148R may also be pathogenic variants according to the in silico prediction for a putative phenotypic effect of those amino acid changes using PolyPhen and SNPs3D web tools. In particular, both variants are predicted to be ‘possibly damaging’ using PolyPhen and variant C148R amino acid change is also predicted to cause ‘electrostatic repulsion and breakage of a disulfide bond’ using SNPs3D, which would be reinforcing the hypothesis of its putative phenotypic effect.

On the other hand, an overdominant model of inheritance was consistently the most parsimonious, as suggested by Akaike information criteria for all group comparisons. Therefore, a molecular positive heterosis effect (heterozygotes show a significantly greater effect for a trait than homozygotes) may seem likely for the C148R variant in CRC risk, either sporadic or familial as shown by our results. This heterosis effect was already proposed for both sporadic and familial melanoma, reinforcing this inheritance hypothesis (12).

The effect of ARLTS1 on cancer risk has been investigated in several neoplasms, but so far the more consistent results have been achieved for breast cancer and melanoma, and particularly for the more common C148R variant (6,10,12). Our results would be in agreement with a hypothetical effect of this variant on the CRC risk in both sporadic and familial cases. Indeed, the associated CRC risk could be moderately increased in R148 carriers around 1.5 times. Different clinical approaches for R148 carriers in terms of increased frequency of endoscopic screening and surveillance should not be advised until further scientific evidence becomes available.

On the contrary, the effect of W149X on CRC risk has not been confirmed by our study, also in agreement with previous results for CRC or other neoplasms (8,10–12). Similarly, although a potential effect of P131L on CRC risk could be suggested on the basis of the in silico prediction, this correlation was not confirmed in our analysis. Whereas our sample size seems to be large enough to detect the C148R-associated risk for CRC, as proved by the genetic power calculation, the proposed effect of the rare variants W149X or P131L on CRC risk cannot be definitely excluded or confirmed with this study since our sample size might be still limiting to detect it. Larger association studies or a meta-analysis would be needed to clarify this matter.

In conclusion, the ARLTS1 C148R variant seem to affect CRC risk both in sporadic and familial cases, and it could be regarded as one of the many common low-penetrance genetic components involved in genetic predisposition to several tumors, including CRC.


   Appendix
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
References
 
Investigators from the Gastrointestinal Oncology Group of the Spanish Gastroenterological Association who participated in the study
Hospital 12 de Octubre, Madrid: Juan Diego Morillas (local coordinator), Raquel Muñoz, Marisa Manzano, Francisco Colina, Jose Díaz, Carolina Ibarrola, Guadalupe López and Alberto Ibáñez; Hospital Clínic, Barcelona: Antoni Castells (local coordinator), Virgínia Piñol, Sergi Castellví-Bel, Francisco Rodríguez-Moranta, Francesc Balaguer, Antonio Soriano, Rosa Cuadrado, Maria Pellisé, Rosa Miquel, J.Ignasi Elizalde and Josep M.Piqué; Hospital Clínico Universitario, Zaragoza: Ángel Lanas (local coordinator), Javier Alcedo and Javier Ortego; Hospital Cristal-Piñor, Complexo Hospitalario de Ourense: Joaquin Cubiella (local coordinator), Ma Soledad Díez, Mercedes Salgado, Eloy Sánchez and Mariano Vega; Hospital del Mar, Barcelona: Montserrat Andreu (local coordinator), Xavier Bessa, Agustín Panadés, Asumpta Munné, Felipe Bory, Miguel Nieto and Agustín Seoane; Hospital Donosti, San Sebastián: Luis Bujanda (local coordinator), Juan Ignacio Arenas, Isabel Montalvo, Julio Torrado and Ángel Cosme; Hospital General Universitario de Alicante: Artemio Payá (local coordinator), Rodrigo Jover, Juan Carlos Penalva and Cristina Alenda; Hospital General de Granollers, Hospital General de Vic: Joan Saló (local coordinator), Eduard Batiste-Alentorn, Josefina Autonell and Ramon Barniol; Hospital General Universitario de Guadalajara: Ana María García (local coordinator), Fernando Carballo, Antonio Bienvenido, Eduardo Sanz, Fernando González and Jaime Sánchez; Hospital General Universitario de Valencia: Enrique Medina (local coordinator), Jaime Cuquerella, Pilar Canelles, Miguel Martorell, José Ángel García, Francisco Quiles and Elisa Orti; Hospital do Meixoeiro, Vigo: Juan Clofent (local coordinator), Jaime Seoane, Antoni Tardío and Eugenia Sanchez; Hospital San Eloy, Baracaldo: Luis Bujanda (local coordinator), Carmen Muñoz, María del Mar Ramírez and Araceli Sánchez; Hospital Universitari Germans Trias i Pujol, Badalona: Xavier Llor (local coordinator), Elisenda Pons, Rosa M.Xicola, Marta Piñol, Mercè Rosinach, Anna Roca, José M. Hernández and Miquel A.Gassull; Hospital Universitari Mútua de Terrassa: Fernando Fernández-Bañares (local coordinator), Josep M.Viver, Antonio Salas, Jorge Espinós, Montserrat Forné and Maria Esteve; Hospital Universitari Arnau de Vilanova, Lleida: Josep M.Reñé (local coordinator), Carmen Piñol, Juan Buenestado and Joan Viñas; Hospital Universitario de Canarias: Enrique Quintero (local coordinator), David Nicolás, Adolfo Parra and Antonio Martín; Hospital Universitario La Fe, Valencia: Lidia Argüello (local coordinator), Vicente Pons, Virginia Pertejo and Teresa Sala and Hospital Universitario Reina Sofía, Córdoba: Antonio Naranjo (local coordinator), María del Valle García, Patricia López, Fernando López, Rosa Ortega, Javier Briceño and Javier Padillo.


   Footnotes
 
{dagger} All authors are listed in the Appendix. Back


   Acknowledgments
 
We are sincerely grateful to all patients participating in this study that were recruited in 25 Spanish hospitals as part of the EPICOLON project. This work was supported by grants from the Fondo de Investigación Sanitaria (03/0070, 05/0071 and 05/2031), from the Ministerio de Educación y Ciencia (SAF 04-07190) and from Merck, Co. S.C.-B. is supported by a contract from the Fondo de Investigación Sanitaria (CP 03-0070, Ministerio de Sanidad) and R.d.C. is supported by the National Center of Genotyping-CEGEN funded by Genoma España. F.B. received a research grant from the Hospital Clínic and the Instituto de Salud Carlos III and V.G. from the Hospital Clínic.

Conflict of Interest statement: None declared.


   References
Top
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 Introduction
 Patients and methods
 Results
 Discussion
 Appendix
 References
 

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Received February 28, 2007; revised March 28, 2007; accepted April 11, 2007.


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