[show abstract][hide abstract] ABSTRACT: BACKGROUND: Colorectal cancer (CRC) is a disease of complex aetiology, with much of the expected inherited risk being due to several common low risk variants. Genome-Wide Association Studies (GWAS) have identified 20 CRC risk variants. Nevertheless, these have only been able to explain part of the missing heritability. Moreover, these signals have only been inspected in populations of Northern European origin. RESULTS: Thus, we followed the same approach in a Spanish cohort of 881 cases and 667 controls. Sixty-four variants at 24 loci were found to be associated with CRC at p-values <10-5. We therefore evaluated the 24 loci in another Spanish replication cohort (1481 cases and 1850 controls). Two of these SNPs, rs12080929 at 1p33 (Preplication=0.042; Ppooled=5.523x10-03; OR (CI95%)=0.866(0.782-0.959)) and rs11987193 at 8p12 (Preplication=0.039; Ppooled=6.985x10-5; OR (CI95%)=0.786(0.705-0.878)) were replicated in the second Phase, although they did not reach genome-wide statistical significance. CONCLUSIONS: We have performed the first CRC GWAS in a Southern European population and by these means we were able to identify two new susceptibility variants at 1p33 and 8p12 loci. These two SNPs are located near the SLC5A9 and DUSP4 loci, respectively, which could be good functional candidates for the association signals. We therefore believe that these two markers constitute good candidates for CRC susceptibility loci and should be further evaluated in other larger datasets. Moreover, we highlight that were these two SNPs true susceptibility variants, they would constitute a decrease in the CRC missing heritability fraction.
[show abstract][hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have successfully identified 20 colorectal cancer (CRC) susceptibility loci. Amongst these, four of the signals are defined by tagging SNPs on regions 14q22.2 (rs4444235 and rs1957636) and 20p12.3 (rs961253 and rs4813802). These markers are located close to two of the genes involved in BMP signalling (BMP4 and BMP2, respectively). By investigating these four SNPs in an initial cohort of Spanish origin, we found substantial evidence that minor allele frequencies (MAFs) may be different in Northern and Southern European populations. Therefore, we genotyped 3 additional Southern European cohorts comprising a total of 2,028 cases and 4,273 controls. The meta-analysis results show that only one of the association signals (rs961253) is effectively replicated in the Southern European populations, despite adequate power to detect all four. The other three SNPs (rs4444235, rs1957636 and rs4813802) present discordant results in MAFs and LD patterns between Northern and Southern European cohorts. We hypothesize that this lack of replication could be the result of differential tagging of the functional variant in both sets of populations. Were this true, it would have complex consequences in both our ability to understand the nature of the real causative variants, as well as for further study designs.
[show abstract][hide abstract] ABSTRACT: The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale.The Pharmacogenomics Journal advance online publication, 7 February 2012; doi:10.1038/tpj.2012.2.
The Pharmacogenomics Journal 02/2012; · 5.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: Colorectal cancer (CRC) is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low-penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase) are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category) and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium.
CRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in ADH1C, APC, CCDN1, IL6, IL8, IRS1, MTHFR, PPARG, VDR and ARL11, and 18 selected variants in the mucin gene family.
None of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a P-value < 0.05 in EPICOLON stage 1 [rs698 in ADH1C (OR = 1.63, 95% CI = 1.06-2.50, P-value = 0.02, recessive), rs1800795 in IL6 (OR = 1.62, 95% CI = 1.10-2.37, P-value = 0.01, recessive), rs3803185 in ARL11 (OR = 1.58, 95% CI = 1.17-2.15, P-value = 0.007, codominant), and rs2102302 in GALNTL2 (OR = 1.20, 95% CI = 1.00-1.44, P-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06-1.69, P-value = 0.01, recessive). In the joint analysis for both stages, results were only significant for rs3803185 (OR = 1.12, 95% CI = 1.00-1.25, P-value = 0.04, log-additive 0, 1, 2 alleles) and borderline significant for rs698 and rs2102302. The rs3803185 variant was not significantly associated with CRC risk in an external cohort (MCC-Spain), but it still showed some borderline significance in the pooled analysis of both cohorts (OR = 1.08, 95% CI = 0.98-1.18, P-value = 0.09, log-additive 0, 1, 2 alleles).
ARL11, ADH1C, GALNTL2 and IL6 genetic variants may have an effect on CRC risk. Further validation and meta-analyses should be undertaken in larger CRC studies.
[show abstract][hide abstract] 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.
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.
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 x 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 x 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 x 10(-4)).
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.
[show abstract][hide abstract] ABSTRACT: En un estudio poblacional previo en España (Eur J Gastroenterol Hepatol 2004; 16:39–45), el diagnóstico clínico de CCHNP y otras formas familiares de CCR se observó en un 2,5% y 27%, respectivamente. Mientras el CCHNP es una enfermedad bien caracterizada, existen pocos datos sobre las características de los pacientes con CCR familiar no sindrómico.
Comparar las características epidemiológicas del CCHNP respecto a otras formas familiares de CCR en nuestro medio.
Estudio prospectivo, multicéntrico de ámbito nacional (EPICOLON-II). Se registraron todos los pacientes con CCR diagnosticado de novo atendidos en el período de Junio 2006 a Diciembre 2007 en hospitales de ámbito nacional. Se recogieron de forma sistemática las características demográficas, clínicas, relativas al tumor del probando, así como una detallada historia familiar
Los resultados corresponden a los primeros 699 casos de CCR de 10 hospitales con una historia familiar completa. El diagnóstico clínico de CCHNP se estableció en 9 (1,3%) pacientes en base a los criterios de Amsterdam II. La comparación entre los pacientes que cumplian los criterios de Amsterdam I o II no mostró diferencia alguna en relación a las características demográficas, clínicas o en relación al tumor. Un total de 189 (26,8%) pacientes cumplían los criterios revisados de Bethesda. Todos los CCHNP cumplían al menos uno de los criterios de Bethesda. Del total de pacientes, 145 (20,7%) presentaban una historia familiar de CCR y 543 (78%) pacientes no presentaban ninguna historia familiar de CCR, representando el grupo de CCR esporádico. Estos grupos se diferenciaban en la localización colon derecho del tumor (p<0,06), la presencia de adenomas sincrónicos (P<0,05) y la presencia de adenomas sincrónicos en el colon derecho (p<0,02).
Estos datos clínico-epidemiológicos aportan información adicional en la caracterización del CCHNP y otras formas de CCR familiar en España. De forma peculiar, la localización del CCR y de lesiones sincrónicas adenomatosas pueden sugerir la existencia de una forma familiar de CCR.