Narrow-band imaging and high-definition white-light endoscopy in patients with serrated lesions not fulfilling criteria for serrated polyposis syndrome: a randomized controlled trial with tandem colonoscopy.

BACKGROUND: It is unknown whether narrow-band imaging (NBI) could be more effective than high-definition white-light endoscopy (HD-WLE) in detecting serrated lesions in patients with prior serrated lesions > 5 mm not completely fulfilling serrated polyposis syndrome (SPS) criteria. METHODS: We conducted a randomized, cross-over trial in consecutive patients with prior detection of at least one serrated polyp ≥10 mm or ≥ 3 serrated polyps larger than 5 mm, both proximal to the sigmoid colon. Five experienced endoscopists performed same-day tandem colonoscopies, with the order being randomized 1:1 to NBI-HD-WLE or HD-WLE-NBI. All tandem colonoscopies were performed by the same endoscopist. RESULTS: We included 41 patients. Baseline characteristics were similar in the two cohorts: NBI-HD-WLE (n = 21) and HD-WLE-NBI (n = 20). No differences were observed in the serrated lesion detection rate of NBI versus HD-WLE: 47.4% versus 51.9% (OR 0.84, 95% CI: 0.37-1.91) for the first and second withdrawal, respectively. Equally, no differences were found in the polyp miss rate of NBI versus HD-WLE: 21.3% versus 26.1% (OR 0.77, 95% CI: 0.43-1.38). Follow-up colonoscopy in nine patients (22%) allowed them to be reclassified as having SPS. CONCLUSIONS: In patients with previous serrated lesions, the serrated lesion detection rate was similar with NBI and HD-WLE. A shorter surveillance colonoscopy interval increases the detection of missed serrated polyps and could change the diagnosis of SPS in approximately one in every five patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02406547, registered on April 2, 2015.

Genetic association between CD96 locus and immunogenicity to anti-TNF therapy in Crohn's disease.

The production of antibodies to anti-tumor necrosis factor alpha (TNF) agents is one of the main causes of treatment failure in Crohn's disease (CD). To date, however, the contribution of genetics to anti-TNF immunogenicity in CD is still unknown. The objective of the present study was to identify genetic variation associated with anti-TNF immunogenicity in CD. We performed a two-stage genome-wide association study in a cohort of 96 and 123 adalimumab-treated patients, respectively. In the discovery stage, we identified a genome-wide significant association between the CD96 locus and the production of antibodies to anti-TNF treatment (P = 1.88e-09). This association was validated in the replication stage (P < 0.05). The risk allele for anti-TNF immunogenicity was found to be also associated with a lack of response to anti-TNF therapy (P = 0.019). These findings represent an important step toward the understanding of the immunogenicity-based mechanisms that underlie anti-TNF response in CD.

Meat intake, cooking methods and doneness and risk of colorectal tumours in the Spanish multicase-control study (MCC-Spain).

PURPOSE: Although there is convincing evidence that red and processed meat intake increases the risk of colorectal cancer (CRC), the potential role of meat cooking practices has not been established yet and could partly explain the current heterogeneity of results among studies. Therefore, we aimed to investigate the association between meat consumption and cooking practices and the risk of CRC in a population-based case-control study. METHODS: A total of 1671 CRC cases and 3095 controls recruited in Spain between September 2008 and December 2013 completing a food frequency questionnaire with a meat-specific module were included in the analyses. Odds ratios (OR) and confidence intervals (CI) were estimated by logistic regression models adjusted for known confounders. RESULTS: Total meat intake was associated with increased risk of CRC (OR T3-T1 1.41; 95% CI 1.19-1.67; p trend < 0.001), and similar associations were found for white, red and processed/cured/organ meat. Rare-cooked meat preference was associated with low risk of CRC in red meat (ORrare vs. medium 0.66; 95% CI 0.51-0.85) and total meat (ORrare vs. medium 0.56; 95% CI 0.37-0.86) consumers, these associations being stronger in women than in men. Griddle-grilled/barbecued meat was associated with an increased CRC risk (total meat: OR 1.45; 95% CI 1.13-1.87). Stewing (OR 1.25; 95% CI 1.04-1.51) and oven-baking (OR 1.18; 95% CI 1.00-1.40) were associated with increased CRC risk of white, but not red, meat. CONCLUSIONS: Our study supports an association of white, red, processed/cured/organ and total meat intake with an increased risk of CRC. Moreover, our study showed that cooking practices can modulate such risk.

Relationship between drugs affecting the renin-angiotensin system and colorectal cancer: The MCC-Spain study.

The potential protective effect of renin-angiotensin system (RAS) inhibitors is a subject of increasing interest due to their possible role as chemopreventive agents against colorectal cancer (CRC). To evaluate this association, we conducted a case-control study with 2165 cases of colorectal cancer, diagnosed between 2007 and 2012, and 3912 population controls frequency matched (by age, sex and region) from the Spanish multicenter case-control study MCC-Spain. We found a significant protective effect of the angiotensin-converting enzyme Inhibitors (ACEIs) against CRC, limited to the under-65years group (OR=0.65 95%CI (0.48-0.89)) and to a lesser degree to men (OR=0.81 95%CI (0.66-0.99). In contrast, the angiotensin receptor blockers (ARBs) did not show a significant effect. Regarding the duration of use, a greater protection was observed in men as the length of consumption increases. In contrast, in the under-65 stratum, the strongest association was found in short-term treatments. Finally, by analyzing ACEIs effect by colon subsite, we found no differences, except for under 65years old, where the maximum protection was seen in the proximal intestine, descending in the distal and rectum (without statistical significance). In conclusion, our study shows a protective effect on CRC of the ACEis limited to males and people under 65years old, which increases in proximal colon in the latter. If confirmed, these results may suggest a novel approach to proximal CRC prevention, given the shortcomings of colonoscopy screening in this location.

Association of a let-7 miRNA binding region of TGFBR1 with hereditary mismatch repair proficient colorectal cancer (MSS HNPCC).

The purpose of this study was to identify novel colorectal cancer (CRC)-causing alleles in unexplained familial CRC cases. In order to do so, coding regions in five candidate genes (MGMT, AXIN2, CTNNB1, TGFBR1 and TGFBR2) were sequenced in 11 unrelated microsatellite-stable hereditary non-polyposis CRC (MSS HNPCC) cases. Selected genetic variants were genotyped in a discovery set of 27 MSS HNPCC cases and 85 controls. One genetic variant, rs67687202, in TGFBR1 emerged as significant (P = 0.002), and it was genotyped in a replication set of 87 additional MSS HNPCC-like cases and 338 controls where it was also significantly associated with MSS HNPCC cases (P = 0.041). In the combined genotype data, rs67687202 was associated with a moderate increase in CRC risk (OR = 1.68; 95% CI = 1.13-2.50; P = 0.010). We tested a highly correlated SNP rs868 in 723 non-familial CRC cases compared with 629 controls, and it was not significantly associated with CRC risk (P = 0.370). rs868 is contained in a let-7 miRNA binding site in the 3'UTR of TGFBR1, which might provide a functional basis for the association in MSS HNPCC. In luciferase assays, the risk-associated allele for rs868 was associated with half the luciferase expression in the presence of miRNA let-7b-5p compared with protective allele, suggesting more binding of let-7b-5p and less TGFBR1 expression. Thus, rs868 potentially is a CRC risk-causing allele. Our results support the concept that rs868 is associated with lower TGFBR1 expression thereby increasing CRC risk.

Identification of risk loci for Crohn's disease phenotypes using a genome-wide association study.

BACKGROUND & AIMS: Crohn's disease is a highly heterogeneous inflammatory bowel disease comprising multiple clinical phenotypes. Genome-wide association studies (GWASs) have associated a large number of loci with disease risk but have not associated any specific genetic variants with clinical phenotypes. We performed a GWAS of clinical phenotypes in Crohn's disease. METHODS: We genotyped 576,818 single-nucleotide polymorphisms in a well-characterized cohort of 1090 Crohn's disease patients of European ancestry. We assessed their association with 17 phenotypes of Crohn's disease (based on disease location, disease behavior, disease course, age at onset, and extraintestinal manifestations). A total of 57 markers with strong associations to Crohn's disease phenotypes (P < 2 × 10(-4)) were subsequently analyzed in an independent replication cohort of 1296 patients of European ancestry. RESULTS: We replicated the association of 4 loci with different Crohn's disease phenotypes. Variants in MAGI1, CLCA2, 2q24.1, and LY75 loci were associated with a complicated stricturing disease course (Pcombined = 2.01 × 10(-8)), disease location (Pcombined = 1.3 × 10(-6)), mild disease course (Pcombined = 5.94 × 10(-7)), and erythema nodosum (Pcombined = 2.27 × 10(-6)), respectively. CONCLUSIONS: In a GWAS, we associated 4 loci with clinical phenotypes of Crohn's disease. These findings indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease.

Prevalence of MLH1 constitutional epimutations as a cause of Lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer.

BACKGROUND: The prevalence of MLH1 constitutional epimutations in the general population is unknown. We sought to analyse the prevalence of MLH1 constitutional epimutations in unselected and selected series of patients with colorectal cancer (CRC). METHODS: Patients with diagnoses of CRC (n=2123) were included in the unselected group. For comparison, a group of 847 selected patients with CRC who fulfilled the revised Bethesda guidelines (rBG) were also included. Somatic and constitutional MLH1 methylation was assayed via methylation-specific multiplex ligation-dependent probe amplification of cases lacking MLH1 expression. Germline alterations in mismatch-repair (MMR) genes were assessed via Sanger sequencing and methylation-specific multiplex ligation-dependent probe amplification. RESULTS: Loss of MLH1 expression occurred in 5.5% of the unselected series and 12.5% of the selected series (p<0.0001). No constitutional epimutations in MLH1 were detected in the unselected population (0/62); five cases from the selected series were positive for MLH1 epimutations (15.6%, 5/32; p=0.004). CONCLUSIONS: Our results suggest a negligible prevalence of MLH1 constitutional epimutations in unselected cases of CRC. Therefore, MLH1 constitutional epimutation analysis should be conducted only for patients who fulfil the rBG and who lack MLH1 expression with methylated MLH1.

Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer.

BACKGROUND: Colorectal cancers (CRCs) that have microsatellite instability (MSI) and mutL homolog 1 (MLH1) immunoloss are observed in 3 clinical scenarios: Lynch syndrome (LS), sporadic MSI CRC, and Lynch-like syndrome (LLS). v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational analysis is used to differentiate LS from sporadic MSI CRC. The role of MLH1 promoter methylation status for the differential diagnosis of these clinical forms is not well established. The objectives of this study were: 1) to analyze MLH1 promoter methylation in MLH1-deficient CRCs by pyrosequencing, and 2) to assess its role in the differential diagnosis of MLH1-deficient CRCs. METHODS: In total, 165 CRCs were analyzed, including LS (n = 19), MSI BRAF-mutated CRC (n = 37), MSI BRAF wild-type CRC (n = 60), and a control group of CRCs without MSI (microsatellite stable [MSS] CRC; n = 49). MLH1 promoter methylation status was analyzed by pyrosequencing, and the ability of different strategies to identify LS was assessed. RESULTS: The average ± standard deviation methylation in LS (9% ± 7%) was significantly lower than that in MSI BRAF-mutated CRC (42% ± 17%; P < .001) and in MSI BRAF wild-type CRC (25% ± 19%; P = .002). Somatic MLH1 hypermethylation was detected in 3 patients (15.8%) with LS, in 34 patients (91.9%) with MSI BRAF-mutated CRC, and in 37 patients (61.7%) with MSI BRAF wild-type tumors. Patients with MSI BRAF wild-type, unmethylated tumors (ie, LLS) had a stronger family history of CRC than those who had tumors with MLH1 methylation (P < .05). The sensitivity for ruling out LS was 100% for BRAF analysis, 84.2% for MLH1 methylation analysis, and 84.2% for the combination of both analyses. CONCLUSIONS: Somatic MLH1 promoter methylation occurs in up to 15% of LS CRCs. Somatic BRAF analysis is the most sensitive strategy for ruling out LS. Patients who have CRCs with loss of MLH1 protein expression and neither BRAF mutation nor MLH1 methylation resemble patients with LS.

Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening.

BACKGROUND: Colonoscopy and fecal immunochemical testing (FIT) are accepted strategies for colorectal-cancer screening in the average-risk population. METHODS: In this randomized, controlled trial involving asymptomatic adults 50 to 69 years of age, we compared one-time colonoscopy in 26,703 subjects with FIT every 2 years in 26,599 subjects. The primary outcome was the rate of death from colorectal cancer at 10 years. This interim report describes rates of participation, diagnostic findings, and occurrence of major complications at completion of the baseline screening. Study outcomes were analyzed in both intention-to-screen and as-screened populations. RESULTS: The rate of participation was higher in the FIT group than in the colonoscopy group (34.2% vs. 24.6%, P<0.001). Colorectal cancer was found in 30 subjects (0.1%) in the colonoscopy group and 33 subjects (0.1%) in the FIT group (odds ratio, 0.99; 95% confidence interval [CI], 0.61 to 1.64; P=0.99). Advanced adenomas were detected in 514 subjects (1.9%) in the colonoscopy group and 231 subjects (0.9%) in the FIT group (odds ratio, 2.30; 95% CI, 1.97 to 2.69; P<0.001), and nonadvanced adenomas were detected in 1109 subjects (4.2%) in the colonoscopy group and 119 subjects (0.4%) in the FIT group (odds ratio, 9.80; 95% CI, 8.10 to 11.85; P<0.001). CONCLUSIONS: Subjects in the FIT group were more likely to participate in screening than were those in the colonoscopy group. On the baseline screening examination, the numbers of subjects in whom colorectal cancer was detected were similar in the two study groups, but more adenomas were identified in the colonoscopy group. (Funded by Instituto de Salud Carlos III and others; ClinicalTrials.gov number, NCT00906997.).

Risk stratification for advanced colorectal neoplasia according to fecal hemoglobin concentration in a colorectal cancer screening program.

BACKGROUND & AIMS: The latest generation of fecal immunochemical tests (FIT) allows for quantitation of hemoglobin in feces, allowing for selection of optimal cut-off concentrations. We investigated whether individuals with positive results from quantitative FITs, in combination with other factors, could be identified as being at greatest risk for advanced colorectal neoplasia. METHODS: In a retrospective study, we analyzed data from a consecutive series of 3109 participants with positive results from FITs (≥20 µg/g of feces) included in the first round of the Barcelona colorectal cancer screening program, from December 2009 through February 2012. All participants underwent colonoscopy and were assigned to groups with any advanced colorectal neoplasia or with nonadvanced colorectal neoplasia (but with another diagnosis or normal examination findings). RESULTS: Median fecal hemoglobin concentrations were significantly higher in participants with advanced colorectal neoplasia (105 µg/g; interquartile range, 38-288 µg/g) compared with participants with nonadvanced colorectal neoplasia (47 µg/g; interquartile range, 23-119 µg/g) (P < .001). Positive predictive values for advanced colorectal neoplasia, determined using arbitrary fecal hemoglobin concentrations, differed with sex and age. Multivariate logistic regression analysis identified sex (men: odds ratio [OR], 2.07; 95% confidence interval, 1.78-2.41), age (60-69 y: OR, 1.24; 95% confidence interval, 1.07-1.44), and fecal hemoglobin concentration (>177 µg/g: OR, 3.80; 95% confidence interval, 3.07-4.71) as independent predictive factors for advanced colorectal neoplasia. Combining these factors, we identified 16 risk categories associated with different probabilities of identifying advanced colorectal neoplasia. Risk for advanced colorectal neoplasia increased 11.46-fold among individuals in the highest category compared with the lowest category; positive predictive values ranged from 21.3% to 75.6%. CONCLUSIONS: Fecal hemoglobin concentration, in addition to sex and age, in individuals with positive results from FITs can be used to stratify probability for the detection of advanced colorectal neoplasia. These factors should be used to prioritize individuals for colonoscopy examination.

Accuracy of magnetic resonance enterography in assessing response to therapy and mucosal healing in patients with Crohn's disease.

BACKGROUND & AIMS: We assessed the accuracy of magnetic resonance enterography (MRE) in monitoring response to therapy in patients with Crohn's disease (CD) using ileocolonoscopy as a reference standard. METHODS: We performed a prospective multicenter study of 48 patients with active CD and ulcers in at least one ileocolonic segment. All patients underwent ileocolonoscopy and MRE at baseline and 12 weeks after completing treatment with corticosteroids (CS) or anti-tumor necrosis factor agents. Disease activity was quantified using Crohn's Disease Endoscopic Index of Severity (CDEIS) and Magnetic Resonance Index of Activity (MaRIA). The primary analysis was to determine the accuracy of MRE in identification of healing, defined as the disappearance of ulcers in endoscopy examination. Additional analyses established the accuracy of MRE in determining endoscopic remission (a CDEIS score <3.5) and change in severity based on consideration of all segments. RESULTS: MRE determined ulcer healing with 90% accuracy and endoscopic remission with 83% accuracy. The mean CDEIS and MaRIA scores significantly changed at week 12 in segments with ulcer healing, based on endoscopic examination (CDEIS: 21.28 ± 9.10 at baseline vs 2.73 ± 4.12 at 12 weeks; P < .001 and MaRIA: 18.86 ± 9.50 at baseline vs 8.73 ± 5.88 at 12 weeks; P < .001). The MaRIA score accurately detected changes in lesion severity (Guyatt score: 1.2 and standardized effect size: 1.07). MRE was as reliable as endoscopy in assessing healing; no significant changes in CDEIS or MaRIA scores were observed in segments with persistent ulcers, based on endoscopic examination (CDEIS: 26.43 ± 9.06 at baseline vs 20.77 ± 9.13 at 12 weeks; P = .18 and MaRIA: 22.13 ± 8.42 at baseline vs 20.77 ± 9.17 at 12 weeks; P = .42). The magnitude of change in CDEIS scores correlated with those in MaRIA scores (r = 0.51; P < .001). CONCLUSIONS: MRE evaluates ulcer healing with a high level of accuracy when ileocolonoscopy is used as the reference standard. The MaRIA is a valid, responsive, and reliable index assessing response to therapy in patients with CD.

Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer.

PURPOSE: Colorectal cancer is an important cause of mortality in the developed world. Hereditary forms are due to germ-line mutations in APC, MUTYH, and the mismatch repair genes, but many cases present familial aggregation but an unknown inherited cause. The hypothesis of rare high-penetrance mutations in new genes is a likely explanation for the underlying predisposition in some of these familial cases. METHODS: Exome sequencing was performed in 43 patients with colorectal cancer from 29 families with strong disease aggregation without mutations in known hereditary colorectal cancer genes. Data analysis selected only very rare variants (0-0.1%), producing a putative loss of function and located in genes with a role compatible with cancer. Variants in genes previously involved in hereditary colorectal cancer or nearby previous colorectal cancer genome-wide association study hits were also chosen. RESULTS: Twenty-eight final candidate variants were selected and validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants in CDKN1B, XRCC4, EPHX1, NFKBIZ, SMARCA4, and BARD1. CONCLUSION: We identified new potential colorectal cancer predisposition variants in genes that have a role in cancer predisposition and are involved in DNA repair and the cell cycle, which supports their putative involvement in germ-line predisposition to this neoplasm.

Risk of cancer in cases of suspected lynch syndrome without germline mutation.

BACKGROUND & AIMS: Colorectal cancers (CRCs) with microsatellite instability (MSI) and a mismatch repair (MMR) immunohistochemical deficit without hypermethylation of the MLH1 promoter are likely to be caused by Lynch syndrome. Some patients with these cancers have not been found to have pathogenic germline mutations and are considered to have Lynch-like syndrome (LLS). The aim of this study was to determine the risk of cancer in families of patients with LLS. METHODS: We studied a population-based cohort of 1705 consecutive patients, performing MSI tests and immunohistochemical analyses of MMR proteins. Patients were diagnosed with Lynch syndrome when they were found to have pathogenic germline mutations. Patients with MSI and loss of MSH2 and/or MSH6 expression, isolated loss of PMS2 or loss of MLH1 without MLH1 promoter hypermethylation, and no pathogenic mutation were considered to have LLS. The clinical characteristics of patients and the age- and sex-adjusted standardized incidence ratios (SIRs) of cancer in families were compared between groups. RESULTS: The incidence of CRC was significantly lower in families of patients with LLS than in families with confirmed cases of Lynch syndrome (SIR for Lynch syndrome, 6.04; 95% confidence interval [CI], 3.58-9.54; SIR for LLS, 2.12; 95% CI, 1.16-3.56; P < .001). However, the incidence of CRC was higher in families of patients with LLS than in families with sporadic CRC (SIR for sporadic CRC, 0.48; 95% CI, 0.27-0.79; P < .001). CONCLUSIONS: The risk of cancer in families with LLS is lower that of families with Lynch syndrome but higher than that of families with sporadic CRC. These results confirm the need for special screening and surveillance strategies for these patients and their relatives.

Rate of detection of advanced neoplasms in proximal colon by simulated sigmoidoscopy vs fecal immunochemical tests.

BACKGROUND & AIMS: We compared the ability of biennial fecal immunochemical testing (FIT) and one-time sigmoidoscopy to detect colon side-specific advanced neoplasms in a population-based, multicenter, nationwide, randomized controlled trial. METHODS: We identified asymptomatic men and women, 50-69 years old, through community health registries and randomly assigned them to groups that received a single colonoscopy examination or biennial FIT. Sigmoidoscopy yield was simulated from results obtained from the colonoscopy group, according to the criteria proposed in the UK Flexible Sigmoidoscopy Trial for colonoscopy referral. Patients who underwent FIT and were found to have ≥75 ng hemoglobin/mL were referred for colonoscopy. Data were analyzed from 5059 subjects in the colonoscopy group and 10,507 in the FIT group. The main outcome was rate of detection of any advanced neoplasm proximal to the splenic flexure. RESULTS: Advanced neoplasms were detected in 317 subjects (6.3%) in the sigmoidoscopy simulation group compared with 288 (2.7%) in the FIT group (odds ratio for sigmoidoscopy, 2.29; 95% confidence interval, 1.93-2.70; P = .0001). Sigmoidoscopy also detected advanced distal neoplasia in a higher percentage of patients than FIT (odds ratio, 2.61; 95% confidence interval, 2.20-3.10; P = .0001). The methods did not differ significantly in identifying patients with advanced proximal neoplasms (odds ratio, 1.17; 95% confidence interval, 0.78-1.76; P = .44). This was probably due to the lower performance of both strategies in detecting patients with proximal lesions (sigmoidoscopy detected these in 19.1% of patients and FIT in 14.9% of patients) vs distal ones (sigmoidoscopy detected these in 86.8% of patients and FIT in 33.5% of patients). Sigmoidoscopy, but not FIT, detected proximal lesions in lower percentages of women (especially those 50-59 years old) than men. CONCLUSIONS: Sigmoidoscopy and FIT have similar limitations in detecting advanced proximal neoplasms, which depend on patients' characteristics; sigmoidoscopy underperforms for women 50-59 years old. Screening strategies should be designed on the basis of target population to increase effectiveness and cost-effectiveness. ClinicalTrials.gov number: NCT00906997.

Participation and detection rates by age and sex for colonoscopy versus fecal immunochemical testing in colorectal cancer screening.

PURPOSE: To compare two strategies for colorectal cancer screening: one-time colonoscopy versus fecal immunochemical testing (FIT) (and colonoscopy for positive) every 2 years, in order to determine which strategy provides the highest participation and detection rates in groups of sex and age. METHODS: This analysis was performed with data from the first screening round within the COLONPREV study, a population-based, multicenter, nationwide trial carried out in Spain. Several logistic regression models were applied to identify the influence of the screening test on participation rates and detection of proximal and distal neoplasms, as well to identify the influence of age and sex: women aged 50-59 years, women aged 60-69 years, men aged 50-59 years, and men aged 60-69 years. RESULTS: Participation was higher in women than in men, especially among women aged 50-59 years (25.91 % for colonoscopy and 35.81 % for FIT). Crossover from colonoscopy to FIT was higher among women than men, especially among those aged 60-69 years (30.37 %). In general, detection of any neoplasm and advanced adenoma was higher with colonoscopy than with FIT, but no significant differences were found between the two strategies for colorectal cancer detection. Detection of advanced adenoma in both arms was lower in women [specifically in women aged 50-59 years (OR 0.31; 95 % CI 0.25-0.38) than in men aged 60-69 years]. Women aged 50-59 years in the colonoscopy arm had a higher probability of detection of advanced adenoma (OR 4.49; 95 % CI 3.18-6.35), as well as of detection of neoplasms in proximal and distal locations (proximal OR 19.34; 95 % CI 12.07-31.00; distal OR 11.04; 95 % CI 8.13-15.01) than women of the same age in the FIT arm. These differences were also observed in the remaining groups but to a lesser extent. CONCLUSION: Women were more likely to participate in a FIT-based strategy, especially those aged 50-59 years. The likelihood of detection of any neoplasm was higher in the colonoscopy arm for all the population groups studied, especially in women aged 50-59 years. Distinct population groups should be informed of the benefits of each screening strategy so that they may take informed decisions.

[Treatment of colorectal cancer with unresectable metastasis with chemotherapy without primary tumor resection: analysis of tumor-related complications]. / Tratamiento del cáncer colorrectal con metástasis irresecables con quimioterapia sin resección del primario: análisis de las complicaciones relacionadas con el tumor.

INTRODUCTION: Although the conventional treatment of patients with stage iv colorectal cancer involves resection of the primary tumor followed by chemotherapy, several studies suggest that in patients with few symptoms the first and only treatment should be chemotherapy. The objective of this study is to analyze the complications related to the primary tumor in a series of patients with unresectable metastatic colorectal cancer treated with chemotherapy without surgery. MATERIAL AND METHODS: Retrospective descriptive study. The study included all patients with unresectable metastatic colorectal cancer treated with chemotherapy without resection of the primary tumor (January 2007-February 2011). RESULTS: The mean age of the 61 patients analyzed was 67±13 years and the performance status was 0-1 in 53 (87%). Twenty (33%) patients developed complications during follow-up. The most common complication was intestinal obstruction in 15 (25%) patients followed by perforation. Complications required surgery in 6 (10%) cases. We did not find differences in patient characteristics between those who had a complication and those without, although the complication rate in patients with a colonic stent (53%) was twice that of other patients (26%). CONCLUSIONS: Chemotherapy without surgery is a good option in most patients with unresectable metastatic colorectal cancer. However, although the percentage of patients requiring surgery is low, the total number of complications related to the primary tumor is not negligible. Studies are needed to identify those patients in whom a prophylactic colectomy could be indicated.

A genome-wide association study on a southern European population identifies a new Crohn's disease susceptibility locus at RBX1-EP300.

OBJECTIVE: Genome-wide association studies (GWAS) have identified multiple risk loci for Crohn's disease (CD). However, the cumulative risk exerted by these loci is low, and the likelihood that additional, as-yet undiscovered loci contribute to the risk of CD is very high. We performed a GWAS on a southern European population to identify new CD risk loci. DESIGN: We genotyped 620 901 genome markers on 1341 CD patients and 1518 controls from Spain. The top association signals representing new candidate risk loci were subsequently analysed in an independent replication cohort of 1365 CD patients and 1396 controls. RESULTS: We identified a genome-wide significant association on chromosome 22q13.2 in the intergenic region between the RBX1 and EP300 genes (single nucleotide polymorphism rs4820425, OR 1.27, 95% CI 1.17 to 1.38, p=3.42E-8). We also found suggestive evidence for the association of the IFNGR2 (21q22.11), FOXP2 (7q31), MACROD2 (20p12.1) and AIF1 (6p21.3) loci with CD risk. CONCLUSIONS: In this GWAS performed on a southern European cohort, we have identified a new risk locus for CD between RBX1 and EP300. This study demonstrates that using populations of different ancestry is a useful strategy to identify new risk loci for CD.

BMP2/BMP4 colorectal cancer susceptibility loci in northern and southern European populations.

Genome-wide association studies have successfully identified 20 colorectal cancer susceptibility loci. Amongst these, four of the signals are defined by tagging single nucleotide polymorphisms (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 bone morphogenetic protein (BMP) signaling (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 three additional southern European cohorts comprising a total of 2028 cases and 4273 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) presented discordant results in MAFs and linkage disequilibrium 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.

Genetic susceptibility variants associated with colorectal cancer prognosis.

Colorectal cancer (CRC) is the second leading cause of cancer-related death among men and women in Western countries. Once a tumour develops, a differentiated prognosis could be determined by lifestyle habits or inherited and somatic genetic factors. Finding such prognostic factors will be helpful in order to identify cases with a shorter survival or at a higher risk of recurrence that may benefit from more intensive treatment and follow-up surveillance. Sixteen CRC genetic susceptibility variants were directly genotyped in a cohort of 1235 CRC patients recruited by the EPICOLON Spanish consortium. Univariate Cox and multivariate regression analyses were performed taking as primary outcomes overall survival (OS), disease-free survival and recurrence-free interval. Genetic variants rs9929218 at 16q22.1 and rs10795668 at 10p14 may have an effect on OS. The G allele of rs9929218 was linked with a better OS [GG genotype, genotypic model: hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.45-0.93, P = 0.0179; GG/GA genotypes, dominant model: HR = 0.66, 95% CI 0.47-0.94, P = 0.0202]. Likewise, the G allele of rs10795668 was associated with better clinical outcome (GG genotype, genotypic model: HR = 0.73, 95% CI 0.53-1.01, P = 0.0570; GA genotype, genotypic model: HR = 0.66, 95% CI 0.47-0.92, P = 0.0137; GG/GA genotypes, dominant model: HR = 0.68, 95% CI 0.50-0.94, P = 0.0194). In conclusion, CRC susceptibility variants rs9929218 and rs10795668 may exert some influence in modulating patient's survival and they deserve to be further tested in additional CRC cohorts in order to confirm their potential as prognosis or predictive biomarkers.

A colorectal cancer genome-wide association study in a Spanish cohort identifies two variants associated with colorectal cancer risk at 1p33 and 8p12.

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.