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Background Current guidelines recommend genetic counseling and intensive colonoscopy surveillance for patients with ≥ 10 colorectal adenomas based on scarce data. We investigated the prevalence of this condition in a fecal immunochemical test (FIT)-based colorectal (CRC) screening program, and the incidence of metachronous lesions during follow-up. Methods We retrospectively included all FIT-positive participants with ≥ 10 adenomas at index colonoscopy between 2010 and 2018. Surveillance colonoscopies were collected until 2019. Patients with inherited syndromes, serrated polyposis syndrome, total colectomy, or lacking surveillance data were excluded. The cumulative incidence of CRC and advanced neoplasia were analyzed by Kaplan–Meier analysis. Risk factors for metachronous advanced neoplasia were investigated by multivariable logistic regression analysis. Results 215 of 9582 participants (2.2 %) had ≥ 10 adenomas. Germline genetic testing was performed in 92 % of patients with ≥ 20 adenomas, identifying two inherited syndromes (3.3 %). The 3-year cumulative incidence of CRC and advanced neoplasia were 1 % and 16 %, respectively. In 39 patients (24.2 %), no polyps were found on first surveillance colonoscopy. The presence of an advanced adenoma was independently associated with a higher risk of advanced neoplasia at first surveillance colonoscopy (odds ratio 3.91, 95 %CI 1.12–13.62; P = 0.03). Beyond the first surveillance colonoscopy, the risk of metachronous advanced neoplasia was lower. Conclusions The prevalence of ≥ 10 adenomas in a FIT-based CRC screening program was 2.2 %; a small proportion of inherited syndromes were detected, even amongst those with ≥ 20 adenomas. A low rate of post-colonoscopy CRC was observed and the risk of advanced neoplasia beyond the first surveillance colonoscopy tended to progressively decrease throughout successive follow-ups.

The World Health Organization (WHO) recently updated the diagnostic criteria for serrated polyposis syndrome (SPS). One of the three previous diagnostic criteria (criterion II 2010) is now abandoned: ≥ 1 serrated polyp (SP) proximal to the sigmoid in a first-degree relative (FDR) of a patient with SPS. Individuals fulfilling this abandoned criterion now receive the same surveillance recommendations as all FDRs of patients with SPS. We aimed to compare the incidence of advanced neoplasia (AN) in FDRs with vs. without fulfillment of the abandoned criterion II 2010. We retrospectively recruited FDRs of patients with SPS who underwent a colonoscopy, and stratified them according to fulfilment of criterion II 2010 at baseline. Our primary and secondary outcomes were AN incidence during surveillance and at baseline, respectively. We included 224 FDRs of patients with SPS, of whom 36 (16%) fulfilled criterion II 2010 at baseline. One hundred and five underwent surveillance after baseline. Criterion II 2010-positive FDRs were at increased risk of AN, both during surveillance (hazard ratio 8.94, 95% CI 2.15–37.1, p =.003) as well as at baseline (adjusted odds-ratio 9.30, 95% CI 3.7–23.3, p 2010 for SPS diagnosis were at increased risk of AN at baseline and during surveillance in this small, retrospective cohort study. Our results should be interpreted with caution but suggest that adherence to surveillance recommendations for all FDRs of patients with SPS is important, especially for those that would have fulfilled the now abandoned criterion II 2010.

Pancreatic cancer (PC) is a highly lethal disease, mostly incurable when detected. Thus, despite advances in PC treatments, only around 7% of patients survive 5-years after diagnosis. This morbid outcome is secondary to multifactorial reasons, such as late-stage diagnosis, rapid progression and minimal response to chemotherapy. Based on these factors, it is of special relevance to identify PC high-risk individuals in order to establish preventive and early detection measures. Although most PC are sporadic, approximately 10% cases have a familial basis. No main causative gene of PC has been identified but several known germline pathogenic mutations are related with an increased risk of this tumor. These inherited cancer syndromes represent 3% of all PC. On the other hand, in 7% of cases of PC, there is a strong family history without a causative germline mutation, a situation known as familial pancreatic cancer (FPC). In recent years, there is increasing evidence supporting the benefit of genetic germline analysis in PC patients, and periodic pancreatic screening in PC high-risk patients (mainly those with a lifetime risk greater than 5%), although there is no general agreement in the group of patients and individuals to study and screen. In the present review, we expose an update in the field of hereditary and FPC, with the aim of describing the current strategies and implications in genetic counseling, surveillance and therapeutic interventions.

Background and aimsSerrated polyposis syndrome (SPS) is associated with an increased risk of colorectal cancer (CRC). International guidelines recommend surveillance intervals of 1–2 years. However, yearly surveillance likely leads to overtreatment for many. We prospectively assessed a surveillance protocol aiming to safely reduce the burden of colonoscopies.MethodsBetween 2013 and 2018, we enrolled SPS patients from nine Dutch and Spanish hospitals. Patients were surveilled using a protocol appointing either a 1-year or 2-year interval after each surveillance colonoscopy, based on polyp burden. Primary endpoint was the 5-year cumulative incidence of CRC and advanced neoplasia (AN) during surveillance.ResultsWe followed 271 SPS patients for a median of 3.6 years. During surveillance, two patients developed CRC (cumulative 5-year incidence 1.3%[95% CI 0% to 3.2%]). The 5-year AN incidence was 44% (95% CI 37% to 52%), and was lower for patients with SPS type III (26%) than for patients diagnosed with type I (53%) or type I and III (59%, pConclusionRisk stratification substantially reduced colonoscopy burden while achieving CRC incidence similar to previous studies. AN incidence is considerable in SPS patients, but extension of surveillance intervals was not associated with increased AN in those identified as low-risk by the protocol. We identified SPS type III patients as low-risk group that might benefit from even less frequent surveillance.Trial registration numberThe study was registered on http://www.trialregister.nl; trial-ID NTR4609.

BACKGROUND & AIMS: Colonoscopy reduces colorectal cancer (CRC) incidence and mortality in Lynch syndrome (LS) carriers. However, a high incidence of postcolonoscopy CRC (PCCRC) has been reported. Colonoscopy is highly dependent on endoscopist skill and is subject to quality variability. We aimed to evaluate the impact of key colonoscopy quality indicators on adenoma detection and prevention of PCCRC in LS. METHODS: We conducted a multicenter study focused on LS carriers without previous CRC undergoing colonoscopy surveillance (n = 893). Incident colorectal neoplasia during surveillance and quality indicators of all colonoscopies were analyzed. We performed an emulated target trial comparing the results from the first and second surveillance colonoscopies to assess the effect of colonoscopy quality indicators on adenoma detection and PCCRC incidence. Risk analyses were conducted using a multivariable logistic regression model. RESULTS: The 10-year cumulative incidence of adenoma and PCCRC was 60.6% (95% CI, 55.5%-65.2%) and 7.9% (95% CI, 5.2%-10.6%), respectively. Adequate bowel preparation (odds ratio [OR], 2.07; 95% CI, 1.06-4.3), complete colonoscopies (20% vs 0%; P = .01), and panchromoendoscopy use (OR, 2.14; 95% CI, 1.15-3.95) were associated with significant improvement in adenoma detection. PCCRC risk was significantly lower when colonoscopies were performed during a time interval of less than every 3 years (OR, 0.35; 95% CI, 0.14-0.97). We observed a consistent but not significant reduction in PCCRC risk for a previous complete examination (OR, 0.16; 95% CI, 0.03-1.28), adequate bowel preparation (OR, 0.64; 95% CI, 0.17-3.24), or previous use of high-definition colonoscopy (OR, 0.37; 95% CI, 0.02-2.33). CONCLUSIONS: Complete colonoscopies with adequate bowel preparation and chromoendoscopy use are associated with improved adenoma detection, while surveillance intervals of less than 3 years are associated with a reduction of PCCRC incidence. In LS, high-quality colonoscopy surveillance is of utmost importance for CRC prevention.

Simple Summary Gastric cancer is one of the most common cancers worldwide, showing high mortality rates. A small portion of gastric cancer patients, known as early onset gastric cancer (EOGC) patients, develop the disease before age 50, and their characteristics are poorly described. Thus, our main objective was to describe the clinical, molecular, and genetic characteristics of EOGC in a large multicenter cohort of patients. We were able to identify that most EOGC cases have similar characteristics: diagnosed at advanced stage, diffuse type, and infrequent DNA mismatch repair somatic deficiency. Although familial aggregation of gastric cancer was uncommon, a germline genetic mutation was identified in 25% of the patients tested. Our results show that EOGC has a marked genetic heterogeneity. Thus, it is essential to consider familial history of tumors, not only GC, in order to select adequate patients to perform a suitable genetic counseling and enhance the emerging use of multigene panels. Abstract Gastric adenocarcinoma (GC) is a common tumor with high morbidity and mortality. Only 7% of patients with GC are diagnosed before age 50 (early onset gastric cancer (EOGC)), and their characteristics have been poorly described. We aimed to describe clinical, molecular, and genetic characteristics of EOGC. A total of 309 patients with EOGC were retrospectively studied in four Spanish centers. Personal information, family history, and tumor information were registered. Germinal genetic analysis was performed in patients who met current criteria of a hereditary syndrome at the time of diagnosis. The median age at diagnosis was 44 years. The majority (73.3%) of tumors were diffuse, and 78.3% were diagnosed in an advanced stage. Familial aggregation of GC was present in 18/117 (15.4%) cases, and 5/117 (4.3%) met criteria for familial GC. MMR-IHC was performed in 126/309 (40.7%) tumors: 4/126 (3.1%) had loss of expression in MLH1/PMS2, without an associated germline mutation. Sixteen germline genetic analyses were performed, detecting a pathogenic variant in four (25%) cases: one in BRCA2, one in TP53, and two in CDH1. Most EOGC are diffuse and diagnosed in an advanced stage. In these patients, DNA MMR system deficiency is uncommon. Although familial aggregation was observed in only 15% of cases, a germline mutation was found in 25% of patients tested with clinical criteria. This demonstrates that EOGC has a marked genetic heterogeneity, reinforcing the importance of an accurate genetic counseling and enhancing the emerging use of multigene panels.

Background and study aims Serrated polyposis syndrome (SPS) is a condition with high risk for colorectal cancer. The Endocuff device has been shown to increase adenoma detection in the general and screening population. We aimed to ascertain whether Endocuff-assisted colonoscopy increases detection of serrated lesions in comparison with standard colonoscopy during the surveillance of patients with SPS. Methods In a multicenter randomized controlled study, patients who met SPS criteria I and/or III under surveillance (previous resection of all serrated lesions ≥ 4 mm) were consecutively randomly allocated 1:1 to Endocuff-assisted colonoscopy or standard colonoscopy, performed by expert endoscopists. The main outcome was the mean number of serrated lesions detected per patient. Results 122 patients (standard colonoscopy n = 60; Endocuff-assisted colonoscopy n = 62; 59 % men; mean age 60.6 (standard deviation [SD] 7.5) were included at 4 centers. Baseline variables (demographic data, SPS phenotype, colorectal cancer [CRC] history, cumulative polyps, and follow-up), cecal intubation rate, and withdrawal time were similar between groups. There was no statistically significant difference between Endocuff-assisted colonoscopy and standard colonoscopy for the mean number of serrated lesions detected per patient: 5.8 (95 % confidence interval [95 %CI] 4.4 – 7.2) and 5.0 (3.9 – 6.1), respectively (P = 0.36). There were also no differences between Endocuff-assisted and standard colonoscopy for detection of sessile serrated lesions (mean number per patient 2.5 [1.3 – 3.6] vs. 2.0 [1.1 – 3.0], P = 0.54) and adenomas (0.9 [0.5 – 1.3] vs. 0.5 [0.3 – 0.7], P = 0.12). Conclusion Use of Endocuff-assisted colonoscopy did not significantly increase the number of serrated lesion detected per patient during surveillance of SPS.

Early-onset (

Resumen Este documento actualiza las recomendaciones realizadas por la Sociedad Espanola de Medicina Familiar y Comunitaria y la Asociacion Espanola de Gastroenterologia para el diagnostico y la prevencion del cancer colorrectal (CCR). Para establecer la calidad de la evidencia y los niveles de recomendacion de las intervenciones se ha utilizado la metodologia basada en el sistema GRADE (Grading of Recommendations Assessment, Development and Evaluation). Este documento establece intervalos de demora optimos en funcion de los sintomas y el test de SOH inmunologico (SOHi) y recomienda reducir las barreras para la confirmacion diagnostica en los pacientes con sintomas. En cuanto al cribado en poblacion de riesgo medio, se proponen estrategias para conseguir la implantacion universal del cribado poblacional basado en SOHi bienal e incrementar la participacion de la poblacion diana, incluyendo la implicacion de atencion primaria. Esta guia de practica clinica recomienda el cribado universal del sindrome de Lynch mediante la inmunohistoquimica de las proteinas reparadoras o la inestabilidad de microsatelites en los CCR incidentes y el uso de paneles de genes en los pacientes con poliposis adenomatosas. Tambien actualiza las estrategias para reducir la incidencia y la mortalidad tanto de CCR como de otros tumores asociados a los sindromes hereditarios. En cuanto al CCR familiar no hereditario y la vigilancia tras reseccion de CCR, adenomas y lesiones serradas, se establecen recomendaciones en funcion del riesgo atribuible y la reduccion del riesgo de la intervencion propuesta. Finalmente, en el documento se incluyen recomendaciones respecto a los intervalos de vigilancia en la enfermedad inflamatoria intestinal y la actitud ante la displasia.

The identification of high-risk groups of gastric (GC) and pancreatic adenocarcinoma (PC) due to a hereditary basis could imply a benefit in the affected families by establishing personalized preventive strategies. We aimed at assessing the diagnostic yield of GC/PC hereditary syndromes in individuals evaluated based on specific clinical criteria. In total, 77 unrelated individuals (45 from GC group/32 from PC group) were recruited: 51 (66.2%) cancer diagnosis &lt, 60 years, 3 (4%) with personal history of GC/PC and other cancer and 23 (29.8%) due to family history. Immunohistochemical analysis of DNA mismatch repair proteins was performed in 38 (49.3%) available tumors, being pathological in one (2%) GC. A genetic analysis was performed if clinical criteria of hereditary syndrome were fulfilled, identifying a mutation in 10/22 (45.5%) families [7/16 (43.7%) with GC and 3/6 (50%) with PC] and 19 (24.7%) fulfilled criteria of familial cancer. Diagnosis of cancer &lt, 40 years and personal history of other cancers were independent risk factors of a hereditary syndrome [OR:11.3 (95%IC 1.9&ndash, 67), p = 0.007 and OR:17.4 (95% IC 2.5&ndash, 119.9), p = 0.004, respectively]. The selection of patients based on clinical criteria leads to high diagnostic yield, detecting a causative germline mutation in almost half of the cases, therefore, both meticulous genetic counseling and use of multi-gen panels is crucial.

Surveillance colonoscopies focused to detect dysplasia are recommended to prevent colorectal cancer in patients with long-standing colonic inflammatory bowel disease (IBD). To date, histologic diagnosis and gradation of IBD-related dysplasia has been challenged by a high variability among pathologists. We aimed to analyze the observer characteristics that are correlated with concordance deviations in this diagnosis. Eight pathologists evaluated a set of 125 endoscopic biopsy samples with a representative distribution of nondysplastic and dysplastic lesions from long-standing IBD patients. Two rounds of diagnosis were carried out during a period of 18 months. The κ test was applied to analyze concordance. Pathologists were grouped on the basis of their experience. A subanalysis was performed by eliminating the highly prevalent nondysplastic samples, as well as an analysis after observers' grouping. Overall interobserver agreement was good (κ=0.73), with an even higher pairwise value (κ=0.86) as well as the intraobserver agreement values (best κ=0.85). After eliminating the highly prevalent nondysplastic samples, the interobserver agreement was still moderate to good (best overall κ=0.50; best paired κ=0.72). Notable differences were seen between the pathologists with a high-volume and low-volume practice (best overall κ=0.61 and 0.41, respectively). The agreement in the diagnosis of dysplasia in IBD endoscopic biopsies may have been undervalued over time. This is the first study evaluating pathologists' diagnostic robustness in this field. The results suggest that examining a large volume of samples is the key factor to increase the consistency in the diagnosis and gradation of IBD-related dysplasia.

// Clara Esteban-Jurado 1 , David Gimenez-Zaragoza 2 , Jenifer Munoz 1 , Sebastia Franch-Exposito 1 , Miriam Alvarez-Barona 3 , Teresa Ocana 1 , Miriam Cuatrecasas 4 , Sabela Carballal 1 , Maria Lopez-Ceron 1 , Maria Marti-Solano 5 , Marcos Diaz-Gay 1 , Tom van Wezel 6 , Antoni Castells 1 , Luis Bujanda 7 , Judith Balmana 8 , Victoria Gonzalo 9 , Gemma Llort 10 , Clara Ruiz-Ponte 3 , Joaquin Cubiella 11 , Francesc Balaguer 1 , Rosa Aligue 2 , Sergi Castellvi-Bel 1 1 Gastroenterology Department, Hospital Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Catalonia, Spain 2 Biomedical Sciences Department, School of Medicine, University de Barcelona, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain 3 Galician Public Foundation of Genomic Medicine (FPGMX), Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Genomics Medicine Group, Hospital Clinico, Santiago de Compostela, University of Santiago de Compostela, Galicia, Spain 4 Department of Pathology, Hospital Clinic, Biobanc Clinic-IDIBAPS, Barcelona, Catalonia, Spain 5 Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany 6 Leiden University Medical Center (LUMC), Leiden, Netherlands 7 Gastroenterology Department, Hospital Donostia–Instituto Biodonostia, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Basque Country University (UPV/EHU), San Sebastian, Spain 8 High Risk and Cancer Prevention Unit, Medical Oncology Department, University Hospital Vall d’Hebron and Vall d’Hebron Institute of Oncology, Barcelona, Spain 9 Gastroenterology Department, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain 10 Clinical Oncology Department, Corporacio Parc Tauli, Sabadell, Barcelona, Spain 11 Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Instituto de Investigacion Biomedica Ourense, Pontevedra y Vigo, Ourense, Spain Correspondence to: Sergi Castellvi-Bel, email: sbel@clinic.cat Keywords: colorectal neoplasm, colorectal adenoma, genetic predisposition to disease, POLE, POLD1 Received: January 04, 2017 Accepted: February 18, 2017 Published: March 01, 2017 ABSTRACT Germline mutations in POLE and POLD1 have been shown to cause predisposition to colorectal multiple polyposis and a wide range of neoplasms, early-onset colorectal cancer being the most prevalent. In order to find additional mutations affecting the proofreading activity of these polymerases, we sequenced its exonuclease domain in 155 patients with multiple polyps or an early-onset colorectal cancer phenotype without alterations in the known hereditary colorectal cancer genes. Interestingly, none of the previously reported mutations in POLE and POLD1 were found. On the other hand, among the genetic variants detected, only two of them stood out as putative pathogenic in the POLE gene, c.1359 + 46del71 and c.1420G > A (p.Val474Ile). The first variant, detected in two families, was not proven to alter correct RNA splicing. Contrarily, c.1420G > A (p.Val474Ile) was detected in one early-onset colorectal cancer patient and located right next to the exonuclease domain. The pathogenicity of this change was suggested by its rarity and bioinformatics predictions, and it was further indicated by functional assays in Schizosaccharomyces pombe . This is the first study to functionally analyze a POLE genetic variant outside the exonuclease domain and widens the spectrum of genetic changes in this DNA polymerase that could lead to colorectal cancer predisposition.

Background & Aims Dye-based pancolonic chromoendoscopy is recommended for colorectal cancer surveillance in patients with Lynch syndrome. However, there is scarce evidence to support its superiority to high-definition white-light endoscopy. We performed a prospective study assess whether in the hands of high detecting colonoscopists, high-definition, white-light endoscopy is noninferior to pancolonic chromoendoscopy for detection of adenomas in patients with Lynch syndrome. Methods We conducted a parallel controlled study, from July 2016 through January 2018 at 14 centers in Spain of adults with pathogenic germline variants in mismatch repair genes (60% women; mean age, 47 ± 14 years) under surveillance. Patients were randomly assigned to groups that underwent high-definition white-light endoscopy (n = 128) or pancolonic chromoendoscopy (n = 128) evaluations by 24 colonoscopists who specialized in detection of colorectal lesions in high-risk patients for colorectal cancer. Adenoma detection rates (defined as the proportion of patients with at least 1 adenoma) were compared between groups, with a noninferiority margin (relative difference) of 15%. Results We found an important overlap of confidence intervals (CIs) and no significant difference in adenoma detection rates by pancolonic chromoendoscopy (34.4%; 95% CI 26.4%–43.3%) vs white-light endoscopy (28.1%; 95% CI 21.1%–36.4%; P = .28). However, pancolonic chromoendoscopy detected serrated lesions in a significantly higher proportion of patients (37.5%; 95% CI 29.5–46.1) than white-light endoscopy (23.4%; 95% CI 16.9–31.4; P = .01). However, there were no significant differences between groups in proportions of patients found to have serrated lesions of 5 mm or larger (9.4% vs 7.0%; P = .49), of proximal location (11.7% vs 10.2%; P = .68), or sessile serrated lesions (3.9% vs 5.5%; P = .55), respectively. Total procedure and withdrawal times with pancolonic chromoendoscopy (30.7 ± 12.8 minutes and 18.3 ± 7.6 minutes, respectively) were significantly longer than with white-light endoscopy (22.4 ± 8.7 minutes and 13.5 ± 5.6 minutes; P Conclusions In a randomized parallel trial, we found that for Lynch syndrome surveillance, high-definition white-light endoscopy is not inferior to pancolonic chromoendoscopy if performed by experienced and dedicated endoscopists. ClinicalTrials.gov no: NCT02951390.

Contains fulltext : 208519pub.pdf (Publisher’s version ) (Closed access) INTRODUCTION: Serrated polyposis syndrome (SPS) is accompanied by a substantially increased colorectal cancer (CRC) risk. To prevent or treat CRC in patients with a very high polyp burden, (sub)total colectomy with ileorectal or ileosigmoidal anastomosis is regularly performed. The CRC risk after (sub)total colectomy might be decreased, but evidence is lacking. We aimed to assess the yield of endoscopic surveillance in patients with SPS who underwent (sub)total colectomy. METHODS: For this post hoc analysis, we used prospectively collected data from a large international prospective cohort study. We included patients diagnosed with SPS (World Health Organization type I and/or III) who underwent (sub)total colectomy. Primary endpoint was the cumulative 5-year incidence of CRC and advanced neoplasia (AN). RESULTS: Forty-eight patients (mean age 61 [+/-7.8]; 52% men) were included and followed up for a median of 4.7 years (interquartile range 4.7-5.1). None of the patients developed CRC during follow-up. Five patients developed AN, corresponding to a cumulative 5-year AN incidence of 13% (95% confidence interval 1.2-23). In 4 patients, AN was diagnosed at the first surveillance endoscopy after study inclusion, and in 1 patient, AN was detected during subsequent rounds of surveillance. The risk of AN was similar for patients with ileorectal and ileosigmoidal anastomosis (logrank P = 0.83). DISCUSSION: (Sub)total colectomy mitigates much of the excess risk of CRC in patients with SPS. Advanced neoplasms are mainly detected at the first endoscopy after (sub)total colectomy. Based on these results, after the first surveillance, intervals might be extended beyond the currently recommended 1-2 years.

SUPPLEMENTARY MATERIAL accompanies this paper athttp://links.lww.com/CTG/A114 OBJECTIVES: Serrated polyposis syndrome (SPS) is a complex disorder with a high risk of colorectal cancer for which the germline factors remain largely unknown. Here, we combined whole-exome sequencing (WES) and linkage studies in families with multiple members affected by SPS to identify candidate genes harboring rare variants with higher penetrance effects. METHODS: Thirty-nine affected subjects from 16 extended SPS families underwent WES. Genome-wide linkage analysis was performed under linear and exponential models. The contribution of rare coding variants selected to be highly pathogenic was assessed using the gene-based segregation test. RESULTS: significant linkage peak was identified on chromosome 3p25.2-p22.3 (maxSNP = rs2293787; LODlinear = 2.311, LODexp = 2.11), which logarithm of the odds (LOD) score increased after fine mapping for the same marker (maxSNP = rs2293787; LODlinear = 2.4, LODexp = 2.25). This linkage signal was replicated in 10 independent sets of random markers from this locus. To assess the contribution of rare variants predicted to be pathogenic, we performed a family-based segregation test with 11 rare variants predicted to be deleterious from 10 genes under the linkage intervals. This analysis showed significant segregation of rare variants with SPS in CAPT7, TMEM43, NGLY1, and FBLN2 genes (weighted Pvalue > 0.007). DISCUSSION: Protein network analysis suggested FBLN2 as the most plausible candidate genes for germline SPS predisposition. Etiologic rare variants implicated in disease predisposition may be identified by combining traditional linkage with WES data. This powerful approach was effective for the identification of a new candidate gene for hereditary SPS. M.D.-G. was supported by a contract from Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (Generalitat de Catalunya, 2018FI_B1_00213). S.F.-E., C.A.-C. and J.M. were supported by a contract from CIBEREHD. Y.S.L. was supported by a fellowship (LCF/BQ/DI18/11660058) from "la Caixa" Foundation (ID 100010434) funded EU Horizon 2020 Programme (Marie Sklodowska-Curie grant agreement no. 713673). LB was supported by a Juan de la Cierva postdoctoral contract (FJCI-2017-32593). CIBEREHD and CIBERONC are funded by the Instituto de Salud Carlos III. CT, BJO, and JMF were supported by Australian National Health and Medical Research (NHMRC) Project Grants 1063960 and 1066177. This research was supported by grants from Fondo de Investigacion Sanitaria/FEDER (16/00766, 17/00878), Fundacion Cientifica de la Asociacion Espanola contra el Cancer (GCB13131592CAST), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Programme (Generalitat de Catalunya), and Agencia de Gestio d'Ajuts Universitaris i de Recerca (Generalitat de Catalunya, GRPRE 2017SGR21, GRC 2017SGR653). This article is based on work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology). www.cost.eu.Potential competing interests: None to report.

Background and study aims Serrated polyposis syndrome (SPS) is a high risk condition for colorectal cancer (CRC). Surveillance strategies for patients with serrated lesions remain controversial. We aimed to evaluate a diagnostic strategy to detect SPS consistently during reassessment colonoscopy in patients with proximal serrated lesions. Methods This was a retrospective study of all individuals from a fecal immunochemical test (FIT)-based CRC screening program (2010 – 2013) with one or more serrated lesions of ≥ 5 mm proximal to the sigmoid colon on baseline colonoscopy. We analyzed all individuals empirically scheduled for a reassessment colonoscopy aimed at diagnosing SPS within 1 year. Reassessment colonoscopy was performed with standard white-light or chromoendoscopy ± high definition endoscopy depending on availability. SPS diagnosis was based on the cumulative number of polyps in both the baseline and reassessment colonoscopies. Factors associated with SPS diagnosis were analyzed. Results From 3444 screening colonoscopies, 196 patients met the study entry criteria, of whom 11 patients (0.32 %) met the criteria for SPS on baseline colonoscopy. Reassessment colonoscopies were performed in 71 patients at 11.9 ± 1.7 months and detected 20 additional patients with SPS, a tripling of the rate of SPS up to 0.90 %. Independent factors associated with SPS diagnosis were: having five or more proximal serrated lesions (odds ratio [OR] 4.01 [95 % confidence interval 1.20 – 13.45]; P = 0.02) or two or more sessile serrated polyps ≥ 10 mm (OR 6.35 [1.40 – 28.81]; P = 0.02) on baseline colonoscopy and the use of chromoendoscopy ± high definition endoscopy during reassessment colonoscopy (OR 4.99 [1.11 – 22.36]; P = 0.04). Conclusions A 1-year reassessment colonoscopy using chromoendoscopy and high definition endoscopes substantially improves SPS detection in individuals from a FIT-based screening program with proximal serrated lesions. Five or more proximal serrated lesions or two or more sessile serrated polyps ≥ 10 mm could be thresholds for requiring a reassessment colonoscopy. Prospective studies are required to validate these results and adjust surveillance recommendations in patients with serrated lesions.

Colorectal adenomas and serrated polyps are the best characterised premalignant lesions involved in the development of colorectal cancer (CRC). Therefore, the identification and removal of these lesions, as well as post-polypectomy surveillance of affected patients, are key goals in the field of CRC prevention. Current post-polypectomy surveillance strategies differ among the various scientific societies and have several limitations that hamper their application in clinical practice. First, current surveillance intervals are based only on polyp characteristics, excluding other potential clinical conditions, such as diabetes or metabolic syndrome. Second, serrated polyps and adenomas are considered separately, but there is no recommendation in cases of the simultaneous occurrence of both types of lesion. Third, the incorporation of endoscopic technologies implies an increase in polyp detection, whose clinical impact is controversial and directly affects the number of scheduled colonoscopies with an indication of surveillance. Some of the studies presented at the AGA (American Gastroenterological Association) meeting aimed to provide new evidence on the follow-up of colorectal polyps, with a view to optimising the applicability and suitability of current surveillance strategies.

The most common hereditary gastrointestinal cancers are colorectal, mainly hereditary nonpolyposis colorectal cancer (Lynch syndrome) and familial adenomatous polyposis. Other extracolonic neoplasms, including the gastric and pancreatic adenocarcinomas, are less well known and studied because they account for a relatively small percentage of hereditary gastrointestinal cancers. Nonetheless, they merit special attention because of the high associated morbidity and mortality rates. We review the hereditary and familial syndromes associated with gastric and pancreatic cancers with a view to improving knowledge and understanding of these diseases, in order to heighten diagnostic suspicion and thus implement appropriate diagnostic strategies, screening, surveillance and treatment.

The most common hereditary gastrointestinal cancers are colorectal, mainly hereditary nonpolyposis colorectal cancer (Lynch syndrome) and familial adenomatous polyposis. Other extracolonic neoplasms, including the gastric and pancreatic adenocarcinomas, are less well known and studied because they account for a relatively small percentage of hereditary gastrointestinal cancers. Nonetheless, they merit special attention because of the high associated morbidity and mortality rates. We review the hereditary and familial syndromes associated with gastric and pancreatic cancers with a view to improving knowledge and understanding of these diseases, in order to heighten diagnostic suspicion and thus implement appropriate diagnostic strategies, screening, surveillance and treatment.

Background Serrated polyposis syndrome (SPS) has been associated with an increased risk of colorectal cancer (CRC). Accordingly, intensive surveillance with annual colonoscopy is advised. The aim of this multicenter study was to describe the risk of advanced lesions in SPS patients undergoing surveillance, and to identify risk factors that could guide the prevention strategy. Methods From March 2013 to April 2015, 296 patients who fulfilled criteria I and/or III for SPS were retrospectively recruited at 18 centers. We selected patients in whom successful clearing colonoscopy had been performed and who underwent subsequent endoscopic surveillance. Advanced neoplasia was defined as CRC, advanced adenoma, or advanced serrated lesion that were ≥ 10 mm and/or with dysplasia. Cumulative incidence of advanced neoplasia was calculated and independent predictors of advanced neoplasia development were identified. Results In 152 SPS patients a total of 315 surveillance colonoscopies were performed (median 2, range 1 – 7). The 3-year cumulative incidence of CRC and advanced neoplasia were 3.1 % (95 % confidence interval [CI] 0 – 6.9) and 42.0 % (95 %CI 32.4 – 51.7), respectively. Fulfilling both I + III criteria and the presence of advanced serrated lesions at baseline colonoscopy were independent predictors of advanced neoplasia development (odds ratio [OR] 1.85, 95 %CI 1.03 – 3.33, P = 0.04 and OR 2.62, 95 %CI 1.18 – 5.81, P = 0.02, respectively). During follow-up, nine patients (5.9 %) were referred for surgery for invasive CRC (n = 4, 2.6 %) or because of polyp burden (n = 5, 3.3 %). After total colectomy, 17.9 % patients developed advanced neoplasia in the retained rectum. Conclusions Patients with SPS have a substantial risk of developing advanced neoplasia under endoscopic surveillance, whereas CRC incidence is low. Personalized endoscopic surveillance based on polyp burden and advanced serrated histology could help to optimize prevention in patients with SPS.

This document updates the recommendations made by the Spanish Society of Family and Community Medicine and the Spanish Association of Gastroenterology for the diagnosis and prevention of colorectal cancer (CRC). In order to evaluate the quality of the evidence and determine the recommendation levels of the interventions, we used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. This document establishes optimal delay intervals based on symptoms and the faecal immunochemical test (FIT) and recommends reducing the barriers for diagnostic confirmation in symptomatic subjects. With regard to CRC screening in the average-risk population, we propose strategies to achieve the universal implementation of organised CRC screening programmes based on biennial FIT and to increase the participation of the target population, including the involvement of Primary Healthcare. This Clinical Practice Guideline recommends universal screening for Lynch syndrome with mismatch repair proteins immunohistochemistry or microsatellite instability in incident CRCs and the use of gene panels in patients with adenomatous polyposis. It also updates the strategies to reduce the incidence and mortality of both CRC and other tumours associated with hereditary syndromes. Regarding non-hereditary familial CRC and surveillance after resection of adenomas, serrated lesions or CRC, we established the recommendations based on the attributable risk and the risk reduction of the proposed intervention. Finally, the document includes recommendations regarding surveillance intervals in inflammatory bowel disease and the attitude towards dysplasia.

Serrated polyps (SPs) are considered the precursor lesions of up to 15–30% of all colorectal carcinomas through the “serrated neoplasia pathway.” Serrated polyposis syndrome (SPS), characterized by the presence large and/or numerous serrated lesions spreading throughout the colorectum, is emerging as one of the most common colorectal cancer polyp syndromes. This condition is associated with an increased personal and familial colorectal cancer risk. Clinical management includes yearly surveillance colonoscopy and surgery. Although the majority of cases occur in patients older than 50 years old with no family history of CRC, several lines of evidence support that a proportion of SPS could be the phenotypic expression of an inherited genetic syndrome, but the genetic basis for SPS remains elusive. Recent studies provided proof of the pathogenicity of RNF43 germline mutation in a small subset of patients. Future research in SPS should be focused on understanding the phenotype and clinical management and on unraveling the pathogenesis of the syndrome.

ObjectiveOutside clinical trials, the effectiveness of chromoendoscopy (CE) for long-standing IBD surveillance is controversial. We aimed to assess the effectiveness of CE for neoplasia detection and characterisation, in real-life.DesignFrom June 2012 to 2014, patients with IBD were prospectively included in a multicentre cohort study. Each colonic segment was evaluated with white light followed by 0.4% indigo carmine CE. Specific lesions' features were recorded. Optical diagnosis was assessed. Dysplasia detection rate between expert and non-expert endoscopists and learning curve were ascertained.ResultsNinety-four (15.7%) dysplastic (1 cancer, 5 high-grade dysplasia, 88 low-grade dysplasia) and 503 (84.3%) non-dysplastic lesions were detected in 350 patients (47% female; mean disease duration: 17 years). Colonoscopies were performed with standard definition (41.5%) or high definition (58.5%). Dysplasia miss rate with white light was 40/94 (57.4% incremental yield for CE). CE-incremental detection yield for dysplasia was comparable between standard definition and high definition (51.5% vs 52.3%, p=0.30). Dysplasia detection rate was comparable between expert and non-expert (18.5% vs 13.1%, p=0.20). No significant learning curve was observed (8.2% vs 14.2%, p=0.46). Sensitivity, specificity, and positive and negative predictive values for dysplasia optical diagnosis were 70%, 90%, 58% and 94%, respectively. Endoscopic characteristics predictive of dysplasia were: proximal location, loss of innominate lines, polypoid morphology and Kudo pit pattern III–V.ConclusionsCE presents a high diagnostic yield for neoplasia detection, irrespectively of the technology and experience available in any centre. In vivo, CE optical diagnosis is highly accurate for ruling out dysplasia, especially in expert hands. Lesion characteristics can aid the endoscopist for in situ therapeutic decisions.Trial registration numberNCT02543762.

Objective Serrated polyposis syndrome (SPS) is associated with an increased colorectal cancer (CRC) risk, although the magnitude of the risk remains uncertain. Whereas intensive endoscopic surveillance for CRC prevention is advised, predictors that identify patients who have high CRC risk remain unknown. We performed a multicentre nationwide study aimed at describing the CRC risk in patients with SPS and identifying clinicopathological predictors independently associated with CRC. Design From March 2013 through September 2014, patients with SPS were retrospectively recruited at 18 Spanish centres. Data were collected from medical, endoscopy and histopathology reports. Multivariate logistic regression was performed to identify CRC risk factors. Results In 296 patients with SPS with a median follow-up time of 45 months (IQR 26–79.7), a median of 26 (IQR 18.2–40.7) serrated polyps and 3 (IQR 1–6) adenomas per patient were detected. Forty-seven patients (15.8%) developed CRC at a mean age of 53.9±12.8, and 4 out of 47 (8.5%) tumours were detected during surveillance (cumulative CRC incidence 1.9%). Patients with >2 sessile serrated adenomas/polyps (SSA/Ps) proximal to splenic flexure and ≥1 proximal SSA/P with high-grade dysplasia were independent CRC risk factors (incremental OR=2, 95% CI 1.22 to 3.24, p=0.006). Patients with no risk factors showed a 55% decrease in CRC risk (OR=0.45, 95% CI 0.24 to 0.86, p=0.01). Conclusions Patients with SPS have an increased risk of CRC, although lower than previously published. Close colonoscopy surveillance in experienced centres show a low risk of developing CRC (1.9% in 5 years). Specific polyp features (SSA/P histology, proximal location and presence of high-grade dysplasia) should be used to guide clinical management.

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. Conclusion 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.

SUMMARY Colorectal cancer (CRC) is one of the most common malignancies and the second-leading cause of cancer death in both sexes in developed countries. Over the last 25 years, highly penetrant monogenic germline mutations that predispose to CRC and other digestive tumors have been identified, accounting for up to 5% of all CRC cases. Identification and characterization of these disorders have allowed modification of their natural history, with a substantial decrease in morbidity and mortality among high-risk patients. Recognizing hereditary CRC has also impacted predictive genetic testing and personalized medicine based on genomic information. This review summarizes the current knowledge on hereditary CRC regarding pathogenesis, clinical features, diagnostic evaluation and management recommendations.

Resumen Los polipos serrados del colon constituyen un grupo heterogeneo de lesiones con potencial de transformacion a cancer colorrectal a traves de la «via serrada» de la carcinogenesis. El descubrimiento de estas lesiones ha supuesto un cambio de paradigma en el concepto de la secuencia adenoma-carcinoma, de modo que hasta un 30% de los tumores se desarrollan por esta via. Los principales factores que se asocian a un mayor riesgo de malignizacion en los polipos serrados son el tamano ≥ 10 mm, la multiplicidad, la histologia de adenoma serrado sesil, la presencia de displasia asociada y la localizacion proximal. La evidencia actual indica que estas lesiones deben ser resecadas completamente y que el paciente requiere un programa de vigilancia endoscopica. El sindrome de poliposis serrada es una entidad clinico-patologica asociada a un aumento del riesgo de padecer cancer colorrectal. Estos pacientes y sus familiares requieren una evaluacion multidisciplinar en unidades de alto riesgo de cancer colorrectal.

Serrated polyps of the colorectum are a heterogeneous group of lesions with potential malignant transformation through the «serrated pathway» of carcinogenesis. The discovery of these lesions has been a paradigm shift in the concept of the adenoma-carcinoma sequence, so that up to 30% of tumors develop through this pathway. The main factors associated with an increased risk of malignancy in serrated polyps are size≥10mm, multiplicity, sessile serrated adenoma histology, presence of associated dysplasia and proximal location. Current evidence indicates that these lesions should be resected completely, and the patient requires an endoscopic surveillance program. Serrated polyposis syndrome is a clinicopathological entity characterized by multiple and/or large serrated polyps with an increased risk of developing colorectal cancer. These patients and their families, require multidisciplinary assessment in specialized high risk colorectal cancer units.

Familial adenomatous polyposis (FAP) is an inherited disorder that represents the most common gastrointestinal polyposis syndrome. Germline mutations in the APC gene were initially identified as responsible for FAP, and later, several studies have also implicated the MUTYH gene as responsible for this disease, usually referred to as MUTYH-associated polyposis (MAP). FAP and MAP are characterized by the early onset of multiple adenomatous colorectal polyps, a high lifetime risk of colorectal cancer (CRC), and in some patients the development of extracolonic manifestations. The goal of colorectal management in these patients is to prevent CRC mortality through endoscopic and surgical approaches. Individuals with FAP and their relatives should receive appropriate genetic counseling and join surveillance programs when indicated. This review is focused on the description of the main clinical and genetic aspects of FAP associated with germline APC mutations and MAP.

Constitutional Mismatch Repair Deficiency (CMMR-D) syndrome is an inherited childhood cancer syndrome due to bi-allelic mutations in one of the four DNA mismatch repair genes involved in Lynch syndrome. The tumor spectrum of this syndrome includes hematological, brain and Lynch syndrome associated malignancies, with an increased risk of synchronous and metachronous cancers, and signs of Neurofibromatosis type-1 syndrome such as café-au-lait macules during the first three decades of life. Here, we report the first Argentinian patient with CMMR-D syndrome, focusing on her history of cancer and gastrointestinal manifestations, and the challenging molecular algorithm to finally reach her diagnosis. Fil: Antelo, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; Argentina Fil: Milito, Daniela. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; Argentina Fil: Rhees, Jennifer. Baylor University Medical Center; Estados Unidos Fil: Roca, Enrique. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; Argentina Fil: Barugel, Miguel. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; Argentina Fil: Cuatrecasas, Miriam. Universidad de Barcelona; España Fil: Moreira, Leticia. Universidad de Barcelona; España Fil: Leoz, Maria Liz. Universidad de Barcelona; España Fil: Carballal, Sabela. Universidad de Barcelona; España Fil: Ocaña, Teresa. Universidad de Barcelona; España Fil: Pellisé, Maria. Universidad de Barcelona; España Fil: Castells, Antoni. Universidad de Barcelona; España Fil: Boland, C. Richard. Baylor University Medical Center; Estados Unidos Fil: Goel, Ajay. Baylor Research Institute; Fil: Balaguer, Francesc. Universidad de Barcelona; España

Serrated polyposis syndrome (SPS) is a recently recognised high risk condition for colorectal cancer (CRC) characterised by the presence of large and/or multiple serrated polyps in the colon.1 ,2 The prevalence of SPS has been previously estimated out of CRC endoscopy-based screening programmes on average risk individuals; in this setting, the prevalence ranged from 0.033% (1/3000 sigmoidoscopies)3 to 0.055% (1/1818 colonoscopies).4 However, Biswas et al 5 recently published a higher prevalence based on a guaiac faecal occult blood testing (gFOBT) CRC screening programme in the UK (NHS Bowel Cancer Screening Programme). In this programme, between April 2010 and January 2012, 5/755 (0.66%) patients attended for index screening colonoscopy after a positive gFOBT met the WHO criteria for SPS, which represented a 20-fold increase …