Background and aims Serrated 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. Methods Between 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. Results We 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%, p<0.001). Most patients were recommended a 2-year interval, and those recommended a 2-year interval were not at increased risk of AN: AN incidence after a 2-year recommendation was 15.6% compared with 24.4% after a 1-year recommendation (OR 0.57, p=0.08). Conclusion Risk 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 number The study was registered on http://www.trialregister.nl; trial-ID NTR4609.

The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC patients without previous germline mutation identified. WES was also performed in nine tumor samples to analyze the somatic profile using SigProfilerExtractor tool. Sequencing germline data were filtered to select those variants with plausible pathogenicity, rare frequency and previously involved in cancer. Then, a manual filtering was performed to prioritize genes according to current knowledge and function. These genetic variants were prevalidated with Integrative Genomics Viewer 2.8.2 (IGV). Subsequently, a further selection step was carried out according to function and information obtained from tumor samples. After IGV and selection step, 58 genetic variants in 52 different candidate genes were validated by Sanger sequencing. Among them, APC, FAT4, CTNND1 and TLR2 seem to be the most promising genes because of their role in hereditary cancer syndromes, tumor suppression, cell adhesion and Helicobacter pylori recognition, respectively. These encouraging results represent the open door to the identification of new genes involved in GC germline predisposition.