Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer.

Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.

Broader anti-EBV TCR repertoire in multiple sclerosis: disease specificity and treatment modulation.

Epstein-Barr virus (EBV) infection has long been associated with the development of multiple sclerosis (MS). MS patients have elevated titers of EBV-specific antibodies in serum and show signs of CNS damage only after EBV infection. Regarding CD8+ T-cells, an elevated but ineffective response to EBV was suggested in MS patients, who present with a broader MHC-I-restricted EBV-specific T-cell receptor beta chain (TRB) repertoire compared to controls. It is not known whether this altered EBV response could be subject to dynamic changes, e.g., by approved MS therapies, and whether it is specific for MS. 1317 peripheral blood TRB repertoire samples of healthy donors (n=409), patients with MS (n=710) before and after treatment, patients with neuromyelitis optica spectrum disorder (n=87), myelin-oligodendrocyte-glycoprotein antibody-associated disease (n=64) and Susac's syndrome (n=47) were analyzed. Apart from MS, none of the evaluated diseases presented with a broader anti-EBV TRB repertoire. In MS patients undergoing autologous hematopoietic stem-cell transplantation, EBV reactivation coincided with elevated MHC-I-restricted EBV-specific TRB sequence matches. Therapy with ocrelizumab, teriflunomide or dimethyl fumarate reduced EBV-specific, but not CMV-specific MHC-I-restricted TRB sequence matches. Together, this data suggests that the aberrant MHC-I-restricted T-cell response directed against EBV is specific to MS with regard to NMO, MOGAD and Susac's Syndrome and that it is specifically modified by MS treatments interfering with EBV host cells or activated lymphocytes.

Variations in candidalysin amino acid sequence influence toxicity and host responses.

Candida albicans causes millions of mucosal infections in humans annually. Hyphal overgrowth on mucosal surfaces is frequently associated with tissue damage caused by candidalysin, a secreted peptide toxin that destabilizes the plasma membrane of host cells thereby promoting disease and immunopathology. Candidalysin was first identified in C. albicans strain SC5314, but recent investigations have revealed candidalysin "variants" of differing amino acid sequence in isolates of C. albicans, and the related species C. dubliniensis, and C tropicalis, suggesting that sequence variation among candidalysins may be widespread in natural populations of these Candida species. Here, we analyzed ECE1 gene sequences from 182 C. albicans isolates, 10 C. dubliniensis isolates, and 78 C. tropicalis isolates and identified 10, 3, and 2 candidalysin variants in these species, respectively. Application of candidalysin variants to epithelial cells revealed differences in the ability to cause cellular damage, changes in metabolic activity, calcium influx, MAPK signalling, and cytokine secretion, while biophysical analyses indicated that variants exhibited differences in their ability to interact with and permeabilize a membrane. This study identifies candidalysin variants with differences in biological activity that are present in medically relevant Candida species. IMPORTANCE: Fungal infections are a significant burden to health. Candidalysin is a toxin produced by Candida albicans that damages host tissues, facilitating infection. Previously, we demonstrated that candidalysins exist in the related species C. dubliniensis and C. tropicalis, thereby identifying these molecules as a toxin family. Recent genomic analyses have highlighted the presence of a small number of candidalysin "variant" toxins, which have different amino acid sequences to those originally identified. Here, we screened genome sequences of isolates of C. albicans, C. dubliniensis, and C. tropicalis and identified candidalysin variants in all three species. When applied to epithelial cells, candidalysin variants differed in their ability to cause damage, activate intracellular signaling pathways, and induce innate immune responses, while biophysical analysis revealed differences in the ability of candidalysin variants to interact with lipid bilayers. These findings suggest that intraspecies variation in candidalysin amino acid sequence may influence fungal pathogenicity.

Nonunion After First Metatarsophalangeal Joint Arthrodesis: The Association With Shoe Size.

INTRODUCTION: First metatarsophalangeal joint (MTPJ) arthrodesis is a common treatment for various foot conditions, with nonunion as a frequent complication. The incidence of nonunion varies widely in the literature. In particular, males have a higher risk of nonunion than females. This is possibly due to biomechanical and anatomical differences, as men have on average larger feet than women. This study therefore aims to explore whether shoe size, as a proxy for foot size, affects nonunion rates and could explain the gender disparity in nonunion rates. METHODOLOGY: An exploratory analysis of retrospectively collected data from patients who underwent primary first MTPJ arthrodesis in a single secondary hospital between January 2012 and December 2019. Additional data on body weight, height, and shoe size were prospectively collected from patients. RESULTS: Among 261 included patients, 57 (21.8%) experienced nonunion. Nonunion incidence was higher in males (18, 26.9%) than in females (39, 20.1%). Self-reported shoe size showed no significant association with nonunion in both univariate and multivariate analyses. DISCUSSION: The study's findings suggest that shoe size, as a proxy for foot size, is not associated with nonunion after the first MTPJ arthrodesis. Despite observing a gender difference in nonunion rates, this disparity could not be explained by shoe size. CONCLUSIONS: Shoe size as a proxy for foot size appears to have no clinical association with nonunion following the first MTPJ arthrodesis.

Microbial signatures and continuum in endometrial cancer and benign patients.

BACKGROUND: Endometrial cancer is a multifactorial disease with inflammatory, metabolic and potentially microbial cues involved in disease pathogenesis. The endometrial cancer microbiome has been poorly characterised so far and studies have often overestimated bacterial biomass due to lack of integration of appropriate contamination controls. There is also a scarcity of evidence on the functionality of microbial microenvironments in endometrial cancer. This work addresses that knowledge gap by interrogating the genuine, contamination-free microbial signatures in the female genital tract and rectum of women with endometrial cancer and the mechanistic role of microbiome on carcinogenic processes. RESULTS: Here we sampled different regions of the reproductive tract (vagina, cervix, endometrium, fallopian tubes and ovaries) and rectum of 61 patients (37 endometrial cancer; 24 benign controls). We performed 16S rRNA gene sequencing of the V1-V2 hypervariable regions and qPCR of the 16S rRNA gene to qualitatively and quantitatively assess microbial communities and used 3D benign and endometrial cancer organoids to evaluate the effect of microbial products of L. crispatus, which was found depleted in endometrial cancer patients following primary analysis, on endometrial cell proliferation and inflammation. We found that the upper genital tract of a subset of women with and without endometrial cancer harbour microbiota quantitatively and compositionally distinguishable from background contaminants. Endometrial cancer was associated with reduced cervicovaginal and rectal bacterial load together with depletion of Lactobacillus species relative abundance, including L. crispatus, increased bacterial diversity and enrichment of Porphyromonas, Prevotella, Peptoniphilus and Anaerococcus in the lower genital tract and endometrium. Treatment of benign and malignant endometrial organoids with L. crispatus conditioned media exerted an anti-proliferative effect at high concentrations but had minimal impact on cytokine and chemokine profiles. CONCLUSIONS: Our findings provide evidence that the upper female reproductive tract of some women contains detectable levels of bacteria, the composition of which is associated with endometrial cancer. Whether this is a cause or consequence of cancer pathophysiology and what is the functional significance of this finding remain to be elucidated to guide future screening tools and microbiome-based therapeutics. Video Abstract.

Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly.

The mitochondrial chaperonin, mitochondrial heat shock protein 60 (mtHsp60), promotes the folding of newly imported and transiently misfolded proteins in the mitochondrial matrix, assisted by its co-chaperone mtHsp10. Despite its essential role in mitochondrial proteostasis, structural insights into how this chaperonin progresses through its ATP-dependent client folding cycle are not clear. Here, we determined cryo-EM structures of a hyperstable disease-associated human mtHsp60 mutant, V72I. Client density is identified in three distinct states, revealing interactions with the mtHsp60 apical domains and C termini that coordinate client positioning in the folding chamber. We further identify an asymmetric arrangement of the apical domains in the ATP state, in which an alternating up/down configuration positions interaction surfaces for simultaneous recruitment of mtHsp10 and client retention. Client is then fully encapsulated in mtHsp60-10, revealing prominent contacts at two discrete sites that potentially support maturation. These results identify distinct roles for the apical domains in coordinating client capture and progression through the chaperone cycle, supporting a conserved mechanism of group I chaperonin function.

Advancing head and neck cancer management: Unveiling the diagnostic and therapeutic potentials of molecular profiling.

BACKGROUND: Head and neck cancers (HNC) present diagnostic challenges due to multifocal disease manifestations, posing difficulties in distinguishing between metastatic disease and second primary malignancies (SPM). This complexity underscores the need for advanced diagnostic approaches. Emerging technologies, such as next-generation sequencing (NGS) and molecular classifier assays, show promise in providing precise insights into the diverse etiologies of HNC. METHOD: In this article, we employed NGS and molecular classifier assays to delve into three distinct clinical cases. The objective was to showcase the instrumental role of these technologies in facilitating accurate diagnoses and differentiating between metastatic disease and SPM in HNC cases. RESULTS: The results of this series highlight the effectiveness of NGS and molecular classifier assays in enhancing diagnostic accuracy for HNC and contributing to the precise differentiation of disease etiologies. The utilization of these advanced technologies proved instrumental in avoiding unnecessary interventions and paved the way for more targeted and effective treatment strategies. CONCLUSION: Our findings underscore the necessity of incorporating advanced molecular testing technologies into the diagnostic and therapeutic approaches for HNC, thereby championing a more nuanced and effective approach to managing these complex cases.

Towards a better future for DNA barcoding: Evaluating monophyly- and distance-based species identification using COI gene fragments of Dacini fruit flies.

The utility of a universal DNA 'barcode' fragment (658 base pairs of the Cytochrome C Oxidase I [COI] gene) has been established as a useful tool for species identification, and widely criticized as one for understanding the evolutionary history of a group. Large amounts of COI sequence data have been produced that hold promise for rapid species identification, for example, for biosecurity. The fruit fly tribe Dacini holds about a thousand species, of which 80 are pests of economic concern. We generated a COI reference library for 265 species of Dacini containing 5601 sequences that span most of the COI gene using circular consensus sequencing. We compared distance metrics versus monophyly assessments for species identification and although we found a 'soft' barcode gap around 2% pairwise distance, the exceptions to this rule dictate that a monophyly assessment is the only reliable method for species identification. We found that all fragments regularly used for Dacini fruit fly identification >450 base pairs long provide similar resolution. 11.3% of the species in our dataset were non-monophyletic in a COI tree, which is mostly due to species complexes. We conclude with recommendations for the future generation and use of COI libraries. We revise the generic assignment of Dacus transversus stat. rev. Hardy 1982, and Dacus perpusillus stat. rev. Drew 1971 and we establish Dacus maculipterus White 1998 syn. nov. as a junior synonym of Dacus satanas Liang et al. 1993.

3D printed rectal swabs for assessing the gut microbiome, metabolome and inflammation.

Investigating the gut microbiome and metabolome frequently requires faecal samples, which can be difficult to obtain. Previous studies have shown that rectal swabs are comparable to faecal samples for analysing gut microbiota composition and key metabolites. In this study, 3D printed rectal swabs were compared with conventional flocked swabs and faecal samples, due to the potential advantages 3D printing as a technique offers for swab production and development. 16S rRNA gene sequencing, qPCR and metabolite profiling (using 1H-NMR spectroscopy) were performed on swab and faecal samples from healthy participants. Faecal calprotectin and total protein analysis were performed on samples from inflammatory bowel disease (IBD) patients. There were no significant differences between both swab types and faecal samples when assessing key measures of alpha and beta diversity, and differences in the abundance of major phyla. There was a strong correlation between both swab types and faecal samples for all combined metabolites detected by NMR. In IBD patients, there was no significant difference in faecal calprotectin and total protein levels between both swab types and faecal samples. These data lead us to conclude that 3D printed swabs are equivalent to flocked swabs for the analysis of the gut microbiome, metabolome and inflammation.

The Role of the Airway and Gut Microbiome in the Development of Chronic Lung Disease of Prematurity.

Chronic lung disease (CLD) of prematurity, a common cause of morbidity and mortality in preterm-born infants, has a multifactorial aetiology. This review summarizes the current evidence for the effect of the gut and airway microbiota on the development of CLD, highlighting the differences in the early colonisation patterns in preterm-born infants compared to term-born infants. Stool samples from preterm-born infants who develop CLD have less diversity than those who do not develop CLD. Pulmonary inflammation, which is a hallmark in the development of CLD, may potentially be influenced by gut bacteria. The respiratory microbiota is less abundant than the stool microbiota in preterm-born infants. There is a lack of clear evidence for the role of the respiratory microbiota in the development of CLD, with results from individual studies not replicated. A common finding is the presence of a single predominant bacterial genus in the lungs of preterm-born infants who develop CLD. Probiotic preparations have been proposed as a potential therapeutic strategy to modify the gut or lung microbiota with the aim of reducing rates of CLD but additional robust evidence is required before this treatment is introduced into routine clinical practice.

Human cytomegalovirus induces neuronal gene expression for viral maturation.

Viral invasion of the host cell causes some of the most dramatic changes in biology. Human cytomegalovirus (HCMV) extensively remodels host cells, altering nuclear shape and generating a cytoplasmic viral-induced assembly compartment (vIAC). How these striking morphology changes take place in the context of host gene regulation is still emerging. Here, we discovered that histone variant macroH2A1 is essential for producing infectious progeny. Because virion maturation and cellular remodeling are closely linked processes, we investigated structural changes in the host cell upon HCMV infection. We discovered that macroH2A1 is necessary for HCMV-induced reorganization of the host nucleus, cytoskeleton, and endoplasmic reticulum. Furthermore, using RNA-seq we found that while all viral genes were highly expressed in the absence of macroH2A1, many HCMV-induced host genes were not. Remarkably, hundreds of these HCMV-induced macroH2A1-dependent host genes are associated with neuronal synapse formation and vesicle trafficking. Knock-down of these HCMV-induced neuronal genes during infection resulted in malformed vIACs and smaller plaques, establishing their importance to HCMV infection. Together, our findings demonstrate that HCMV manipulates host gene expression by hijacking a dormant neuronal secretory pathway for efficient virion maturation.

snpAIMeR: R package for evaluating ancestry informative marker contributions in non-model population diagnostics.

MOTIVATION: Single nucleotide polymorphism (SNP) markers are increasingly popular for population genomics and inferring ancestry for individuals of unknown origin. Because large SNP datasets are impractical for rapid and routine analysis, diagnostics rely on panels of highly informative markers. Strategies exist for selecting these markers, however, resources for efficiently evaluating their performance are limited for non-model systems. RESULTS: snpAIMeR is a user-friendly R package that evaluates the efficacy of genomic markers for the cluster assignment of unknown individuals. It is intended to help minimize panel size and genotyping effort by determining the informativeness of candidate diagnostic markers. Provided genotype data from individuals of known origin, it uses leave-one-out cross-validation to determine population assignment rates for individual markers and marker combinations. AVAILABILITY AND IMPLEMENTATION: snpAIMeR is available on CRAN (https://CRAN.R-project.org/package=snpAIMeR).

Novel phages of Pseudomonas syringae unveil numerous potential auxiliary metabolic genes.

Relatively few phages that infect plant pathogens have been isolated and investigated. The Pseudomonas syringae species complex is present in various environments, including plants. It can cause major crop diseases, such as bacterial canker on apricot trees. This study presents a collection of 25 unique phage genomes that infect P. syringae. These phages were isolated from apricot orchards with bacterial canker symptoms after enrichment with 21 strains of P. syringae. This collection comprises mostly virulent phages, with only three being temperate. They belong to 14 genera, 11 of which are newly discovered, and 18 new species, revealing great genetic diversity within this collection. Novel DNA packaging systems have been identified bioinformatically in one of the new phage species, but experimental confirmation is required to define the precise mechanism. Additionally, many phage genomes contain numerous potential auxiliary metabolic genes with diversified putative functions. At least three phages encode genes involved in bacterial tellurite resistance, a toxic metalloid. This suggests that viruses could play a role in bacterial stress tolerance. This research emphasizes the significance of continuing the search for new phages in the agricultural ecosystem to unravel novel ecological diversity and new gene functions. This work contributes to the foundation for future fundamental and applied research on phages infecting phytopathogenic bacteria.

Novel Staged Free-Fall Reactor for the (Catalytic) Pyrolysis of Lignocellulosic Biomass and Waste Plastics.

Pyrolysis of lignocellulosic biomass and waste plastics has been intensely studied in the last few decades to obtain renewable fuels and chemicals. Various pyrolysis devices have been developed for use in a laboratory setting, operated either in batch or continuously at scales ranging from milligrams per hour to tenths of g per hour. We report here the design and operation of a novel staged free-fall (catalytic) pyrolysis unit and demonstrate that the concept works very well for the (catalytic) pyrolysis of pinewood sawdust, paper sludge, and polypropylene as representative feeds. The unit consists of a vertical tube with a pretreatment section, a pyrolysis section, a solid residue collection section, a gas-liquid separation/collection section, and a catalytic reaction section to optionally perform ex situ catalytic upgrading of the pyrolysis vapor. The sample is placed in a tube, which is transported by gravity through various sections of the unit. It allows for rapid testing with semicontinuous feeding (e.g., 50 g h-1) and the opportunity to perform reactions under an (inert) gas (e.g., N2) at atmospheric as well as elevated pressure (e.g., 50 bar). Liquid yields for noncatalytic sawdust pyrolysis at optimized conditions (475 °C and atmospheric pressure) were 63 wt % on biomass intake. A lower yield of 51 wt % (on a biomass basis) was obtained for the noncatalytic pyrolysis of paper sludge, likely due to the presence of minerals (e.g., CaCO3) in the feed. The possibility of using the unit for ex situ catalytic pyrolysis (pyrolysis at 475 °C and catalytic upgrading at 550 °C) was also successfully demonstrated using paper sludge as the feed and H-ZSM-5 as the catalyst (21 wt % catalyst on biomass). This resulted in a biphasic liquid product with 25.6 wt % of an aqueous phase and 11 wt % of an oil phase. The yield of benzene, toluene, and xylenes was 1.9 wt % (on a biomass basis). Finally, the concept was also proven for a representative polyolefin (polypropylene), both noncatalytic as well as in situ catalytic pyrolysis using H-ZSM-5 as the catalyst at 500 °C. The liquid yield of thermal, noncatalytic plastic pyrolysis was as high as 77 wt % on plastic intake, while in situ catalytic pyrolysis gave a combined 7.8 wt % yield of benzene, toluene, and xylenes on plastic intake.

Genome-wide association analysis uncovers rice blast resistance alleles of Ptr and Pia.

A critical step to maximize the usefulness of genome-wide association studies (GWAS) in plant breeding is the identification and validation of candidate genes underlying genetic associations. This is of particular importance in disease resistance breeding where allelic variants of resistance genes often confer resistance to distinct populations, or races, of a pathogen. Here, we perform a genome-wide association analysis of rice blast resistance in 500 genetically diverse rice accessions. To facilitate candidate gene identification, we produce de-novo genome assemblies of ten rice accessions with various rice blast resistance associations. These genome assemblies facilitate the identification and functional validation of novel alleles of the rice blast resistance genes Ptr and Pia. We uncover an allelic series for the unusual Ptr rice blast resistance gene, and additional alleles of the Pia resistance genes RGA4 and RGA5. By linking these associations to three thousand rice genomes we provide a useful tool to inform future rice blast breeding efforts. Our work shows that GWAS in combination with whole-genome sequencing is a powerful tool for gene cloning and to facilitate selection of specific resistance alleles for plant breeding.

Survival analysis and gender differences in hypertrophic cardiomyopathy proband patients referred for genetic testing.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is believed to have low overall mortality rate, that could be influenced by gender, particularly among probands. We aimed to evaluate the survival rates and possible gender differences in a homogeneous cohort of HCM proband patients, referred for genetic testing, from the same geographical area, without differences in medical care access nor clinical referral pathways. METHODS: we compared the mortality rates of a cohort of consecutive HCM probands referred for genetic testing (2000-2022), from a Spanish region (xxx1) with a centralized genetic testing pathway, with its control reference population by Ederer II method. Gender differences were analyzed. RESULTS: Among the 649 HCM probands included in this study, there were significantly more men than women (61.3% vs 38.7, p < 0.05), with an earlier diagnosis (53.5 vs 61.1 years old, p < 0.05). Clinical evolution or arrhythmogenic HCM profile did no show no significant gender differences. Mean follow up was 9,8 years ±6,6 SD (9,9 ± 7 vs 9,6 ± 6,1, p = 0.59). No statistically significant differences in observed mortality, expected survival and excess mortality were found in the general HCM proband cohort. However, we found a significant excess mortality in female probands with HCM. No additional differences in analysis by genetic status were identified. CONCLUSION: Expected survival in our HCM probands did not differ from its reference population. However, despite no gender differences in phenotype severity were identified, proband HCM women did present a diagnosis delay and worse mortality outcomes.

Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated "Big Bang" pathway to CRC in three of the four Lynch syndromes.

BACKGROUND: Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes. MATERIALS AND METHODS: We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms. RESULTS: Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers. CONCLUSIONS: Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.

Updated European guidelines for clinical management of familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), gastric adenocarcinoma, proximal polyposis of the stomach (GAPPS) and other rare adenomatous polyposis syndromes: a joint EHTG-ESCP revision.

BACKGROUND: Hereditary adenomatous polyposis syndromes, including familial adenomatous polyposis and other rare adenomatous polyposis syndromes, increase the lifetime risk of colorectal and other cancers. METHODS: A team of 38 experts convened to update the 2008 European recommendations for the clinical management of patients with adenomatous polyposis syndromes. Additionally, other rare monogenic adenomatous polyposis syndromes were reviewed and added. Eighty-nine clinically relevant questions were answered after a systematic review of the existing literature with grading of the evidence according to Grading of Recommendations, Assessment, Development, and Evaluation methodology. Two levels of consensus were identified: consensus threshold (≥67% of voting guideline committee members voting either 'Strongly agree' or 'Agree' during the Delphi rounds) and high threshold (consensus ≥ 80%). RESULTS: One hundred and forty statements reached a high level of consensus concerning the management of hereditary adenomatous polyposis syndromes. CONCLUSION: These updated guidelines provide current, comprehensive, and evidence-based practical recommendations for the management of surveillance and treatment of familial adenomatous polyposis patients, encompassing additionally MUTYH-associated polyposis, gastric adenocarcinoma and proximal polyposis of the stomach and other recently identified polyposis syndromes based on pathogenic variants in other genes than APC or MUTYH. Due to the rarity of these diseases, patients should be managed at specialized centres.