Serrated polyposis syndrome: defining the epidemiology and predicting the risk of dysplasia.

BACKGROUND: Serrated polyposis syndrome is the most common polyposis syndrome that has neoplastic potential. However, the natural history, genetic basis, and risk of dysplasia and neoplasia of serrated polyposis syndrome are incompletely understood. The objective of this study is to define the epidemiology of serrated polyposis syndrome. Using this data, we aim to evaluate candidate variables for predicting the risk of dysplasia and neoplasia in sessile serrated lesions found in serrated polyposis syndrome patients. Finally, we aim to use this data to create and evaluate clinical prediction models for accuracy in predicting dysplastic sessile serrated lesions in serrated polyposis syndrome patients. METHODS: This was a regional Australian single-centre retrospective cohort study. Data was prospectively collected data from the clinical record database of a regional Australian gastroenterology practice. All patients undergoing colonoscopy at Port Macquarie Gastroenterology between January 2015 and September 2021 were screened for this study. Collected data included patient demographic, endoscopic, and histopathological findings. Clinical and endoscopic multivariate logistic regression models were created to predict dysplastic sessile serrated lesions. Model performance was examined using the area under the receiver operating curve. RESULTS: In total 8401 patients underwent a colonoscopy procedure during the study period. Serrated polyposis syndrome was diagnosed in 247, representing a prevalence of 2.94% (mean age 67.15 years, 62.75% female). Logistic regression identified; older age at serrated polyposis syndrome diagnosis, a personal history of colorectal cancer, size of the largest sessile serrated lesions removed, and total sessile serrated lesions count as predictors of dysplastic sessile serrated lesions. The clinical and endoscopic model had an area under the receiver operating curve of 0.75. CONCLUSION: Serrated polyposis syndrome is more common than previously described. The clinical and endoscopic variables identified in logistic regression have acceptable accuracy in predicting the risk of dysplasia, however other populations need to be studied to achieve generalisability and improve model performance.

Feasibility and Safety of Endoscopic Control for Patients with Serrated Polyposis Syndrome.

INTRODUCTION: Despite advances in endoscopic treatment, patients with serrated polyposis syndrome (SPS) occasionally require surgery due to numerous or unresectable polyps, recurrence, and treatment-related adverse events. METHODS: We retrospectively evaluated 43 patients with SPS undergoing diagnosis and treatment at Omori Red Cross Hospital from 2011 to 2022. Resection of all polyps ≥3 mm in size was planned during the clearing phase; endoscopic control was defined as complete, endoscopic polyp removal. During the surveillance phase, patients underwent annual colonoscopy and resection of newly detected polyps ≥3 mm in size. RESULTS: Thirty-eight patients (88%) achieved endoscopic control, two (5%) required surgery after endoscopic treatment because of colorectal cancer (CRC), and three (7%) have not yet achieved endoscopic control and are planning treatment. Endoscopic control was achieved with a median of four colonoscopies at 8 months. Ten polyps (median value) were resected per patient during the clearing phase. Three polyps ≥50 mm in size, six located in the appendiceal orifice, and seven with severe fibrosis could be resected by endoscopic submucosal dissection (ESD). All patients underwent treatment with a combination of cold snare polypectomy (CSP), endoscopic mucosal resection/hot polypectomy, and/or ESD. No case required surgery due to difficulty with endoscopic treatment. Delayed bleeding was observed in 2 cases (0.3%). Twenty-one patients underwent colonoscopies during the surveillance phase. Fifty-three polyps were resected using CSP; no CRC, sessile serrated lesions with dysplasia, or advanced adenoma were detected. CONCLUSION: SPS can be effectively, efficiently, and safely controlled with appropriate endoscopic management.

Risk of Colorectal Cancer in Serrated Polyposis Syndrome: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Serrated polyposis syndrome (SPS) is characterized by development of numerous serrated lesions throughout the colorectum and increased risk of colorectal cancer (CRC). However, SPS has been an underrecognized CRC predisposition syndrome, and the true risk of CRC in SPS, both overall and in surveillance, is not known. The aim of this systematic review and meta-analysis is to describe the risk of CRC in patients with SPS. METHODS: Electronic databases were searched on March 25, 2021, for studies describing CRC risk in SPS. Random-effects meta-analysis was performed to assess pooled risk of CRC among SPS patients. Primary outcomes were risk of CRC at time of SPS diagnosis and during surveillance following diagnosis of SPS. Secondary outcomes included risk of CRC prior to diagnosis of SPS and effect of World Health Organization subtype on CRC risk. RESULTS: Thirty-six studies including 2788 patients with SPS were included in the analysis. Overall risk of CRC in SPS was 19.9% (95% confidence interval [CI], 15.3%-24.5%). CRC risk at the time of diagnosis was 14.7% (95% CI, 11.4%-18.8%), while risk during surveillance was 2.8% (95% CI, 1.8%-4.4%), or 7 cases per 1000 person-years. SPS patients also had a high incidence of history of CRC prior to SPS diagnosis (7.0%; 95% CI, 4.6%-11.7). Subgroup analysis did not reveal any significant differences based on World Health Organization subtype. CONCLUSIONS: Our meta-analysis demonstrated that patients with SPS have an elevated risk of CRC, which is highest at the time of diagnosis and suggests the importance of early SPS recognition and screening to modify CRC risk. The persistently elevated CRC risk during surveillance supports current guidelines recommending heightened surveillance protocols.

RNF43 pathogenic Germline variant in a family with colorectal cancer.

The role of RNF43 as a cause of an inherited predisposition to colorectal cancer (CRC) is yet to be fully explored. This report presents our findings of two individuals with CRC from a single family carrying a likely-pathogenic inherited germline variant in RNF43. The proband (III:1) and the proband's mother (II:2) were diagnosed with mismatch repair proficient CRCs at the age of 50 years and 65 years, respectively. Both patients had BRAFV600E mutated colon tumours, indicating that the CRCs arose in sessile serrated lesions. The germline variant RNF43:c.375+1G>A was identified in both patients. RNA studies showed that this variant resulted in an aberrantly spliced transcript, which was predicted to encode RNF43:p.Ala126Ilefs*50 resulting in premature termination of protein synthesis and was classified as a likely-pathogenic variant. Our report adds further evidence to the hereditary role of RNF43 as a tumour suppressor gene in colorectal tumorigenesis and supports the inclusion of RNF43 as a gene of interest in the investigation of CRC predispositions outside the setting of serrated polyposis.

Body Mass Index, sex, non-steroidal anti-inflammatory drug medications, smoking and alcohol are differentially associated with World Health Organisation criteria and colorectal cancer risk in people with Serrated Polyposis Syndrome: an Australian case-control study.

OBJECTIVE: The unknown aetiology of Serrated Polyposis Syndrome (SPS) impedes risk prediction and prevention. We investigated risk factors for SPS, overall and stratified by World Health Organization (WHO)2010 clinical criteria and by colorectal cancer (CRC). METHOD: A retrospective case-control study involving a cross-sectional analysis from 350 unrelated individuals with SPS from the Genetics of Colonic Polyposis Study and 714 controls from the Australasian Colorectal Cancer Family Registry. Univariate and multivariate logistic regression modelling was used to determine the association between risk factors and SPS and risk factors associated with CRC in SPS. RESULTS: Female biological sex (odds ratio (OR) = 4.54; 95%Confidence interval (CI) = 2.77-7.45), increasing body mass index (BMI) at age 20 years (OR = 1.09; 95%CI = 1.04-1.13), hormone replacement therapy (OR = 0.44; 95%CI = 0.20.98), and increasing weekly folate intake (OR = 0.82; 95%CI = 0.75-0.90) were associated with SPS by multivariate analysis. Increasing weekly calcium intake (OR = 0.79; 95%CI = 0.64-0.97) and smoking > 10 cigarettes daily (OR = 0.45; 95%CI = 0.23-0.86) were associated with WHO criterion I only. The consumption of 1-100 g of alcohol per week (OR = 0.39; 95%CI = 0.18-0.83) was associated with WHO criterion III only. Smoking 1-5 cigarettes daily (OR = 2.35; 95%CI = 1.09-5.05), weekly non-steroidal anti-inflammatory drug (NSAIDs) intake (OR = 0.88; 95%CI = 0.78-0.99), and increased height (OR = 1.09; 95% = 1.05-1.13), were associated with SPS fulfilling both WHO criteria I and III. Moreover, weekly NSAIDs intake (OR = 0.81; 95%CI = 0.67-0.98) was associated with a reduced likelihood of CRC in SPS. CONCLUSION: We identified novel risk and potential protective factors associated with SPS, some specific for certain WHO2010 criteria. Weekly use of NSAIDs may reduce the risk of CRC in people with SPS.

RNF43 mutation analysis in serrated polyposis, sporadic serrated polyps and Lynch syndrome polyps.

AIMS: RNF43 is suggested to be involved in the serrated pathway towards colorectal cancer and encodes a transmembrane Ring-type E3 ubiquitin ligase that negatively regulates the Wnt pathway. This study aimed to elucidate the role of RNF43 gene variants in serrated polyposis syndrome (SPS) and serrated polyps. METHODS AND RESULTS: Three cohorts were tested. The first cohort included germline DNA of 26 SPS patients tested for pathogenic variants in RNF43 by Sanger sequencing all exons. In the second cohort we tested somatic DNA for RNF43 mutations from sporadic serrated lesions: 25 hyperplastic polyps, 35 sessile serrated lesions and 38 traditional serrated adenomas (TSA). In the third cohort we investigated RNF43 mutations in 49 serrated polyps and 60 conventional adenomas from 40 patients with Lynch syndrome. No germline RNF43 pathogenic variants were detected in our SPS cohort. In sporadic colorectal lesions we detected RNF43 deleterious frameshift mutations in three TSA and one SSL. The RNF43 mutations in previously described homopolymeric hot-spots were detected in microsatellite-instable (MSI) polyps and the other RNF43 mutations in microsatellite-stable (MSS) serrated polyps. RNF43 hot-spot mutations were discovered in seven serrated polyps and 12 conventional adenomas from Lynch patients. CONCLUSION: Truncating germline RNF43 mutations are uncommon in SPS patients. Somatic mutations in RNF43 were found in sporadic TSA and SSL and both serrated polyps and adenomas from Lynch syndrome patients, suggesting that they do not develop early in the pathway to CRC and are not specific for serrated polyp subtypes.

Colorectal cancer genetic variants are also associated with serrated polyposis syndrome susceptibility.

BACKGROUND: Serrated polyposis syndrome (SPS) is a clinical entity characterised by large and/ormultiple serrated polyps throughout the colon and increased risk for colorectal cancer (CRC). The basis for SPS genetic predisposition is largely unknown. Common, low-penetrance genetic variants have been consistently associated with CRC susceptibility, however, their role in SPS genetic predisposition has not been yet explored. OBJECTIVE: The aim of this study was to evaluate if common, low-penetrance genetic variants for CRC risk are also implicated in SPS genetic susceptibility. METHODS: A case-control study was performed in 219 SPS patients and 548 asymptomatic controls analysing 65 CRC susceptibility variants. A risk prediction model for SPS predisposition was developed. RESULTS: Statistically significant associations with SPS were found for seven genetic variants (rs4779584-GREM1, rs16892766-EIF3H, rs3217810-CCND2, rs992157-PNKD1/TMBIM1, rs704017-ZMIZ1, rs11196172-TCF7L2, rs6061231-LAMA5). The GREM1 risk allele was remarkably over-represented in SPS cases compared with controls (OR=1.573, 1.21-2.04, p value=0.0006). A fourfold increase in SPS risk was observed when comparing subjects within the highest decile of variants (≥65) with those in the first decile (≤50). CONCLUSIONS: Genetic variants for CRC risk are also involved in SPS susceptibility, being the most relevant ones rs4779584-GREM1, rs16892766-EIF3H and rs3217810-CCND2.

[Gastrointestinal polyposis syndromes]. / Gastrointestinale Polyposissyndrome.

BACKGROUND: Gastrointestinal polyposis syndromes are the second most common cause of hereditary colorectal carcinomas after Lynch syndrome (hereditary non-polyposis colon cancer, HNPCC). The detection of a causal germline mutation in an affected family member serves for differential diagnosis, assessment of the recurrence risk and predictive testing of healthy individuals at risk. OBJECTIVES: The present article aims to provide an overview of the differential diagnosis of different gastrointestinal polyposis syndromes based on the endoscopic findings, polyp histology, extraintestinal phenotype and molecular genetic diagnostics. MATERIALS AND METHODS: The present article is based on a literature search on gastrointestinal polyposis syndromes. RESULTS: In addition to familial adenomatous polyposis (FAP), there are further subtypes of adenomatous polyposis that can often only be distinguished by the detection of a causative germline mutation and are sometimes associated with different extracolonic manifestations. In hamartomatous polyposis syndromes, the clinical overlaps often cause differential diagnostic problems. Serratated polyposis syndrome is possibly the most frequent polyposis syndrome, although its cause is currently largely unexplained. CONCLUSIONS: Early detection and correct classification of polyposis is crucial for adequate prevention and therapy. Access to multidisciplinary expert centres is useful for the care of families.

Hereditary gastrointestinal carcinomas and their precursors: An algorithm for genetic testing.

Recognition of hereditary forms of gastrointestinal cancer is of great importance for patients and their families and pathologists play a crucial role in this. This review recapitulates the clinical, pathological and molecular aspects of Hereditary Diffuse Gastric Cancer and Gastric Adenocarcinoma and Proximal Polyposis of the Stomach, as well as hereditary colorectal cancer syndromes such as Lynch syndrome and gastrointestinal polyposis syndromes (including Familial Adenomatous Polyposis, Peutz-Jeghers syndrome and Juvenile Polyposis syndrome). Histopathological clues to recognize hereditary forms of gastrointestinal cancer and possible ancillary studies that can support an underlying syndrome and guide genetic testing are discussed.

Translational Research in Familial Colorectal Cancer Syndromes.

Growing knowledge of inherited colorectal cancer syndromes has led to better surveillance and better care of this subset of patients. The most well-known entities, including Lynch syndrome and familial adenomatous polyposis, are continually being studied and with the advent of more sophisticated genetic testing, additional genetic discoveries have been made in the field of inherited cancer. This article will summarize many of the updates to both the familiar and perhaps less familiar syndromes that can lead to inherited or early-onset colorectal cancer.

Recent Discoveries in the Genetics of Familial Colorectal Cancer and Polyposis.

The development of genome-wide massively parallel sequencing, ie, whole-genome and whole-exome sequencing, and copy number approaches has raised high expectations for the identification of novel hereditary colorectal cancer genes. Although relatively successful for genes causing adenomatous polyposis syndromes, both autosomal dominant and recessive, the identification of genes associated with hereditary non-polyposis colorectal cancer has proven extremely challenging, mainly because of the absence of major high-penetrance genes and the difficulty in demonstrating the functional impact of the identified variants and their causal association with tumor development. Indeed, most, if not all, novel candidate non-polyposis colorectal cancer genes identified so far lack corroborative data in independent studies. Here we review the novel hereditary colorectal cancer genes and syndromes identified and the candidate genes proposed in recent years as well as discuss the challenges we face.

Exome sequencing characterizes the somatic mutation spectrum of early serrated lesions in a patient with serrated polyposis syndrome (SPS).

BACKGROUND: Serrated or Hyperplastic Polyposis Syndrome (SPS, HPS) is a yet poorly defined colorectal cancer (CRC) predisposition characterised by the occurrence of multiple and/or large serrated polyps throughout the colon. A serrated polyp-CRC sequence (serrated pathway) of CRC formation has been postulated, however, to date only few molecular signatures of serrated neoplasia (BRAF, KRAS, RNF43 mutations, CpG Island Methylation, MSI) have been described in a subset of SPS patients and neither the etiology of the syndrome nor the distinct genetic alterations during tumorigenesis have been identified. METHODS: To identify somatic point mutations in potential novel candidate genes of SPS-associated lesions and the involved pathways we performed exome sequencing of eleven early serrated polyps obtained from a 41 year-old female patient with clinically confirmed SPS. For data filtering and analysis, standard pipelines were used. Somatic mutations were identified by comparison with leukocyte DNA and were validated by Sanger sequencing. RESULTS: The BRAF p.V600E or KRAS p.G12D mutation was identified in six polyps (~50%) and not found in polyps from the distal colon. In addition, we found seven unique rare somatic alterations of seven different genes in four serrated tumours, all of which are missense variants. The variant in ABI3BP and CATSPERB are predicted to be deleterious. No established cancer gene or candidate genes related to serrated tumorigenesis were affected. CONCLUSIONS: Somatic mutations seem to be rare events in early hyperplastic and serrated lesions of SPS patients. Neither frequently affected genes nor enrichment of specific pathways were observed. Thus, other alterations such as non-coding variants or epigenetic changes might be the major driving force of tumour progression in SPS.

Novel findings in colorectal polyp surveillance. / Novedades en la vigilancia de pólipos colorrectales.

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.

Serrated Polyps and Serrated Polyposis Syndrome.

Colorectal serrated polyps are intermediate lesions in the serrated neoplastic pathway, which account for up to 30% of colorectal cancers. This pathway is biologically distinct from the adenoma-to-carcinoma sequence, with associated cancers exhibiting mutations in the BRAF oncogene, DNA promoter hypermethylation, and microsatellite instability. An evolving understanding of these unique lesions has led to the development of a more accurate classification, improved endoscopic identification, and tailored clinical management guidelines. This article reviews serrated polyps and serrated polyposis syndrome.

[New advances in hereditary colorectal cancer]. / Novedades en el cáncer colorrectal hereditario.

Colorectal cancer is the most frequent malignancy in both sexes in Spain. Between 20% and 25% of affected individuals have a family history of the disease, and 5% to 6% have a germ mutation, i.e. the disease develops in the context of a hereditary syndrome. The importance of identifying patients with hereditary syndromes predisposing them to colorectal cancer lies in the possibility of applying preventive measures, screening, and more appropriate management of both patients and their families. The present article outlines the most important studies presented at the congress of the American Gastroenterological Association.

The endoscopist's guide to serrated polyposis.

AIM: Serrated polyposis is a condition of the colon characterized by multiple serrated polyps. This review aims to provide a practical guide to the day-to-day management of serrated polyposis, including diagnosis, endoscopic identification of serrated polyps, surveillance, the role of endoscopic and surgical management and the screening of family members. METHOD: The literature was searched using PubMed and MEDLINE databases for the terms "serrated polyp", "serrated polyposis" and "hyperplastic polyposis". English-language abstracts were read and the full article was retrieved if relevant to the review. Expert opinion from the authors was also sought. RESULTS: Advances in our knowledge of the molecular pathways involved in serrated polyposis and an improved clinical picture of the disease from retrospective studies have led to better understanding of its pathogenesis and natural history. However, there are still areas not answered by the literature, and hence empirical management or expert opinion has to be followed. CONCLUSION: Improvements in our understanding of serrated polyposis, together with improvements in endoscopic equipment and technique, have enabled the endoscopist to be at the forefront of managing this condition from diagnosis to endoscopic surveillance and control of the polyps.

[Hereditary and familial colorectal cancer]. / Cáncer colorrectal familiar y hereditario.

Up to 5% of all colorectal cancer cases are caused by a known hereditary syndrome. These hereditary types often need a higher degree of clinical suspicion to be diagnosed and require specific and specialized management. In addition, diagnosing hereditary colorectal cancer has significant consequences not only for the patient, for whom there are effective preventative measures, but also for their families, who could be carriers of the condition. The most significant advances in the field of colorectal cancer have come from the diagnosis and characterization of these syndromes.

Phenotype characteristics of patients with colonic serrated polyposis syndrome: a study of 23 cases.

INTRODUCTION: Serrated polyposis syndrome (SPS) is a rare entity characterized by the presence of multiple hyperplastic polyps in the colon and an increased risk of presentation and development of colorectal cancer (CRC). OBJECTIVE: To evaluate the clinical and phenotypical characteristics of patients that present one of the 3 WHO criteria for the diagnosis of SPS diagnosed and treated a tour hospital. PATIENTS AND METHODS: Patients with the diagnosis of SPS during 2005-2012 were revised; 24.208 colonoscopies were performed during this period. Age, sex, family history of CRC (APC/MYH), proximal/mixed/distal phenotype, indication for colonoscopy, number, size, location of the hyperplastic polyps, presence of mixed/adenomatous polyps, CRCI, follow-up and endoscopio/surgical treatment. RESULTS: A total of 23 cases were included (19 male). The median age was 51. A total of 34% had a prior family history of CRC or polpyps. Distal phenotype was more frequent (48%). Another 73% presented synchronous adenomatous polyps, and 26% a CRC. A total of 57% were asymptomatic. Surgery was performed in 9 cases (6 for cancer and 3 for polyposis), and 14 were treated by polypectomy and observation. Eleven patients (47%) presented recurrent/persistent lesions after initial surgical/endoscopic treatment. CONCLUSION: SPS is an heterogeneous syndrome that is variable in the type, size, distribution and number of polyps, and is more common in male smokers with a distal phenotype. The majority of patients also present synchronous adenomatous polyps. These patients require an organized multidisciplinary evaluation.

Pathology of Gastrointestinal Polyposis Disorders.

Gastrointestinal polyposis disorders are a group of syndromes defined by clinicopathologic features that include the predominant histologic type of colorectal polyp and specific inherited gene mutations. Adenomatous polyposis syndromes comprise the prototypical familial adenomatous polyposis syndrome and other recently identified genetic conditions inherited in a dominant or recessive manner. Serrated polyposis syndrome is defined by arbitrary clinical criteria. The diagnosis of hamartomatous polyposis syndromes can be suggested from the histologic characteristics of colorectal polyps and the association with various extraintestinal manifestations. Proper identification of affected individuals is important due to an increased risk of gastrointestinal and extragastrointestinal cancers.