Hereditary Polyposis Syndromes Research Articles

Clinical Assessment and Genetic Testing for Hereditary Polyposis Syndromes in an Italian Cohort of Patients with Colorectal Polyps

Background: Hereditary polyposis syndromes are clinically and genetically heterogeneous conditions associated with increased colorectal cancer risk. They are classified based on polyp histology, inheritance mode, causal gene, and colonic and extracolonic manifestations. Their diagnosis is challenging due to overlapping and heterogeneous clinical presentations. Methods: A multigene next-generation sequencing panel was used to screen 75 index cases with colorectal polyps and a personal/family history of cancer for key hereditary polyposis-associated genes (APC, BMPR1A, MUTYH, PTEN, SMAD4, and STK11) in order to identify germline genetic variants. Results: In the screened index cases, we found 14 pathogenic variants involving APC, MUTYH, SMAD4, and STK11 and 6 variants of uncertain significance involving APC, BMPR1A, and SMAD4. In this cohort, four patients not fulfilling the recommended eligibility criteria of current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing were molecularly diagnosed with a hereditary polyposis syndrome. Conclusions: Our findings indicate that stringent NCCN eligibility criteria for molecular screening may lead to missing some of the patients affected by hereditary polyposis syndromes. This highlights the need for a careful evaluation of patients’ clinical manifestations, polyp number, age of polyp onset, and family history to select appropriate candidates for molecular diagnosis of these conditions.

Large-scale application of ClinGen-InSiGHT APC-specific ACMG/AMP variant classification criteria leads to substantial reduction in VUS

Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUSs), APC-specific variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) based on the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). A streamlined algorithm using the APC-specific criteria was developed and applied to assess all APC variants in ClinVar and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) international reference APC Leiden Open Variation Database (LOVD) variant database, which included a total of 10,228 unique APC variants. Among the ClinVar and LOVD variants with an initial classification of (likely) benign or (likely) pathogenic, 94% and 96% remained in their original categories, respectively. Incontrast, 41% ClinVar and 61% LOVD VUSs were reclassified into clinically meaningful classes, the vast majority as (likely) benign.The total number of VUSs was reduced by 37%. In 24 out of 37 (65%) promising APC variants that remained VUS despite evidence for pathogenicity, a data-mining-driven work-up allowed their reclassification as (likely) pathogenic. These results demonstrated that the application of APC-specific criteria substantially reduced the number of VUSs in ClinVar and LOVD. The study also demonstrated the feasibility of a systematic approach to variant classification in large datasets, which might serve as a generalizable model for other gene- or disease-specific variant interpretation initiatives. It also allowed for the prioritization of VUSs that will benefit from in-depth evidence collection. This subset of APC variants was approved by the VCEP and made publicly available through ClinVar and LOVD for widespread clinical use.

Hereditary Colorectal Cancer and Polyposis Syndromes Caused by Variants in Uncommon Genes.

A substantial number of hereditary colorectal cancer (CRC) and colonic polyposis cannot be explained by alteration in confirmed predisposition genes, such as mismatch repair (MMR) genes, APC and MUTYH. Recently, a certain number of potential predisposition genes have been suggested, involving each a small number of cases reported so far. Here, we describe the detection of rare variants in the NTLH1, AXIN2, RNF43, BUB1, and TP53 genes in nine unrelated patients who were suspected for inherited CRC and/or colonic polyposis. Seven of them were classified as pathogenic or likely pathogenic variants (PV/LPV). Clinical manifestations of carriers were largely consistent with reported cases with, nevertheless, distinct characteristics. PV/LPV in these uncommon gene can be responsible for up to 2.7% of inherited CRC or colonic polyposis syndromes. Our findings provide supporting evidence for the role of these genes in cancer predisposition, and contribute to the determination of related cancer spectrum and cancer risk for carriers, allowing for the establishment of appropriate screening strategy and genetic counseling in affected families.

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.

Hereditary adenomatous polyposis syndromes, including familial adenomatous polyposis and other rare adenomatous polyposis syndromes, increase the lifetime risk of colorectal and other cancers. 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%). One hundred and forty statements reached a high level of consensus concerning the management of hereditary adenomatous polyposis syndromes. 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.

Familial Adenomatous Polyposis within the Pediatric Hereditary Polyposis Registry

Background/Objective: 
 Familial Adenomatous Polyposis (FAP) is a condition characterized by values exceeding hundreds of colorectal adenomatous polyps. FAP has a prevalence of 1 in 8,300 people, demonstrating an autosomal dominant inheritance pattern. This condition follows a pathogenic variation of the Adenomatous Polyposis Coli (APC) gene, located on chromosome 5q21-22. These mutations are heavily correlated with the incidence of colorectal carcinoma, requiring prophylactic colectomy. The management and treatment of FAP requires routine surveillance to reduce gastrointestinal polyp burden. The objective for this study is to characterize the current patient population at Riley with polyposis syndromes and assess clinical surveillance in patients diagnosed with FAP. 
 Methods: 
 Historical data from 2020-2022 GI clinical visits were reviewed using the diagnostic codes Family history of colonic polyps, Benign neoplasm of colon unspecified, and Other phakomatoses not elsewhere classified. These criteria identified 93 patients of which 64 patients were diagnosed with a hereditary polyposis syndrome for inclusion within the registry. Of the 64 patients, 42 had a diagnosis of FAP. Clinical data reviewed included the patient’s age of diagnosis, completion of genetic testing and follow-up, surgical treatment, routine endoscopic surveillance, and modes of imaging. 
 Results: 
 Results indicated a median age of diagnosis of 10 years, lower than previously reported national averages of 13.5-17 years. Evaluation of routine follow-up indicated a rate of endoscopy at 0.822 scopes per year and demonstrated that abdominal CT scans as well as abdominal X-rays were the most common supplemental modes of imaging. 
 Conclusion/ Future Directions: 
 The data from this registry will help direct care of patients with FAP, ensuring they receive treatment in accordance with national guidelines for routine surveillance and prophylactic colectomy. Moving forward, the intention is to expand the registry's date range to incorporate more patients and elaborate further on endoscopic findings for the specific subtypes of FAP.

Endoscopy in pediatric polyposis syndromes: why, when and how.

Single or multiple polyps are frequently encountered during colonoscopy among children and adolescents and may be indicative of hereditary polyposis syndrome (HPS). The management of children with single or multiple polyps is guided by the number of polyps, their distribution and the histological findings. Children with HPS carry a high risk of complications, including intestinal and extra-intestinal malignancies. The goals of surveillance in pediatric HPS are to treat symptoms, monitor the burden of polyps and prevent short- and long-term complications. Therefore, the management of children with HPS is based on therapeutic endoscopy. The strategy of therapeutic endoscopy is a careful assessment and characterization of the polyps and performing polypectomies using advanced endoscopic techniques. A multidisciplinary approach, comprising clinical, interventional endoscopy, cancer surveillance and support of familial and emotional aspects is essential in the management of children with HPS.

Clinical characteristics and risk factors related to polyposis recurrence and advanced neoplasm development among patients with non-hereditary colorectal polyposis.

Patients with more than 10 cumulative polyps might involve a greater genetic risk of colorectal neoplasia development. However, few studies have investigated the risk factors of polyposis recurrence and development of advanced neoplasms among patients with non-hereditary colorectal polyposis. This study included patients (n=855) with 10 or more cumulative polyps diagnosed at Severance Hospital from January 2012 to September 2021. Patients with known genetic mutations related to polyposis, known hereditary polyposis syndromes, insufficient information, total colectomy, and less than 3 years of follow-up were excluded. Finally, 169 patients were included for analysis. We collected clinical data, including colonoscopy surveillance results, and performed Cox regression analyses of risk factors for polyposis recurrence and advanced neoplasm development. The 169 patients were predominantly male (84.02%), with a mean age of 64.19±9.92 years. The mean number of adenomas on index colonoscopy was 15.33±8.47. Multivariable analysis revealed history of cancer except colon cancer (hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.23-4.01), current smoking (HR, 2.39; 95% CI, 1.17-4.87), and detection of many polyps (≥15) on index colonoscopy (HR, 2.05; 95% CI, 1.21-3.50) were significant risk factors for recurrence of polyposis. We found no statistically significant risk factors for advanced neoplasm development during surveillance among our cohort. The presence of many polyps (≥15) on index colonoscopy, history of cancer except colon cancer, and current smoking state were significant risk factors for polyposis recurrence among patients with non-hereditary colorectal polyposis.

Gene-specific ACMG/AMP classification criteria for germline APC variants: Recommendations from the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

PurposeThe Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) was established by the International Society for Gastrointestinal Hereditary Tumours and the Clinical Genome Resource, who set out to develop recommendations for the interpretation of germline APC variants underlying Familial Adenomatous Polyposis, the most frequent hereditary polyposis syndrome. MethodsThrough a rigorous process of database analysis, literature review, and expert elicitation, the APC VCEP derived gene-specific modifications to the ACMG/AMP (American College of Medical Genetics and Genomics and Association for Molecular Pathology) variant classification guidelines and validated such criteria through the pilot classification of 58 variants. ResultsThe APC-specific criteria represented gene- and disease-informed specifications, including a quantitative approach to allele frequency thresholds, a stepwise decision tool for truncating variants, and semiquantitative evaluations of experimental and clinical data. Using the APC-specific criteria, 47% (27/58) of pilot variants were reclassified including 14 previous variants of uncertain significance (VUS). ConclusionThe APC-specific ACMG/AMP criteria preserved the classification of well-characterized variants on ClinVar while substantially reducing the number of VUS by 56% (14/25). Moving forward, the APC VCEP will continue to interpret prioritized lists of VUS, the results of which will represent the most authoritative variant classification for widespread clinical use.

Role of Genetic Testing and Complex Endoscopic Examination in Differential Diagnosis of Hereditary Polyposes in Pediatric and Adolescent Patients: 10 Years Clinical Experience

Background. Hereditary polyposis syndromes (HPS) are a group of rare genetic diseases characterized by multiple epithelial lesions in the gastrointestinal tract (GIT) with high risk of malignancy and neoplasia development in other localizations. The case follow-up tactics in hereditary polyposes have significant differences, and differential diagnosis can be complicated due to the phenotype variability and the clinical manifestations similarity. Objective. The aim of the study is to determine the role of molecular genetic testing and endoscopic examination in the diagnosis and management of children with HPS. Materials and methods. The retrospective observational study included 17 patients with clinical signs of hereditary polyposes who applied to the L.A. Durnov Research Institute of Pediatric Oncology and Hematology during the period from 2013 to 2023. All patients underwent molecular genetic testing and comprehensive endoscopic examination of upper and lower GIT. Results. We have divided patients into 7 groups according to the results of genetic testing. Patients had various mutations in genes associated with hereditary tumor syndromes: STK11 (35.3%; n = 6), APC (17.6%; n = 3), PTEN (11.8%; n = 2), SMAD4 (5.9%; n = 1), BMPR1A (5.9%; n = 1), MUTYH (5.9%; n = 1), MLH1 (5.9%; n = 1). One female patient with colorectal cancer with history of adenomatous polyp had pathogenic variants in the ATM and CHEK2 genes; it could be considered as multi-locus tumor syndrome (MINAS) (5.9%, n = 1). Another female patient (5.9%) had multiple gastric body hamartoma polyps and multiple gastric gastrointestinal stromal tumors (GIST) but with no pathogenic mutations. Complex endoscopic examination was performed in 14 (82.3%) patients. Epithelial or non-epithelial lesions of the stomach and intestine were revealed in all cases. Malignant tumors of duodenum and colon were diagnosed in 3 out of 14 patients (21.4%). Morphological variants of these GIT lesions were represented by hamartoma, hyperplastic, and juvenile polyps, adenomas, serrated adenomas, adenocarcinoma, and GIST. The diagnosed epithelial lesions of the stomach, duodenum, and colon were removed via endoscopic polypectomy and endoscopic mucosal resection in 8 out of 14 patients (57.1%). Some cases required small bowel resection (14.3%, n = 2), total colectomy (14.3%, n = 2), and gastrectomy (14.3%, n = 2). Conclusion. Understanding the molecular and biological etiology of HPS, its endoscopic diagnosis, and treatment features allows us to optimize the management of such patients and to minimize the risks of developing malignant tumors in upper and lower GIT, as well as extraintestinal tumors by carrying out timely medical and preventive measures.

The Role of Capsule Endoscopy in the Management of Pediatric Hereditary Polyposis Syndromes.

The Role of Capsule Endoscopy in the Management of Pediatric Hereditary Polyposis Syndromes.

Whole genome sequencing and disease pattern in patients with juvenile polyposis syndrome: a nationwide study.

Juvenile polyposis syndrome (JPS) is a hereditary hamartomatous polyposis syndrome characterized by gastrointestinal juvenile polyps and increased risk of gastrointestinal cancer. Germline pathogenic variants are detected in SMAD4 or BMPR1A, however in a significant number of patients with JPS, the etiology is unknown. From Danish registers, and genetic department and laboratories, we identified all patients in Denmark with a clinical diagnosis of JPS and/or a pathogenic variant in BMPR1A or SMAD4. In patients where no variant had been detected, we performed genetic analysis, including whole genome sequencing. We collected clinical information on all patients to investigate the phenotypic spectrum. Sixty-six patients (mean age 40years) were included of whom the pathogenic variant was unknown in seven patients. We detected a pathogenic variant in SMAD4 or PTEN in additional three patients and thus ≈95% of patients had a pathogenic germline variant. Endoscopic information was available in fifty-two patients (79%) and of these 31 (60%) fulfilled the clinical criteria of JPS. In 41 patients (79%), other types of polyps than juvenile had been removed. Our results suggest that almost all patients with a clinical diagnosis of JPS has a pathogenic variant in mainly BMPR1A, SMAD4, and more rarely PTEN. However, not all patients with a pathogenic variant fulfil the clinical criteria of JPS. We also demonstrated a wide clinical spectrum, and that the histopathology of removed polyps varied.

Lorpucitinib (JNJ-64251330) in patients with familial adenomatous polyposis (FAP): Results from a phase 1b study.

10514 Background: FAP is the most common hereditary adenomatous polyposis syndrome and, if left untreated, will lead to colorectal cancer development in nearly all patients. Chronic inflammation, driven in part by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, may promote polyp formation. Enteric-selective inhibition of the JAK/STAT pathway may provide a treatment for FAP. Lorpucitinib is an oral, small molecule, potent pan-JAK inhibitor with favorable enteric-selective properties. Here, we report the efficacy, safety, and pharmacokinetic (PK) results from a phase 1b study of lorpucitinib in patients with FAP (NCT05014360). Methods: Patients aged ≥18 years with ≥6 polyps ≥2 mm in diameter in the rectum or colon with FAP ( APC germline mutation or obligate carrier) received lorpucitinib 75 mg twice daily for 24 weeks. The primary objective was to evaluate the effect of lorpucitinib on colorectal polyp burden at Week 24, assessed by endoscopy at baseline and Week 24. Secondary objectives were safety, PK, and biomarker assessments of lorpucitinib activity. Results: Overall, 42 (23 pre-colectomy; 19 post-colectomy) patients with FAP were enrolled, with a median age of 33 (range, 19-61) years. No clear effect on polyp burden was observed at Week 24. Gut mucosal and polyp concentrations of lorpucitinib were much higher than plasma concentrations, indicating an enteric-selective distribution. Mean sigmoid colon, rectum, and polyp concentrations of lorpucitinib at Week 8 were 112-, 473-, and 108-fold higher, respectively, than the observed maximum plasma concentration at Week 8 (1 hour). At Week 8, lorpucitinib achieved JAK tyrosine kinase inhibition in mucosal biopsies as evidenced by a median 37% reduction in normalized pSTAT-3 levels. Lorpucitinib reduced serum-based inflammatory biomarkers such as C-reactive protein and serum amyloid A by Week 16 of therapy. Some patients reported an improvement of clinical symptoms such as less frequent bowel movements and less blood in the stool. The most common adverse events (AEs) were abdominal pain (16%), bilirubin increased (13%), headache (13%), lipase increased (13%), and diarrhea (13%). There were no treatment-related serious AEs, grade 3 treatment-emergent AEs, serious infections, or venous thromboembolisms. Conclusions: These results show that lorpucitinib had no clear effect on polyp burden. The study found that lorpucitinib is safe and exhibits an enteric-selective distribution in FAP patients. Inhibition of JAK tyrosine kinase signaling was associated with reduced STAT-3 phosphorylation in mucosal biopsies from FAP patients. While reductions observed in polyp burden were not clinically significant, lorpucitinib treatment lowered levels of several serum inflammatory biomarkers. Treatment with lorpucitinib was safe and well tolerated, and may improve clinical symptoms associated with FAP. Clinical trial information: NCT05014360 .

Large Rearrangements in Genes Responsible for Familial Adenomatous Polyposis, <i>MUTYH</i>-Associated Polyposis and Peutz–Jeghers Syndrome in Russian Patients

Аim: to reveal the rate of large rearrangements in the genes responsible for familial adenomatous polyposis, MUTYH-associated polyposis and Peutz–Jeghers syndrome.Materials and methods. The MLPA method was used for identification of large rearrangements. A total number of 135 patients was included in the study: 83 patients with a clinical diagnosis of “familial adenomatous polyposis”, 18 — with suspected MUTYH-associated polyposis, and 34 — with a clinical diagnosis of “Peutz–Jeghers syndrome”.Results. Seven large deletions and one large duplication in the APC gene were identified in 83 patients with classic familial adenomatous polyposis, with rate of large rearrangements 9.6 % (8/83). In 18 patients with suspected MUTYH-associated polyposis, no large rearrangements were found in the MUTYH gene. Four large deletions in the STK11 gene (12 %, 4/34) were detected in 34 patients with Peutz–Jeghers syndrome.Conclusion. For the first time, the expediency of including the method of detecting large rearrangements in routine DNA test list for Russian patients with various hereditary polyposis syndromes is demonstrated. Routine use of MLPA method makes it possible to increase the total frequency of detection of pathogenic variants in the APC and STK11 genes above 90 %. At the same time, the need for searching of large rearrangements in the MUTYH gene were not justified.

Survival, surveillance, and genetics in patients with Peutz-Jeghers syndrome: A nationwide study.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary polyposis syndrome causing increased morbidity and mortality due to complications of polyposis and the development of cancer. STK11 is the only gene known to be associated with PJS, although in 10%-15% of patients fulfilling the diagnostic criteria no pathogenic variant (PV) is identified. The primary aim of this study was to identify the genetic etiology in all known PJS patients in Denmark and to estimate the risk of cancer, effect of surveillance and overall survival. We identified 56 patients (2-83 years old) with PJS. The detection rate of PVs was 96%, including three cases of mosaicism (6%). In two patients a variant was not detected. At the age of 40 years, the probabilities of cancer and death were 21% and 16%, respectively; at the age of 70 years these probabilities were 71% and 69%. Most cases of cancer (92%) were identified between the scheduled examinations in the surveillance program. These observations emphasize that PJS should be regarded as a general cancer predisposition syndrome, where improvement of clinical care is needed.

Abstract 4177: Genetic testing for hereditary colorectal cancer syndromes in Algerian patients: A multicenter study

Abstract Background To date, 5% to 6 % of all colorectal cancers (CRCs) are associated with germline pathogenic variants in cancer predisposition genes that confer inherited predisposition to CRC. The use of genetic testing to identify individuals at risk for hereditary CRC syndromes can help to prevent the development of cancer and in the clinical management of the colorectal patients in the areas of both prevention and treatment. We report here the experience of our research laboratory of genetic testing for hereditary polyposis syndromes and Lynch syndrome (LS), respectively, in 126 patients. Methods Fifty four (54) severe familial adenomatous polyposis (FAP) patients and 72-suspected Lynch syndrome (LS) patients, respectively, were selected from 2851 consecutive colorectal patients at five public hospitals during 2012-2019. Family histories of cancer were obtained from interviews, pedigrees and medical records of patients. Index cases and relatives diagnosed with FAP syndrome or Lynch syndrome have been tested for germline variants in APC, MLH1, MSH2, MSH6 and PMS2 genes, respectively, using PCR-Sanger Sequencing or by NGS using a cancer panel of 30 hereditary cancer genes (Color Genomics). Results We detected 13 germline pathogenic variants in APC gene in 17 unrelated families, one germline pathogenic variant in BMPRA1 gene in juvenile polyposis syndrome (JPS) patient; seven (7) germline pathogenic variants and 2 variants of uncertain clinical significance (VUS) in MMR genes. Interestingly, 4 novel germline pathogenic variants in APC gene and 3 novel germline pathogenic variants in MMR genes, respectively, have been detected in our study. The most occurring germline pathogenic variants in APC gene were c.3927_3931del and c.4728dup that were identified in four and two index cases in 6 unrelated FAP families, respectively. In Lynch syndrome patients, the rare germline pathogenic variant MLH1 c.1546C>T has been found in 21 individuals from 9 LS families, 6 of them related, with two large kindreds. In addition, the recurrent germline pathogenic variant MSH2 c.942+3A>T has been detected in five unrelated index cases with a strong family history of LS syndrome. Moreover, the rare germline VUS PMS2 c.989-107_989-106insA has been detected in 14 unrelated LS patients and could be reclassified as likely benign. Interestingly, our NGS analysis detected the novel BMPR1A pathogenic variant c.1474-1G>C in young JPS patient that has been misdiagnosed as FAP. The in-silico analysis for this novel variant showed an alteration of the wild type acceptor site and an activation of a cryptic acceptor site, respectively, most probably affecting splicing. Conclusions Our current study will contribute to the molecular genetics characterization of hereditary colorectal cancer syndromes in Algerian population that is relevant for clinical management in the areas of genetic testing, early diagnosis, treatment and prevention. Citation Format: Farid Cherbal, Asma-Lamia Boumehdi, Feriel Khider, Karima Landelouci, Abdelwahab Zemam, Sarah Sabri, Adam.Walid Damache, Mohammed Oukkal, Hassen Mahfouf, Ferhat Zebboudj, Mustapha Maaoui. Genetic testing for hereditary colorectal cancer syndromes in Algerian patients: A multicenter study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4177.

Hamartomatous polyps: Diagnosis, surveillance, and management.

Hereditary polyposis syndrome can be divided into three categories: Ade-nomatous, serrated, and hamartomatous polyps. Hamartomatous polyps, malformations of normal tissue presenting in a disorganized manner, are characterized by an autosomal dominant inheritance pattern. These syndromes exhibit hamartomatous gastrointestinal polyps in conjunction to extra-intestinal manifestations, which require conscientious and diligent monitoring. Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome are the most common displays of hamartomatous polyposis syndrome (HPS). Diagnosis can be pursued with molecular testing and endoscopic sampling. Early identification of these autosomal dominant pathologies allows to optimize malignancy sur-veillance, which helps reduce morbidity and mortality in both the affected patient population as well as at-risk family members. Endoscopic surveillance is an important pillar of prognosis and monitoring, with many patients eventually requiring surgical intervention. In this review, we discuss the diagnosis, surveillance, and management of HPS.

Fundic Gland Polyps Lack DNA Content Abnormality Characteristic of Other Adenomatous Precursor Lesions in the Gastrointestinal Tract

Fundic gland polyps (FGPs) develop sporadically (frequently after proton pump inhibitor therapy) or in the setting of a hereditary polyposis syndrome, such as familial adenomatous polyposis (FAP). FAP-related FGPs often demonstrate low-grade dysplasia (LGD) and are frequently associated with APC mutations, even in the absence of dysplasia. Sporadic FGPs with dysplasia are molecularly similar to FAP-related FGPs and demonstrate frequent mutations in APC gene. Despite having similar molecular alterations with colorectal and other adenomatous precursor lesions in the gastrointestinal (GI) tract, FGPs rarely progress to advanced gastric neoplasia (high-grade dysplasia [HGD] or adenocarcinoma), and their role in gastric tumorigenesis remains unclear but likely limited. The clinicopathologic features of 192 patients diagnosed with FGPs, including 86 with FAP-related FGPs (33 with dysplastic FGPs and 53 with nondysplastic FGPs) and 106 with sporadic FGPs (12 with dysplastic FGPs and 94 with nondysplastic FGPs), were analyzed. DNA flow cytometry was performed on 111 FAP-related FGP biopsies, including 32 FGPs with LGD and 79 nondysplastic FGPs, to assess the presence of abnormal DNA content (ie, aneuploidy or elevated 4N fraction). Moreover, 40 sporadic FGP biopsies, including 14 dysplastic (13 LGD and 1 HGD) and 26 nondysplastic FGPs, were examined for DNA content abnormality. Patients with FAP and nondysplastic FGPs were more likely to be younger (mean age, 32 years) and present with multiple FGPs (92%, defined as having ≥2 FGPs) than those with sporadic nondysplastic FGPs (61 years and 65%, respectively; P < .001). They also recorded higher rates of previous or concurrent gastric epithelial dysplasia not occurring in a FGP (8%, P = .016), nongastric GI dysplasia (96%, P < .001), and nongastric GI malignancy (17%, P = .001) compared with those with sporadic nondysplastic FGPs (0%, 52%, and 2%, respectively). The sporadic group was more frequently associated with proton pump inhibitor therapy (78%, P < .001), gastric intestinal metaplasia (24%, P = .004), and a family history of gastric cancer (10%, P = .027) than the FAP group (19%, 6%, and 0%, respectively). Almost all FAP-related FGPs had a polypoid endoscopic appearance (98% vs 84% for sporadic FGPs; P = .009). The mean size of the largest FAP-related FGPs (0.5 cm) was similar to that of sporadic FGPs (0.7 cm) (P = .069). None of the 147 patients with FAP-related or sporadic nondysplastic FGPs were associated with subsequent detection of advanced gastric neoplasia within a mean follow-up time of 54 months (range, <1 to 277 months). However, 2 (4%) of the 45 patients with FAP-related or sporadic dysplastic FGPs developed advanced gastric neoplasia within a mean follow-up time of 59 months (range, <1 to 236 months). One (3%) of the 33 patients with FAP and dysplastic FGPs developed signet ring cell adenocarcinoma, whereas 1 (8%) of the 12 patients with sporadic dysplastic FGPs developed HGD (P = .445). However, none of the FAP-related and sporadic FGP biopsies, regardless of the presence or absence of dysplasia, demonstrated DNA content abnormality. In conclusion, FGPs lack large-scale chromosomal changes that are characteristic of the typical adenoma-carcinoma sequence involved in the development of other GI malignancies. Progression to advanced gastric neoplasia is rare in FGPs, which may be partly explained by the apparent lack of the chromosomal instability phenotype in these lesions.

Hereditary polyposis syndromes remain a challenging disease entity: Old dilemmas and new insights.

In this editorial we present an overview and insights of the management of hereditary polyposis syndromes. The primary focus was on familial adenomatous polyposis, juvenile polyposis syndrome and Peutz-Jegher syndrome. Genetic testing has become increasingly available and is easier than ever to integrate into clinical practice. Furthermore, several genes have been added to the expanding list of genes associated with hereditary polyposis syndromes, allowing for precise diagnostics and tailored follow-up. Endoscopic evaluation of patients with hereditary polyposis syndromes is paramount in the surveillance strategies. Current endoscopic procedures include both diagnostic procedures and surveillance as well as therapeutic interventions. Recommendations for endoscopic procedures in the upper and lower gastrointestinal canal were described. Surgery is still a key component in the management of patients with hereditary polyposis syndromes. The increased cancer risk in these patients often render prophylactic procedures or intended curative procedures in the case of cancer development. Surgical interventions in the upper and lower gastrointestinal canal were described with relevant considerations. Development of chemopreventive medications is ongoing. Few drugs have been investigated, including nonsteroidal anti-inflammatory drugs. It has been demonstrated that cyclooxygenase-2 inhibitors may lower the number of polyps. Other medications are currently under investigation, but none have, to date, consistently been able to prevent development of disease.

Abstract B023: Sox9 drives an aberrant transcriptional program impeding intestinal differentiation in colorectal cancer initiation

Abstract Despite the implementation of screening and preventative strategies, colorectal cancer (CRC) remains the second most deadly cancer worldwide and is responsible for an alarming trend of increasing prevalence among younger patients. Inappropriate WNT activation is the initiating step in sporadic CRC development, typically through deleterious mutations in the pathway negative regulator Adenomatous polyposis coli (APC). WNT pathway hinders whereas transforming growth factor (TGF-β)/bone morphogenetic protein (BMP) signaling supports differentiation of progenitors into mature enterocytes, establishing a crypt-villus gradient. Genomic alterations that dysregulate intestinal stem cell differentiation are central to CRC development. Impairment of differentiation and inappropriate Sox9 overexpression are conserved events in CRC initiation based on the evaluation of two genetically engineered mouse models, two carcinogen-induced mouse models, and a patient with familial adenomatous polyposis (FAP), a hereditary polyposis syndrome in which a mutant copy of APC is inherited. Single cell RNA-sequencing (scRNA-seq) of adenomas from an ApcKO mouse model and FAP sample implicates an aberrant stem cell-like program (herein referred to as AbSC) as a key aspect of CRC initiation. The AbSc program is characterized by selective intestinal stem cell activity, indiscriminate attenuation of differentiated lineages, and aberrant activation of genes associated with fetal intestinal development. Histopathology and scRNA-seq of adenomas and derivative organoids from a patient with FAP demonstrated a partial block in differentiation and confirmed reactivation of genes reserved for intestinal development. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) of APCKO epithelial cells revealed increased chromatin accessibility at fetal intestinal genes. Genetic inactivation of Sox9 prevented adenoma formation in ApcKO mice and induced differentiation of ApcKO organoids, obstructing the emergence of the ApcKO transcriptional state, including reactivation of a fetal-like intestinal program, restored multi-lineage differentiation, and markedly reduced the gained chromatin accessibility at developmental genes in neoplasia. These studies indicate that an aberrant transcriptional state hindering intestinal differentiation mediated by Sox9 is an early conserved event in CRC and carry important implications for developing therapeutics directed at inducing intestinal differentiation. Citation Format: Pratyusha Bala, Jonathan P. Rennhack, Clare Morris, Daulet Aitymbayev, Sydney M. Moyer, Gina Nicole Duronio, Paul Doan, William C. Hahn, Nilay S. Sethi. Sox9 drives an aberrant transcriptional program impeding intestinal differentiation in colorectal cancer initiation [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B023.

356P Biallelic MUTYH germline inactivation in patients with colon polyposis and subjects with sporadic colorectal cancer

MUTYH-associated polyposis (MAP) is a rare recessive condition typically characterized by the presence of 10-100 colorectal polyps and the elevated risk of colorectal cancer (CRC). CRCs arising in biallelic carriers of MUTYH mutation often contain KRAS G12C substitution and frequently arise without concomitant polyposis. This study included 74 consecutive patients with colon polyposis and 3486 consecutive patients with CRC referred to the N.N. Petrov Institute of Oncology (St. Petersburg, Russia) for molecular testing. Normal DNA obtained from subjects with polyposis was analyzed by NGS using custom panel for hereditary cancer genes. CRC patients were screened for recurrent MUTYH pathogenic alleles p.Y179C, p.R245H and p.G396D. The status of the remaining allele in MUTYH-heterozygous CRC cases was analyzed by Sanger sequencing. Biallelic MUTYH mutations were identified in 8/74 (11%) patients with polyposis. MAP was the second most common hereditary polyposis syndrome after familial adenomatous polyposis (47/74, 64%), with Peutz-Jeghers syndrome being in the third place (3/74, 5%). MUTYH biallelic alterations were detected in 9/3486 (0.3%) consecutive CRC patients. Somatic KRAS G12C substitution was observed in 223/3486 (6%) CRCs. Germ-line MUTYH inactivation was identified in 7/223 (3%) KRAS G12C-positive CRCs vs. 2/3253 (0.06%) patients without this mutation (p < 0.00001). Germ-line MUTYH biallelic mutations are significant contributors to the incidence of polyposis, while their impact in CRC morbidity is moderate. However, MUTYH gene analysis is highly feasible in CRC patients whose tumor harbors KRAS G12C substitution.