Familial Polyposis Research Articles

Cribriform-morular Thyroid Carcinoma Arising in a Medulloblastoma Survivor: Two Metachronous Tumors Shared with the Activation of the Wnt Signaling Pathway.

Wnt signaling pathway activation is involved in the pathogenesis of a series of malignant tumors and is characterized by the nuclear accumulation of β-catenin protein. The occurrence of two or more Wnt pathway-associated tumors in a single individual is uncommon and generally attributed to inherited cancer syndrome, especially familial adenomatous polyposis (FAP). Herein, we presented a rare case of a child who suffered from the occurrence of Wnt-activated medulloblastoma and cribriform-morular thyroid carcinoma (CMTC) within a 9-year interval. She had no history of FAP and harbored an unexpected somatic mutation of the APC gene in the CMTC tumor. The potential agents involved in the pathogenesis of the two molecular-linked tumors other than FAP were discussed in this report.

Assessing the efficacy of target adaptive sampling long-read sequencing through hereditary cancer patient genomes

Innovations in sequencing technology have led to the discovery of novel mutations that cause inherited diseases. However, many patients with suspected genetic diseases remain undiagnosed. Long-read sequencing technologies are expected to significantly improve the diagnostic rate by overcoming the limitations of short-read sequencing. In addition, Oxford Nanopore Technologies (ONT) offers adaptive sampling and computationally driven target enrichment technology. This enables more affordable intensive analysis of target gene regions compared to standard non-selective long-read sequencing. In this study, we developed an efficient computational workflow for target adaptive sampling long-read sequencing (TAS-LRS) and evaluated it through application to 33 genomes collected from suspected hereditary cancer patients. Our workflow can identify single nucleotide variants with nearly the same accuracy as the short-read platform and elucidate complex forms of structural variations. We also newly identified several SINE-R/VNTR/Alu (SVA) elements affecting the APC gene in two patients with familial adenomatous polyposis, as well as their sites of origin. In addition, we demonstrated that off-target reads from adaptive sampling, which is typically discarded, can be effectively used to accurately genotype common single-nucleotide polymorphisms (SNPs) across the entire genome, enabling the calculation of a polygenic risk score. Furthermore, we identified allele-specific MLH1 promoter hypermethylation in a Lynch syndrome patient. In summary, our workflow with TAS-LRS can simultaneously capture monogenic risk variants including complex structural variations, polygenic background as well as epigenetic alterations, and will be an efficient platform for genetic disease research and diagnosis.

Long-term mental and physical quality of life outcomes following ileal pouch anal anastomosis surgery.

This study presents the authors' experience over 14 years of performing restorative procto-colectomy with ileal pouch anal anastomosis (IPAA). The aim was to study the long-term quality of life outcomes and analyse the predictors of pouch function as well as physical and mental wellbeing. This is a single-centre retrospective study conducted in a specialised colorectal surgery unit in the UK. The study included patients who underwent two- or three-staged panproctocolectomy with defunctioning ileostomy for ulcerative colitis (UC) or familial adenomatous polyposis between 2004 and 2018. Data were collected from a prospectively, surgeon-maintained database. Pouch function and quality of life scores were obtained via validated questionnaires. A multivariate analysis was utilised to explore predictors of quality of life and pouch function. The study reports 105 patients who underwent IPAA with a covering ileostomy. The majority of operations were performed for UC (97, 92.4%). The median age of patients was 36 years and the male to female ratio was 1:1. Thirty patients (28.5%) suffered early post-IPAA complications, while pouch failure rate was 11.4% (12/105). Late complications were reported at a rate of 45%. On long-term follow-up, the median Pouch Function Score was 7 (IQR 3-14). Both the physical and mental sections of the quality of life score were at a median indistinguishable from the normal population but had different predictors associated with them. Our findings recognise the complex interplay between physical and psychological wellbeing after pouch surgery and advise psychological counselling where appropriate.

Abstract B008: The polyclonal path towards malignant transformation in familial adenomatous polyposis

Abstract The widely accepted paradigm that cancer initiation is a monoclonal event has not been definitively resolved. This is largely due to the limitations of experimental systems to study cancer initiation, a definitively transient step in tumorigenesis. Individuals with familial adenomatous polyposis (FAP) possess a germline APC mutation, leading to hundreds of colonic polyps in adolescence and an eventual 100% lifetime risk of colorectal cancer. As such, total colectomies are performed once polyp burden becomes unmanageable and provide the resected colons from FAP donors provide a source of histologically normal mucosa, benign and dysplastic polyps, and, on rare occasions, adenocarcinomas, and serve as an exemplary model disease to understand human tumorigenesis. Through whole genome sequencing of 123 independent samples from six patients, we reveal the polyclonal origins of tumorigenesis in FAP. We characterize and contrast the genomic landscape and relative timing of driver mutation acquisition across normal to dysplastic and invasive colon tissue and compare this with multi-region sequencing data from sporadic colorectal cancers (CRC). We find that only early sporadic CRC drivers are common across the more heterogeneous premalignant stages. Selection, as assessed based on the ratio of nonsynonymous to synonymous mutations (dN/dS), is higher in benign than dysplastic FAP lesions and in sporadic adenomas relative to carcinomas. Phylogenetic reconstruction and pairwise sample comparisons reveal extensive heterogeneity and subclonal sharing within a patient’s benign and dysplastic lesions. Using a mechanistic mathematical model, we infer polyclonality for 90-100% of benign and 53-83% of dysplastic samples. Based on these findings, we propose a conceptual framework for the polyclonal origin of intestinal malignancies where inconsequential mutations, arising during colon formation in utero, are present across the colon and are valuable markers to uncover polyclonal ancestry. Citation Format: Ryan O. Schenck, Aziz Khan, Aaron M. Horning, Edward D. Esplin, HTAN Consortia, William J. Greenleaf, James M. Ford, Michael P. Snyder, Christina Curtis. The polyclonal path towards malignant transformation in familial adenomatous polyposis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B008.

Desmoid Tumours: Experience of the Medical Oncology Department of Pierre and Marie Curie Center Algiers

Introduction Desmoid tumours, also known as aggressive deep fibromatoses, are soft tissue tumours. Histologically benign, they are characterised by a slow infiltrative course with a high rate of local recurrence. Patients and methods: We report a retrospective series of 10 patients treated in the medical oncology department of the Pierre & Marie Curie Centre over a period of 4 years. 6 were women and 4 men, with a sex ratio of 1.5 in favour of women. The average age was 36 [23-53]. 20% (n=2) of patients had familial adenomatous polyposis. 90% of patients had an extra-abdominal desmoid tumour compared with only 10% in the abdominal wall. 50% of patients underwent initial resection, 60% of whom recurred after 1 year. Only one patient underwent additional radiotherapy. Initial surveillance was proposed in 50% of patients. 60% progressed after 2 years. Only one patient underwent surgical treatment combined with radiotherapy after an initial monitoring period of 9 years. Treatment with IMATINIB 400mg/d was initiated in 60% (n=6) of patients after progression or local recurrence. One patient received tamoxifen for one year. Results: Lesion stability was observed in 6 patients (60%), a partial response (left scapular) in 1 patient and local progression in 1 patient. Tolerability: Grade 3 neutropenia in 1 patient and Grade 2 liver toxicity. Conclusion : Desmoid tumours are rare tumours which progress slowly and are locally aggressive. Their prognosis is closely linked to their recurrence. The current therapeutic approach advocates a "WAIT AND SEE" strategy, particularly in asymptomatic, non-progressive forms. Surgery is only indicated if the immediate vital or functional prognosis is at risk.

Bleeding after endoscopic papillectomy and its risk factors: A single center experience of 196 cases

BackgroundEndoscopic papillectomy (EP) is an effective method to remove an ampulla of Vater (AoV) adenoma with minimal invasiveness. We reviewed the clinical outcomes and prognosis of patients undergoing EP, including tumor recurrence and adverse events. MethodsA total of 196 patients who underwent EP from January 2004 to December 2017 were included. Clinical information was collected through electronic medical records, and risk factors to predict post-procedural bleeding were analyzed using a multivariate logistic regression model. ResultsA total of 93.9% patients (184/196) underwent complete resection. During the follow-up period, 14.7% patients (27/184) experienced tumor recurrence, and two of seven surgically resected tumors were malignant. A total of 45.4% patients (89/196) experienced adverse events related to EP. Delayed bleeding occurred in 16.3% of the patients (32/196), and they were all successfully treated with endoscopic hemostasis and conservative management. The most frequent site of delayed bleeding was the distal end of the papillary orifice, and 56.2% (18/32) patients of delayed bleeding were classified as having mild severity, the others had moderate severity. Familial adenomatous polyposis (FAP) [odds ratio (OR) = 3.80, 95% confidence interval (CI): 1.01-14.29; P < 0.05] and male sex (OR = 2.82, 95% CI: 1.04-7.63; P = 0.04) showed statistical significance in predicting delayed post-EP bleeding. ConclusionsEP for AoV adenoma was a highly effective and safe procedure. The risk of post-EP delayed bleeding was increased in patients with FAP syndrome and male patients, and post-EP bleeding occurred most commonly in the distal part of the AoV.

The Spigelman Staging System and the Risk of Duodenal and Papillary Cancer in Familial Adenomatous Polyposis: A Systematic Review and Meta-Analysis.

Individuals with familial adenomatous polyposis (FAP) have an almost 20% lifetime risk of duodenal adenocarcinoma, currently the leading cause of death in FAP. The Spigelman staging system provides guidance on the surveillance intervals and timing of prophylactic surgery. Still, its accuracy in predicting duodenal and papillary cancer development has not been systematically evaluated. We investigated the sensitivity and cancer risk of the Spigelman stages. We performed a systematic review on PubMed, MEDLINE, EMBASE, and Cochrane and used a random-effects model to pool effect sizes. After removing duplicate entries, we screened 1,170 records and included 27 studies for quantitative analysis. Once duodenal polyposis reaches Spigelman stage IV, the risk of duodenal and papillary cancers increased to 25% (95% confidence interval [CI] 12%-45%). However, the sensitivity of Spigelman stage IV for these cancers was low (51%, 95% CI 42%-60%), especially for papillary adenocarcinoma (39%, 95% CI 16%-68%). We investigated the reasons behind these low values and observed that duodenal cancer risk factors included polyps >10 mm, polyp count >20, and polyps with high-grade dysplasia. Risk factors associated with papillary cancer included a papilla with high-grade dysplasia or >10 mm. The evidence on other risk factors was inconclusive. The current Spigelman staging system had a low sensitivity for duodenal and papillary adenocarcinomas. Two Spigelman variables (duodenal villous histology and polyp count) and the lack of papilla-specific variables likely contributed to the low sensitivity values for duodenal and papillary cancers, respectively. While clinicians may be familiar with its current form, there is an urgent need to update it.

Black raspberry-mediated metabolic changes in patients with familial adenomatous polyposis associated with rectal polyp regression.

Familial adenomatous polyposis (FAP) patients face an almost certain 100% risk of developing colorectal cancer, necessitating prophylactic colectomy to prevent disease progression. A crucial goal is to hinder this progression. In a recent clinical trial involving 14 FAP patients, half received 60 g of black raspberry (BRB) powder orally and BRB suppositories at bedtime, while the other half received only BRB suppositories at bedtime over 9 months. This intervention led to a notable reduction in rectal polyps for 11 patients, although 3 showed no response. In this study, we delved into the metabolic changes induced by BRBs in the same patient cohort. Employing mass spectrometry-based non-targeted metabolomics, we analyzed pre- and post-BRB urinary and plasma samples from the 11 responders. The results showed significant alterations in 23 urinary and 6 plasma metabolites, influencing various pathways including polyamine, glutathione metabolism, the tricarboxylic acid cycle, inositol metabolism, and benzoate production. BRBs notably elevated levels of several metabolites associated with these pathways, suggesting a potential mechanism through which BRBs facilitate rectal polyp regression in FAP patients by modulating multiple metabolic pathways. Notably, metabolites derived from BRB polyphenols were significantly increased post-BRB intervention, emphasizing the potential therapeutic value of BRBs in FAP management.

Differential Diagnoses and Management Approaches for Gastric Polyposis

Multiple gastric polyps are observed in various polyposis syndromes and conditions associated with polypoid lesion development in the stomach. Polyposis syndromes often occur concurrently with specific malignant tumors and can manifest at any point in an individual’s lifespan, thus explaining the diversity in surveillance methods. Furthermore, genetic counseling and surveillance are essential not only for the patients themselves but also for their blood relatives. Therefore, the accurate diagnosis and appropriate surveillance of multiple gastric polyps are crucial for improving patient outcomes. This review aims to provide essential information on such lesions along with representative endoscopic images of familial adenomatous polyposis, Peutz-Jeghers syndrome, Cowden syndrome, Cronkhite-Canada syndrome, juvenile polyposis syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, neuroendocrine tumors in autoimmune gastritis, proton pump inhibitor-related gastric mucosal changes, and multiple submucosal heterotopic glands. We wish for this review to serve as a valuable resource for endoscopists seeking to deepen their comprehension of gastric polyposis.

MUCOSAL SINGLE-CELL PROFILING OF CROHN’S-LIKE DISEASE OF THE POUCH REVEALS COMMON PATHOGENICS AND THERAPEUTIC TARGETS

Abstract BACKGROUND &amp; AIMS After restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC), a subset of patients develop Crohn’s-like disease of the pouch (CDP), an inflammatory condition that affects both the ileoanal pouch and extra-pouch organs including pre-pouch ileum. The cellular and molecular identities of CDP are unknown, and its diagnosis and treatment remain challenging. To define the pathophysiology of CDP, we examined mucosal cells from patients with and without CDP using single cell analyses. METHODS Endoscopic samples from the pouch and pre-pouch ileum of 50 patients with an IPAA were collected for single-cell RNA sequencing (scRNA-seq) or mass cytometry (or CyTOF). We analyzed immune and non-immune cells from pouch and ileal tissues of patients with normal pouch/ileum and CDP (n = 5 or 6) using scRNA-seq. CyTOF was performed on mucosal immune cells from independent cohorts of patients with normal pouch/ileum, CDP, and pouchitis (n = 9 or 10). Mucosal samples from patients with familial adenomatous polyposis (FAP) after pouch formation were also analyzed by CyTOF. Some scRNA-seq and CyTOF findings were independently validated using immunohistochemistry (n = 6 or 8). RESULTS We revealed distinct immune and non-immune cell clusters in normal pouch and pre-pouch ileum. Colitogenic immune cells expanded in normal UC pouch compared to normal FAP pouch. Compared to normal pouch/pre-pouch ileum, CDP tissues exhibited expanded TCR clonotypes, elevated Th17 signaling, and diminished T cell exhaustion markers. Elevated frequencies of plasma cells, inflammatory fibroblasts and monocytes were noted in CDP pouch and ileum (Fig 1; only pouch data were shown). CDP also harbored elevated Th17-inducing cytokines such as IL23, IL1B, and IL6 produced by myeloid cells. ScRNA-seq and CyTOF identified increased CD14+TREM1+ pathogenic monocytes in both pouch and pre-pouch ileum of CDP. Ligand-receptor interactions further uncovered an essential role of proinflammatory myeloid cells in the pathogenesis of CDP. In addition, pouch and pre-pouch ileum of CDP showed prominent activation of the unfolded protein response (UPR) across all major cell compartments (Fig 2), which was not present in UC, CD or pouchitis based on integrated analysis of published databases. CONCLUSIONS CDP demonstrates altered immune and non-immune cell populations/states in the pouch and pre-pouch ileum. CDP represents a distinct entity of inflammatory bowel disease with extensive UPR activation, a unique feature that may serve as novel diagnostic markers and therapeutic targets using ER stress-alleviating agents including chemical chaperones. Fig 1 CDP reshapes immune and non-immune landscapes in pouch and pre-pouch ileum. (A) UMAP visualization of all cells from the pouch and ileum of CLDP and normal controls. (B) Diversity of epithelial cells, stromal cells, myeloid cells, T cells, innate lymphoid cells (ILCs), B cells and plasma cells in CLDP vs. normal controls in the pouch estimated by scRNA-seq (n = 5 or 6). *p&amp;lt;0.01. Fig 2 Extensive UPR activation in CDP tissues. (A) UPR gene expression in major cell compartments in CDP and normal controls, highlighted genes including CALR, XBP1, and SERP1 were upregulated in all 5 cell compartments. (B) ER stress/UPR pathways are enriched in CDP. (C) IHC of UPR proteins XBP1 and HSPA5/BiP.

DOP41 Mucosal single-cell profiling of Crohn's-like disease of the pouch reveal unique pathogenesis and therapeutic targets

Abstract Background After restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC), a subset of patients develop Crohn’s-like disease of the pouch (CDP), a chronic inflammatory condition that affects both the pouch body and extra-pouch organs including the pre-pouch ileum. The cellular and molecular identities of CDP are unknown, and its diagnosis and treatment remain challenging. To define the pathophysiology of CDP, we examined mucosal cells from patients after IPAA with and without CDP using single cell analyses. Methods Endoscopic samples from the pouch body and pre-pouch ileum of 50 patients with an IPAA were collected for single-cell RNA sequencing (scRNA-seq) or mass cytometry (or CyTOF). We analyzed immune and non-immune cells from both pouch body and pre-pouch ileum of patients with normal pouch/ileum and CDP using scRNA-seq. CyTOF was performed on mucosal immune cells from independent cohorts of patients with normal pouch/ileum, CDP, and pouchitis. Mucosal samples from patients with familial adenomatous polyposis (FAP) after colectomy and pouch formation were also analyzed by CyTOF. ScRNA-seq and CyTOF findings were independently validated using immunohistochemistry. Results We revealed distinct cell clusters in normal pouch body versus normal pre-pouch ileum in UC patients. Colitogenic immune cells expanded in normal UC pouch body compared to normal FAP pouch body. Compared to normal pouch/ileum, CDP pouch/ileum exhibited expanded TCR clonotypes, elevated Th17 signaling, and diminished T cell exhaustion markers. Elevated plasma cells, inflammatory fibroblasts and monocytes were noted in CDP pouch/ileum (Figure 1). CDP also harbored elevated Th17-inducing cytokines such as IL23, IL1B, and IL6 produced by myeloid cells. ScRNA-seq and CyTOF identified increased CD14+TREM1+ pathogenic monocytes in both pouch body and pre-pouch ileum of CDP. Ligand-receptor analysis further revealed a stromal – myeloid – lymphocyte circuit in CDP. Integrated analysis showed that upregulated immune mediators in CDP tissues were similar to those in CD and pouchitis, but not UC. In addition, the pouch body and pre-pouch ileum of CDP exhibited prominent activation of the unfolded protein response (UPR) across all major immune and non-immune cell compartments (Figure 2), which was not present in UC, CD or pouchitis based on reanalysis of published databases. Conclusion CDP demonstrates altered immune and non-immune cell populations/states in the pouch body and pre-pouch ileum. CDP represents a distinct entity of inflammatory bowel disease with extensive UPR activation, a unique feature that may serve as novel diagnostic markers and therapeutic targets using ER stress-alleviating agents including chemical chaperones.

P725 Predictive factors for biologic therapy initiation after ileal pouch-anal anastomosis

Abstract Background Patients with ulcerative colitis (UC) undergoing proctocolectomy and Ileal Pouch-Anal Anastomosis (IPAA) frequently develop long-term complications, such as chronic pouchitis and Crohn’s-like disease of the pouch. These may eventually require biologic therapy. We aimed to identify peri-operative predictors for biologic therapy after IPAA. Methods All patients after IPAA followed at Rabin Medical Center pouch clinic and consenting to prospective observational follow up were included. Patients undergoing IPAA due to familial adenomatous polyposis (FAP) and those with ileostomy were excluded. Primary outcome was the initiation of biologic therapy after IPAA. We used Cox proportional hazard models to evaluate the following potential predictors: gender, race, smoking status, BMI category, UC duration until surgery, surgery indication, immediate post-operative complications (bowel obstruction, infection and leakage), and pre-operative treatment with 5-ASA, steroids, immunomodulators, and biologic therapy. Results Out of 174 patients in our cohort, 18 were excluded due to FAP and 8 due to ileostomy, leaving 148 for analysis. Prior to IPAA, 52 patients (35%) were treated with biologic therapy. Median follow-up from ileostomy closure to last documented visit was 15.14 years. During this period, 32 patients (21.6%) initiated biologic therapy, including 18 with adalimumab (12.2%), 10 with infliximab (6.7%), 2 with ustekinumab (1.3%), 1 with golimumab (0.6%), and 1 with vedolizumab (0.6%). Median time-to biologic therapy initiation was 10.1 years (IQR 10.0). Significant hazard ratios (HR) for biologic therapy initiation were pre-operative treatment with biologic therapy (HR 4.8, 95% CI; 2.3-10, p&amp;lt;0.001); Arab descent (HR 4.7, 95% CI; 1.6-14, p=0.005); pre-operative treatment with immunomodulators (HR 3.0, 95% CI; 1.3-7, p=0.011); UC duration of less than 10 years before ileostomy closure (HR 2.7, 95% CI; 1.2-6.3, p=0.02); past smoking status (HR 2.6, 95% CI; 1.22-5.7, p=0.013); and immediate post-operative complications (HR 2.0, 95% CI; 1.0-4.1, p=0.05). None of the patients undergoing IPAA due to dysplasia (n=27), required biologic therapy. Conclusion Pre-operative treatment with either biologic therapy or immunomodulators, Arab descent, short disease duration prior to IPAA, past smoking status, and post-operative complications were significant predictors of biologic therapy initiation post-IPAA. Patients with these risk factors may benefit from closer post-operative follow-up and earlier initiation of biologic therapy.

P503 Differentiation of patients with IBD at increased risk of CRC using UR-CARE: A Single Centre Experience

Abstract Background The United Registries for Clinical Assessment and Research (UR-CARE) platform aims to facilitate and improve the daily clinical care of patients with Inflammatory Bowel Disease (IBD). The possibility of updating the medical data in UR-CARE at each patient visit allows for strict follow-up and enables the doctor to draw relevant recommendations. The study is aimed at identifying registered IBD patients at increased risk of colorectal cancer (CRC) via UR-CARE. Methods Outpatients and inpatients with a confirmed IBD diagnosis, who had signed informed consent, were entered with their clinical data in UR-CARE to the centre UMHAT “Tsaritsa Yoanna-ISUL”. Only the statistical and filter opportunities of the digital platform were used. The study was conducted with our own data from our centre database. Results 274 IBD patients (120 with ulcerative colitis [UC], 144 with Crohn’s disease [CD] and 10 with IBD unclassified [IBD-U]) were entered in UR-CARE. Among all registered patients, colorectal dysplasia was entered for 19 (6.93%) persons (15 males; 14 with UC). The column for “Dysplasia” in the drop-down menu could be left empty. These 19 patients with colorectal dysplasia make up 7.98% of all 238 patients with filled in one of the three options for dysplasia. 7 (2.55%) IBD patients (5 males; 5 with UC) had primary sclerosing cholangitis, and for two of them with UC, colorectal dysplasia was entered. Among all registered IBD patients, four had undergone surgery for CRC, and one patient was operated on for familial adenomatous polyposis. UR-CARE filtered 73 patients with extensive and left-sided UC with a duration of UC ≥ 8 years who should undergo screening colonoscopy for dysplasia. Conclusion UR-CARE can quickly and effectively differentiate patients with IBD and at an increased risk of developing CRC. It enables the provision of graphic data and provides access to the files of patients at high risk of CRC, allowing for their individual follow-up.

Risk of gastric adenoma and adenocarcinoma in patients with familial adenomatous polyposis in Japan: a nationwide multicenter study

BackgroundPatients with familial adenomatous polyposis (FAP) have an increased risk of developing gastric neoplasms. However, the clinical course of FAP with these gastric lesions has not yet been fully clarified. The present study aimed to clarify the changes in the incidence risk of developing gastric adenoma or gastric cancer during the lifespan of patients with FAP.MethodsFour hundred forty-three patients with data regarding gastric adenoma and gastric cancer retrospectively registered in a nationwide Japanese multicenter study were enrolled. The cumulative incidences and hazard rates (HRs) of gastric neoplasms were evaluated.ResultsThe cumulative incidence rates in 50-year-old patients with FAP were 22.8% for gastric adenoma and 7.6% for gastric cancer, respectively. No significant association was found between gastric neoplasms and the colonic phenotype. The peak age for the HR of gastric adenoma was 65 years, with the highest HR (0.043). Regarding the incidence of gastric cancer, the HR increased moderately up to the age of 40 years, but the increase accelerated from the age of 50 years (HR = 0.0067).ConclusionCareful surveillance of the upper gastrointestinal tract in elderly patients with FAP, such as shortening the interval of follow-up according to age, may be helpful for early diagnosis of gastric cancer.

Gardner Syndrome: A Diagnosis Approach, Clinical Evolution and Review

Introduction: Gardner Syndrome is characterized as an autosomal and dominant genetic mutation. Case Presentation: A 28-year-old man from the state of Gioias arrived at the emergency room accompanied by family members, complaining of recurrent diarrhoea with the presence of mucus and blood, in addition to cramps, abdominal distension, rectal tenesmus and episodes of metrorrhagia. After a thorough investigation, the patient reported having a lesion of about 2 cm in size on the left frontal region, with a firm and fixed consistency, which appeared more than 2 years ago and suggests bone involvement. He also mentioned having sought medical attention 5 years ago due to dental problems and recurrent skin lesions, characterized by cystic lesions, but there was no further investigation at the time. Discussion: It is a syndrome with a variant of familial adenomatous polyposis, presenting a wide range of clinical manifestations, with significant intestinal involvement, as well as osteomas and soft tissue tumours, which in general precede the intestinal clinical picture. The diagnosis of Gardner's Syndrome is made with multiple tools, involving clinical, radiological, endoscopic and genetic exams, and, being early, there is a significant improvement in prognosis. In order to avoid the malignant progression of intestinal polyps, prophylactic colectomy is indicated in most cases, but it is necessary to individualize the follow-up according to the phenotype of the disease. Conclusion: Patients with GS should be screened for intracolonic malignancy annually, as desmoid tumours are a common feature of GS/FAP, resulting in significant morbidity. and even mortality. Thus, early diagnosis, once again, will contribute to a better quality of life in the long term.

Clinicopathologic characteristics of patients with early-onset colorectal cancer.

74 Background: Although the incidence of colorectal cancer has been declining in the United States in recent years, the incidence of young patients under 50 years of age has been reported to be increasing by several percent per year. Various studies have been conducted to characterize early-onset colorectal cancer (EO-CRC); however, it has been unclear whether it is a different entity from late-onset colorectal cancer (LO-CRC). In this study, we evaluated the clinicopathologic characteristics of EO-CRC in Japan. Methods: This study included 1,336 patients who underwent surgical resection for colorectal cancer at Tokyo Metropolitan Komagome Hospital from January 2015 to December 2019. We performed genetic testing for patients with suspected Lynch syndrome after providing genetic counseling and obtaining informed consent. The study protocol was approved by the Institutional Review Board. Results: Of the 1,336 colorectal cancer patients, 117 (8.9%) had EO-CRC with a median age at the diagnosis of 44 (17–49) years. Tumors were located at right-sided colon in 23 patients and left-sided colorectum in 92 patients with EO-CRC, respectively. The clinical stage of the tumor was I in 19, II in 23, III in 50, and IV in 23 patients with EO-CRC, respectively. Histologically, differentiated type, undifferentiated type, and mucinous carcinoma were 106, 5, and 3 patients, respectively. KRAS mutation was detected in 25.0% and BRAF V600E was detected in 4.3% of patients with EO-CRC. In the microsatellite status, MSI-High was detected in 6 (5.1%) patients with EO-CRC, of whom 3 (2.6%) were diagnosed with Lynch syndrome by genetic testing. Causative genes were MLH1 in 2 patients and MSH2 in one patient. In hereditary tumors, 2 patients with familial adenomatous polyposis were included in addition to Lynch syndrome. On the other hand, 1,219 (91.2%) had LO-CRC with 34.5% of KRAS mutation and 6.4% of BRAFV600E. MSI-High was detected in 69(5.7%) patients with LO-CRC，of whom 5 (0.4%) were diagnosed with Lynch syndrome. Lynch syndrome was significantly more common in EO-CRC (p=0.026). Conclusions: The alterations of KRAS and BRAF tended to be more frequent in EO-CRC. The frequency of hereditary CRC was more frequent in EO-CRC than in LO-CRC.

Outcomes in patients with pancreatic and ampullary cancer whose tumors harbor pathogenic APC mutations.

693 Background: APC (adenomatous polyposis coli) is master regulator of the WNT signaling and beta-catenin pathway. Pathogenic (path) mutations in APC are well known for their connection to familial adenomatous polyposis, but germline (G) mutations in APC can give rise to other cancers, and somatic (S) mutations in APC can be found in multiple cancer subtypes. The clinical relevance for tumors that harbor path APC mutations is unknown. Methods: An established database of patients whose tumors have undergone genetic testing (Next-generation DNA sequencing, NGS) was queried for the presence of an APC mutation. Each APC mutation identified was assessed using the NCI Clinvar data base for determination of a path/likely path APC mutation. Patient/disease characteristics and treatment (tx) information were captured from electronic medical record review. Median overall survival (OS) was defined from the time of diagnosis of advanced/metastatic disease until death. Median time to progression (TTP) for each tx regimen was defined from the initiation of tx until documented disease progression. Results: A database of over 13000 patients entered from 2018 to present included 133 patients (1%) with G- or S-APC mutations, of which 41 were identified as path/likely path. Of the 41 patients, 56% were male, 73% were Caucasian and 24% African Americans, with a median age of 67 (range 34-90). Only 32% of patients had known G-APC mutations, but 34% had a second primary cancer, and 37% had a family history of known G-APC mutation-associated cancers. Only one patient had clinical manifestations of a polyposis syndrome. Of the 13 patients with known G-APC mutations, clinical characteristics were similar to the larger group, except that 100% of the G-APC-mutated patients were Caucasian, and the rate of family history of APC-associated cancers was 54%. Fifty-four percent of the overall group of 41 patients had a pathological diagnosis of pancreatic cancer, while the remaining 46% were ampullary or duodenal cancers. (Only 2 patients [5%] had tail of the pancreas cancers). Of the 37 patients who had somatic tumor NGS, only 70% harbored a KRAS gene mutation. For the OS analysis (n=24), the mOS was 11.7 months (range 5.2 – 56.9). Of the 22 patients evaluable for TTP, the mTTP for 5FU-based tx was 5.8 months, and 6.4 months for gemcitabine-based tx. Conclusions: APC-mutated pancreatic and ampullary cancers are uncommon, but exhibit survival rates, as well as TTP on both 5FU and gemcitabine-based txs that are similar to that seen with most pancreatic adenocarcinomas. However, 30% of APC-mutated cancers are KRAS wild type, and may harbor other driving mutations. As the loss of APC function triggers an accumulation of beta-catenin, targeted therapies that inhibit beta-catenin-regulated transcription and downregulate WNT-related signaling could be a promising tx approach for patients whose tumors harbor path/likely path APC mutations.

Genomic alteration in sporadic adolescent and young adult-onset colorectal adenocarcinoma.

154 Background: Colorectal cancer (CRC) incidence is increasing in adults younger than 50 years. This study evaluated genomic alteration in adolescent and young adult (AYA)-onset sporadic CRC patients who aged between 15 and 39 years. Methods: DNA from 90 archived formalin-fixed, paraffin-embedded (FFPE) tissue samples that histologically confirmed adenocarcinoma with proficient mismatch repair tumors at Siriraj Hospital (Bangkok, Thailand) were extracted. Patients who clinically suspected familial adenomatous polyposis were excluded. Gene mutational analysis was performed by next-generation sequencing (NGS) using an Oncomine Comprehensive Assay Plus kit (Thermo Fisher Scientific, Inc., Waltham, MA, USA) and compared with previous reported molecular data in adult-onset CRC from our group. Results: The top 5 mutations frequency observed were TP53, KRAS, FBXW7, PIK3CA, and SMAD4 mutations which were comparable to what reported in adult-onset CRC. However, FBXW7, PIK3CA, NOTCH1, FGFR3, ERBB2, and PTEN were reported more frequent in AYA group. No difference in number of KRAS, NRAS, and BRAF mutations among 2 groups. Table below shows key cancer genes mutation frequencies. Conclusions: This study is the comprehensive report hotspot mutations using NGS in sporadic AYA-onset sporadic CRC patients. The most commonly identified gene mutation frequencies among AYA-onset were similar to those reported in adult-onset, except for FBXW7, PIK3CA, NOTCH1, FGFR3, ERBB2, and PTEN mutations that had a slightly higher frequency. Further studies on larger sample set for genetic and epigenetic landscape are required. [Table: see text]

Treatment of Complex Desmoid Tumors in Familial Adenomatous Polyposis Syndrome by Intestinal Transplantation.

Desmoid tumors are fibroblastic lesions which often have an unpredictable and variable clinical course. In the context of familial adenomatous polyposis (FAP), these frequently occur intra-abdominally, especially in the small-bowel mesentery resulting in sepsis, fistulation, and invasion of the abdominal wall and retroperitoneum. In selected cases where other modalities have failed, the most radical option is to perform a total enterectomy and intestinal transplantation (ITx). In this study, we present our center's experience of ITx for desmoid in patients with FAP. We performed a retrospective review of our prospectively collected database between 2007 and 2022. All patients undergoing ITx for FAP-related desmoid were included. Between October 2007 and September 2023, 144 ITx were performed on 130 patients at our center. Of these, 15 patients (9%) were for desmoid associated with FAP (7 modified multivisceral transplants, 6 isolated ITx, and 2 liver-containing grafts). The median follow-up was 57 mo (8-119); 5-y patient survival was 82%, all with functioning grafts without local desmoid recurrence. These patients presented us with several complex surgical issues, such as loss of abdominal domain, retroperitoneal/abdominal wall involvement, ileoanal pouch-related issues, and the need for foregut resection because of adenomatous disease. ITx is a viable treatment in selected patients with FAP and extensive desmoid disease. The decision to refer for ITx can be challenging, particularly the timing and sequence of treatment (simultaneous versus sequential exenteration). Delays can result in additional disease burden, such as secondary liver disease or invasion of adjacent structures.

Modifiable factors of development and recurrence of adenomatous colorectal polyps (literature review)

Relevance. Adenomatous colorectal polyps are associated with a high risk of developing a malignant tumor. They are considered precancerous conditions and can lead to the development of colorectal cancer. To date, colorectal cancer ranks third in the world in frequency of occurrence among all malignant neoplasms.Objective. Improving the results of diagnosis and surgical treatment of patients with colorectal adenomatous neoplasms by identifying development factors and identifying risk groups for this nosology.Materials and methods. Analysis of literary data.Results. Among the factors leading to the development of colorectal polyps, it is worth noting a genetic predisposition, so by immunoblotting, PCR sequencing of the entire exome in cases of patients with familial dentate polyposis, rare variants of the germ line in the WNK2 gene were identified. Functional studies have shown that variants of the WINK2 germ line affect protein function in the context of the MAPK pathway, a molecular trait of this disease. Also, in the course of many domestic and foreign randomized clinical trials, the following modifiable factors for the development of adenomatous colorectal polyps were identified.Conclusion. The study revealed the factors of development and recurrence of colorectal neoplasms and identified risk groups for this nosology. The study revealed low compliance of patients with respect to changes in certain living conditions (the use of ethyl alcohol and products containing it, tobacco smoking, both active and passive, the fight against obesity and inactivity), which leads to recurrence and increases the risks of malignancy of colorectal polyps.