Diagnosis Of Familial Adenomatous Polyposis Research Articles

Pouch abandonment is extremely rare even in the reoperative setting: A high-volume referral center experience

BackgroundIleal pouch anal anastomosis is the preferred method for restoration of intestinal continuity after proctocolectomy. Successful ileal pouch anal anastomosis requires adequate reach of the ileal mesentery to the pelvis. Reach issues are a common cause for intraoperative pouch abandonment; however, data regarding contemporary abandonment rates are rare and nonexistent in the revisional setting. MethodsA retrospective review was conducted of consecutive ileal pouch anal anastomosis surgery at a single referral center. Both initial or “primary” pouches and revisional pouch surgery were included. ResultsIn total, 447 attempts at pouch anal anastomosis were made, with an 1.6% overall rate of intraoperative abandonment. Pouch abandonment was attributed to inadequate mesenteric reach during 3 surgeries, desmoid tumors in 2 surgeries, and insufficient remaining small bowel in 2 surgeries. Twelve patients required lengthening maneuvers including 6 S pouches (1%) and 6 H pouches (1%). One half (49%) of operations were revisional ileal pouch anal anastomosis surgery. Overall, reach issues led to intraoperative abandonment in only 0.4% of attempted primary pouches and 1.0% of revisional surgeries. A preoperative diagnosis of familial adenomatous polyposis was associated with pouch abandonment (P < .001). ConclusionExtremely low pouch abandonment rates as a result of mesenteric reach can be achieved even in the revisional setting at a high-volume center with institutional expertise. In the revisional setting, intra-abdominal desmoids or the potential for short gut affects pouch abandonment rates as much as reach issues.

Identification of driving genes of familial adenomatous polyposis by differential gene expression analysis and weighted gene co-expression network analysis.

Despite the advancement of new screening strategies and the advances in pharmacological therapies, the cancerization rates of familial adenomatous polyposis (FAP) are stable and even increased in the last years. Therefore, it necessitates additional research to characterize and understand the underlying mechanisms of FAP. To determine the genes that drive the pathogenesis of familial adenomatous polyposis (FAP). We performed on a cohort (GSE111156) gene profile, which consist of four group of gene expressions (the gene expressions of cancer, adenoma and normal tissue of duodenal cancer from patients with FAP were defined as Case N, Case A and Case C respectively, while that of adenoma tissue from patients with FAP who did not have duodenal cancer was Ctrl A). Tracking Tumor Immunophenotype (TIP) website was applied to reveal immune infiltration profile and signature genes of FAP. We merged the genes of key module (pink and midnight module) with signature genes to obtained the biomarkers related with FAP pathogenesis. The expression of these five biomarkers in FAP intratumoral region (IT) and tumor rim (TR) was detected with Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). In total, 220, 23 and 63 DEGs were determined in Cases C, A and N, in comparison to Ctrl A. In total, 196 and 10 DEGs were determined in Cases C and A, separately, as compared to Case N. A total of four biomarkers including CCL5, CD3G, CD2 and TLR3 were finally identified associated with pink module, while only one biomarker (KLF2) associated with midnight module was identified. All biomarkers were evidently raised in FAP IT tissues utilizing qRT-PCR. We identified five potential biomarkers for pathogenesis of FAP to understand the fundamental mechanisms of FAP progression and revealed some probable targets for the diagnosis or treatment of FAP.

Familial Adenomatous Polyposis within the Pediatric Hereditary Polyposis Registry

Background/Objective: &#x0D; 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. &#x0D; Methods: &#x0D; 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. &#x0D; Results: &#x0D; 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. &#x0D; Conclusion/ Future Directions: &#x0D; 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.

Integrated genotype–phenotype analysis of familial adenomatous polyposis-associated hepatocellular adenomas

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene, characterized by numerous colorectal adenomas. In addition, FAP patients may develop extraintestinal manifestations. Several cases of hepatocellular adenomas (HCA) detected accidentally in FAP patients have raised the so-far unsolved question of whether they represent a specific manifestation of FAP or a mere coincidence. To investigate the incidence of liver tumors in FAP patients, we analyzed our diagnostic database from 1991 to 2021. Among the 58 hepatic mass lesions identified, five HCAs occurring in three patients with FAP were identified, and comprehensive morphological, immunohistological, and molecular analysis employing targeted next-generation sequencing was conducted for characterization. The HCAs in this study showed no cytological or histological atypia. They displayed a diffuse, strong positivity for glutamine synthetase but no nuclear beta-catenin immunostaining. In two patients, the adenomas showed moderate immunoreactivity against serum amyloid A. Consistent with the diagnosis of FAP, molecular profiling revealed a pathogenic germline mutation of the APC gene in all analyzed adenomas as well as deleterious somatic second hits. All somatic mutations were localized between codons 1345 and 1577. No mutations were found in the catenin beta 1 gene. HCA in FAP patients can be a specific, although rare, neoplastic manifestation of this inborn disease and represents a distinct subgroup of HCAs. These benign tumors represent an important differential diagnosis for hepatic metastases in FAP patients and require adequate clinical and molecular (diagnostic) assessments for optimal patient guidance.

A Transformable Mucoadhesive Microgel Network for Noninvasive Multimodal Imaging And Radioprotection of a Large Area of the Gastrointestinal Tract.

The lack of noninvasive imaging and modulation of a large area of the gastrointestinal (GI) tract constrain the diagnosis and treatment of many GI-related diseases. Recent advances use novel mucoadhesive materials to coat a part of the GI tract and then modulate its functions. High mucoadhesion is the key factor of the partial coating, but also the limitation for not spreading and covering the lower GI tract. Here, a bismuth-pectin organic-inorganic hybrid complex is screened and engineered into a transformable microgel network (Bi-GLUE) with high flowability and mucoadhesion, such that itcan quickly transit through and coat a large area of the GI tract. In murine and porcine models, Bi-GLUE delivers contrast agents to achieve real-time, large-area GI-tract imaging under X-ray or magnetic resonance modalities and to facilitate the non-invasive diagnosis of familial adenomatous polyposis. Moreover, Bi-GLUE, like an intracorporal radiation shield, decreases the radiotoxicity in a whole-abdomen irradiation rat model. This transformable microgel network offers a new direction that can modulate a large area of the GI tract and may have broad applications for GI-related conditions.

Low adenoma burden in unselected patients with a pathogenic APC variant

PurposeGenomic screening can improve clinical outcomes, but presentation of individuals with risk for polyposis identified via genomic screening is unknown. To inform assessment of clinical utility of genomic screening for polyposis risk, clinical presentation of individuals in an unselected health care system cohort with an APC pathogenic or likely pathogenic (P/LP) variant causative of familial adenomatous polyposis are described. MethodsElectronic health records of individuals with an APC P/LP variant identified via the MyCode program (MyCode APC+) were reviewed to assess adenoma burden and compare it among individuals with a clinical diagnosis of familial adenomatous polyposis and matched variant-negative controls. ResultsThe prevalence of APC P/LP variants in this health care cohort is estimated to be 1 in 2800. Twenty-four MyCode APC+ individuals were identified during the study period. Median age at result disclosure was 53 years. Rate of clinical polyposis was 8%. Two of six participants with a classic region variant and none of those with an attenuated region variant had polyposis. MyCode APC+ participants did not differ from controls in cumulative adenoma count. ConclusionAPC P/LP variant prevalence estimate in the MyCode cohort is higher than prior published prevalence rates. Individuals with APC P/LP variants identified via genomic screening had a low adenoma burden.

Update on Surgical Management of FAP.

Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum. Various genetic variants have been confirmed to be associated with corresponding FAP phenotypes, which play important roles in the diagnosis and surgical treatment of FAP. Generally, proctocolectomy is recommended for FAP patients at the age of 20s. Exceptionally, for patients with attenuated FAP, high-risk of desmoid, chemoprevention therapy, or other circumstances, surgery can be postponed. With the wide application of minimal invasive surgery in colorectal cancer, laparoscopic, robotic surgery, and natural orifice specimen extraction are proved to be feasible for FAP patients, but high-level evidences are needed to confirm their safety and advantages. In the times of precise medicine, the surgical management of FAP should vary with individuals based on genotype, phenotype, and clinical practice. Therefore, in addition to innovation in surgical procedures, investigation in links between genetic features and phenotypes will be helpful to optimize the surgical management of FAP in the future.

Primary Adenocarcinoma at Ileostomy—A Rare Late Complication: Three Cases and Literature Review

Introduction Primary adenocarcinoma at the ileostomy site is a rare complication, with only 57 cases reported in the literature. The primary diagnosis is usually ulcerative colitis (UC) or familial adenomatous polyposis (FAP). Cases We present 3 cases of adenocarcinoma at the ileostomy site. Two of our 3 cases have a previous diagnosis of cancer, with no previous diagnosis of UC or FAP. Discussion Adenocarcinoma at ileostomy is a rare late complication of permanent ileostomy. Possible etiologies are chronic irritation and changes in bacterial flora that lead to metaplasia and cancer development. Conclusion Adenocarcinoma at the ileostomy site is a rare complication with good prognosis if detected early. Diagnosis is by biopsy, and treatment is surgical. A biopsy should be considered in any abnormal growth around the ileostomy.

S1538 Clinicopathologic Characterization and Genotype Correlation of Duodenal Polyposis Among Hispanics With Familial Adenomatous Polyposis

Introduction: Prognosis of individuals with familial adenomatous polyposis (FAP) has improved due to the implementation of specialized surveillance guidelines and prophylactic colectomy. Nonetheless, patients remain at increased risk for other neoplasia such as duodenal cancer. The Spigelman Classification for duodenal polyposis was designed to estimate a patient’s risk for duodenal cancer based on endoscopic and histopathologic findings. Prior studies have reported variation in colonic polyposis burden following a genotype-phenotype pattern according to APC gene mutation. The genotype-phenotype relationship in duodenal polyposis remains less clear. Methods: A total of 71 patients with FAP who had undergone at least one complete esophagogastroduodenoscopy (EGD). Age, sex, tobacco use, alcohol use, and BMI were among the sociodemographic factors evaluated. Study population was divided into mutations in the APC gene between codons 1000-1500 (Group 1) versus mutations before codon 1000 and after codon 1500 (Group 2). All participants were recruited as part of the UPR Medical Sciences Campus IRB approved prospective familiar cancer registry (PURIFICAR - http://purificar.rcm.upr.edu/). Results: Seventy-one patients with genetic diagnosis of FAP were evaluated. Duodenal adenomas were present in 42 (59%) patuents. 120 EGDs were evaluated for the study, with a mean of 1.7 EGDs per patient (Range = 1–4). Patients with duodenal adenomas on EGD were more likely to have APC mutations between codons 1000-1500 (65.7% vs 20%; P = 0.001). Differences in Spigelman stage between the 2 genotype groups were not statistically significant (P-value = 0.86). Furthermore, bivariate analysis of gender, age at last contact, BMI, tobacco use, and alcohol use were not independently associated with Spigelman stage. No cases of duodenal or ampullary cancer were observed after an overall follow-up of 304.6 patient-years. Conclusion: Our study provides the first phenotypic and genotypic characterization of duodenal polyposis among Hispanic patients with FAP. Duodenal polyposis was significantly associated with APC mutations within the 1000-1500 codon cluster. No other clinicodemographic or environmental associations were independently associated with presence of duodenal polyposis; no cases of duodenal cancer were observed in 304.6 patient-years of follow up. Our observations provide insightful information about the impact of APC genetic mutation location and endoscopic surveillance.

Congenital hypertrophy of the retinal pigment epithelium in the patients with familial adenomatous polyposis colon (case report)

Familial adenomatous polyposis is one of the most difficult to diagnose diseases in medical practice, at an early stage, multiple colorectal adenomas are clinically most often not manifested in any way, and at a later stage they inevitably transform into colorectal cancer. Poor clinical manifestation rarely make it possible to establish a diagnosis before the onset of malignancy, so extraintestinal symptoms can be a lifeline in the diagnosis of this disease. Congenital retinal pigment epithelium hypertrophy is a benign tumor that develops from the retinal pigment epithelium and can occur both in an isolated form and in patients with familial adenomatous polyposis of the colon. Unfortunately, in the Russian-language clinical literature there are practically no scientific papers devoted to this problem. Clinical case of patient P., 35 years old, who was routinely admitted to the surgical unit with a diagnosis of familial adenomatous polyposis is presented. During the additional examination, multiple tumor-like lesions of the eyes were revealed according to the type of hypertrophy of the retinal pigment epithelium. From the anamnesis, it was found out that in 2017 the patient underwent a check-up by an ophthalmologist, where an early pathological condition was detected for the first time, but the doctor’s attention was not paid to this clinical manifestation, and the patient was not subsequently referred for a consultation with a coloproctologist with suspicion of familial adenomatous polyposis.

Abstract 5773: A one-stop approach in diagnosing hereditary colorectal cancer: A prospective, proof-of-principle, single-center study

Abstract Background: Colorectal cancer (CRC) remains one of the most commonly diagnosed cancers and a leading cause of cancer-related deaths worldwide. Between 3 and 6% of all CRC cases are attributed to hereditary colorectal cancer (HCRC). It is important to distinguish CRCs that arise hereditarily from those that arise sporadically, because patients with HCRC and their relatives can benefit from intensive clinical management and surveillance. The detection of germline variants using tumor tissue and paired non-cancerous tissue/whole blood cells (WBC) (conventional method) is considered as the gold standard for germline confirmation, but which could introduce high cost and long turnaround time. In this work, we aimed to investigate the feasibility of diagnosing HCRC using only tumor next-generation sequencing data without normal tissue/WBC data. Methods: One-hundred patients with suspected HCRC were prospectively enrolled according to the clinical diagnosis. Both tumor tissue and paired WBC were collected from each patient. Capture-based targeted sequencing using a panel consisting of 41 cancer-related genes was performed on both tumor tissue and WBC sample. The germline variants were identified using conventional and ColonCore method, respectively. The sensitivity and positive predictive value (PPV) of ColonCore method in identifying germline alterations were calculated, when conventional method was used as a reference. Results: A total of 636 alterations were identified using ColonCore method, including 606 somatic alterations and 30 germline alterations. Among the somatic alterations detected from this panel, 599 single-nucleotide variants and 7 copy number variants were observed. The most frequently mutated genes were APC, TP53, and KRAS, occurring in 76%, 66%, and 46% of patients, respectively. For ColonCore analysis, 17, 9, 2, and 2 patients harbored germline pathogenic variants in DNA mismatch repair (MMR) genes, APC, MUTYH, and ATM, respectively. Compared to the conventional method, the sensitivity of ColonCore method in the diagnosis of HCRC achieved 88.5% with a PPV of 82.1%. Next, the diagnostic performance of ColonCore method in Lynch syndrome (LS) and familial adenomatous polyposis (FAP) was subsequently investigated. We found its sensitivity in the diagnosis of LS achieved 100% (with a PPV of 98.8%), which was obviously higher than that in the diagnosis of FAP (70.0% with a PPV of 63.6%). Twenty-three patients identified as having a microsatellite instability (MSI)-high tumor using ColonCore method were also identified as having an MMR-deficient (dMMR) tumor using immunohistochemistry staining analysis. Conclusions: Our study suggests that ColorCore method is a one-stop approach for detecting germline/somatic alterations and MSI/dMMR status for suspected HCRC. Furthermore, ColorCore method is a feasible and valid tool to diagnose HCRC, especially LS. Citation Format: Cong Li, Yun Xu, Fangqi Liu, Ye Xu. A one-stop approach in diagnosing hereditary colorectal cancer: A prospective, proof-of-principle, single-center study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5773.

The Mutation Spectrum and Two Novel Point Mutations in the APC Gene in Vietnamese Patients with Familial Adenomatous Polyposis.

Background: Familial adenomatous polyposis (FAP) is a hereditary disorder primarily caused by germline mutations in the APC gene. The most common type of mutation in the APC gene is point mutation, while deletion mutation is much less frequent. The current study was conducted to investigate the mutation spectrum of the APC gene in Vietnamese FAP patients. Methods:Patients with the clinical diagnosis of FAP on colorectal endoscopy were screened for mutations in the APC gene using Sanger sequencing. Those who exhibited no point mutation subsequently underwent MLPA assay to detect deletion and duplication mutations. Besides, the relatives of patients with mutated APC genes were recruited for detecting carrier status. Results:Sixty-three patients with clinical colorectal polyposis were recruited. Mutations in the APC gene were detected in 26/63 patients (41.3%). Genetic analysis of 105 asymptomatic relatives of these 26 patients found mutations in the APC gene in 55 individuals (52.4%). Conclusion:We successfully established the APC gene mutation spectrum in Vietnamese FAP patients for the first time. Of importance, we discovered two novel point mutations in the APC gene. The high prevalence of carrier status in asymptomatic family members of patients with mutation emphasizes the crucial role of appropriate genetic screening for early diagnosis, surveillance, and preventive measurements.

Morphological Analyses of Colorectal Adenocarcinomas in Japanese Familial Adenomatous Polyposis Patients.

Objectives: This retrospective study was conducted to clarify the morphological characteristics of colorectal cancer (CRC) in Japanese familial adenomatous polyposis (FAP) patients. Methods: This study was carried out by the study group for FAP of the Japanese Society for Cancer of the Colon and Rectum. FAP patients who underwent surgical resection between 2000 and 2012 were included in the study. Results: Of the 303 patients enrolled, 119 patients without CRC were excluded. Of 523 lesions, 49 lesions with missing morphological information were excluded; hence, only 474 CRC lesions in 178 patients (328 superficial lesions in 122 patients and 146 non-superficial lesions in 92 patients) were included in the study. Depressed lesions accounted for 3.0% of superficial lesions and ulcerated lesions accounted for 84.9% of non-superficial lesions. The depressed superficial lesions were observed only in patients with sparse and attenuated FAP (P = 0.003). The age of the patients at surgery differed between the two groups, with patients with depressed superficial lesions being significantly older than those with non-depressed superficial lesions (P = 0.009). Moreover, the age of the patients at FAP diagnosis differed between the two groups, with patients with ulcerated non-superficial lesions being significantly older than those with protruded non-superficial lesions (P = 0.006). Conclusions: In patients with FAP, depressed superficial CRC lesions rarely developed but were detected in our study group, and ulcerated non-superficial CRC lesions were also present with similar ratios. Clinicians should pay attention to depressed superficial lesions during endoscopic surveillance of FAP patients.

Long-term prognosis of familial adenomatous polyposis with or without mucosectomy.

This study primarily aimed to compare the long-term prognosis of patients who underwent total colectomy/proctocolectomy with or without mucosectomy to the dentate line for the diagnosis of familial adenomatous polyposis (FAP). Patients who underwent total colectomy/proctocolectomy for FAP between January 1979 and December 2020 and were followed up at Hamamatsu University Hospital were included in this study. Those who underwent total proctocolectomy with hand-sewn ileal pouch-anal anastomosis were defined as the mucosectomy group. Those who underwent total colectomy or total proctocolectomy using the stapled ileal pouch-anal anastomosis approach were defined as the no mucosectomy group. A total of 61 individuals (37 families) were diagnosed during the surveillance period (median, 191months). Between the mucosectomy (n = 24) and no mucosectomy groups (n = 34), metachronous rectal cancer was significantly more common in the no mucosectomy group (21% in no mucosectomy vs. 0% in mucosectomy, P = 0.02). Overall survival in the no mucosectomy group was worse than that in the mucosectomy group (84.5% in no mucosectomy vs. 100% in mucosectomy at 120months, 81.1% vs. 90.0% at 240months, 50.6% vs. 75.0% at 360months, P = 0.09). Cox regression analysis revealed an independent effect of not performing mucosectomy on overall survival (P = 0.03). Long-term surveillance revealed that colectomy or total proctocolectomy without mucosectomy had a negative impact on the overall survival of patients with FAP. Therefore, we recommend total proctocolectomy with mucosectomy, i.e., hand-sewn ileal pouch-anal anastomosis, for FAP.

Recent trends in the morbidity and mortality in patients with familial adenomatous polyposis: a retrospective single institutional study in Japan.

This study aimed to assess current trends in morbidity and mortality among patients with familial adenomatous polyposis (FAP). These data can be used for optimal surveillance and management of such patients. Data (November 2001 and April 2020) of genetically confirmed patients with FAP (n = 87) and their first-degree relatives with FAP phenotype (n = 20) were extracted from the Saitama Medical Center database. Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) were estimated using indirect method. Overall, 46 men and 61 women were included; the median age at FAP diagnosis was 28.0years for both. The SMR for all causes of death was 47.7 (95% confidence interval [CI] 19.1-98.2) in women and 26.5 (95% CI 9.73-57.8) in men. The SIR for colorectal cancer (CRC) was 860 (95% CI 518-1340) in women and 357 (95% CI 178-639) in men. The SMR for CRC was 455 (95% CI 93.7-1330) in women and 301 (95% CI 62.0-879) in men. Thirteen patients died during the observation period, and CRC was the leading cause of death (46%). Other causes of death included desmoid tumor (n = 2), small intestinal cancer (n = 2), ovarian cancer (n = 1), duodenal cancer (n = 1), and sepsis (n = 1). The mortality ratio, estimated using SMR, remained high. CRC was the leading cause of death, whereas almost half of the causes of deaths were extra-colonic tumors. Life-long management of extra-colonic diseases may improve the prognosis in these patients.

A Rare Case of Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is rare one.1 of colorectal cancer associated with FAP. It is a precancerous condition and is having 100 malignant potential. FAP is present in younger age group, so proper screening and prophylactic total colectomy is required. FAP is an autosomal dominant disease that results from mutation in the adenomatous polyposis coli (APC) gene located on chromosome5q21-22. One third of all cases of FAP have nil family history of FAP, and these cases are thought to be caused by a new germ-line mutation. The diagnosis of FAP is based on the detection of more than 100 adenomatous Colon polyps. We had a case of FAP in a 37-year-old man with history of abdominal pain and bleeding per rectum for 6 months.

Presentation, management and outcomes of ileoanal pouch cancer: a single-centre experience.

This study aimed to determine the clinical presentation, management and outcomes for patients with ileoanal pouch cancer. Patients who were diagnosed with ileoanal pouch cancer were identified from our polyposis registry (1978-2019) and operative and referral records (2006-2019). Details of presentation, endoscopic surveillance, cancer staging and management were retrieved from hospital records. Eighteen patients were identified (12 with ulcerative colitis, one with Crohn's disease, three with familial adenomatous polyposis [FAP], two with dual diagnosis of FAP and inflammatory bowel disease). The median time from pouch formation to cancer diagnosis was 16.5years (range 5-34years) and the median age of the patient at pouch cancer diagnosis was 54years (range 35-71years). Eleven of the 18 patients were undergoing surveillance. Four of five FAP patients developed pouch cancer whilst on surveillance. Eight patients were asymptomatic at the time of pouch cancer diagnosis. Two patients had complete clinical response following chemoradiotherapy. Fourteen patients underwent pouch excision surgery (eight with exenteration). Median survival was 54months; however, only eight patients had outcomes available beyond 24months follow-up. Pouch cancer can occur in patients despite routine surveillance and without symptoms, and survival is poor. Centralization of 'high-risk' patients who require surveillance is recommended and a low threshold for referral to centres that can provide expert investigation and management is advised.

Genetic Background of Chronic Active Epstein-Barr Virus Disease

IntroductionEpstein-Barr virus (EBV) is associated with various benign and malignant diseases. Chronic active EBV disease (CAEBV) is a rare EBV-associated disease characterized by persistent EBV infection in natural killer (NK) and/or T cells, which is mainly prevalent in East Asia. While patients with CAEBV initially present with persistent or recurrent symptoms similar to ones present in infectious mononucleosis (IM), they often develop peripheral NK/T-cell lymphoma or multiple organ failure in the long run, and prognosis is dismal.Numerous aspects of the molecular pathogenesis of CAEBV are unresolved; it is unclear whether this disease is a clonal disorder. Although several case reports indicate the presence of primary immunodeficiency (PID) in patients with persistent EBV disease, the prevalence of PID or other inherited diseases in patients with CAEBV remains unclear. To reveal the genetic background of CAEBV, we performed whole-exome and targeted sequencing.Patients and MethodsWe studied 83 patients with CAEBV. The diagnosis of CAEBV was based on the fulfillment of the following criteria: (1) persistent or recurrent symptoms similar to those present in IM, (2) increased quantities of EBV viral load in either affected tissues or peripheral blood, and (3) exclusion of other possible diagnoses. The Institutional Review Board of Nagoya University Graduate School of Medicine approved this study.We performed whole-exome sequencing (WES) of T-, B-, and NK-cell subsets. Subsequently, we performed targeted gene sequencing of 605 genes associated with PID, inherited blood diseases, and hematological malignancies.ResultsRegarding germline mutations, we identified two patients who carried nonsense mutations in EVC2, which led to the diagnosis of Weyers acrofacial dysostosis (WAD). We also identified a patient who carried POLH mutations, which led to the diagnosis of the variant type of xeroderma pigmentosum, and a patient who carried an APC mutation, which led to the diagnosis of familial adenomatous polyposis. Mutations leading to the diagnosis of PID were not identified in any patient.WES led to the identification of at least one somatic mutation in 58% of patients. We identified DDX3X (n= 14; 16%), KMT2D (n= 4; 4.8%), BCOR / BCORL1 (n= 3; 3.6%), KDM6A (n= 3; 3.6%), and TET2 (n= 2; 2.4%) as undergoing recurrent mutations.We analyzed multiple EBV-infected cell subsets within a patient. One patient (UPN125) developed CAEBV in which both T and NK cells were positive for EBV DNA. The patient's CD4+ and CD56+ cells carried 21 and 27 mutations, respectively, of which 8 were shared including a DDX3X p.Arg534Cys driver mutation. Similar to UPN125, CD3+ and CD56+ cells of UPN404 carried a shared DDX3X p.Thr198Pro mutation and private mutations. CD19+ cells of UPN404 also carried the identical DDX3X mutation.In the survival analysis, patients carrying DDX3X mutations at diagnosis demonstrated a significantly worse OS compared with others (5-year OS: 40.6% vs. 78.6%; P= 0.007). Patients carrying KMT2D mutations also demonstrated poor prognosis (5-year OS: 50.0% vs. 73.9%; P= 0.02).DiscussionIn the present study, we found that CAEBV was a malignant disease carrying somatic driver mutations, the spectrum of which showed similarity with that of extranodal NK/T-cell lymphoma (ENKTL) and Burkitt lymphoma. DDX3X mutations and other shared mutations, which were present in multiple cell subsets in a patient, strongly suggest the presence of common ancestry, possibly lymphoid progenitor cells, which acquired driver mutations.We identified the presence of somatic DDX3X mutations as a marker of poor prognosis. A prospective study can be designed using genetic testing for DDX3X mutations and subsequent interventions, possibly chemotherapies used for ENKTL and early hematopoietic stem cell transplantation, to improve patient outcome.Furthermore, we identified several germline mutations. WAD caused by EVC / EVC2 mutations is characterized by the malformation of mesoderm and ectoderm caused by decreased hedgehog signaling mediated via EVC/EVC2 . Together with POLH and APC mutations, EVC / EVC2 mutations may be a genetic predisposition to CAEBV.In conclusion, we revealed the genetic background of CAEBV, which will lead to further clarification of its molecular pathogenesis and the development of therapeutic strategy. Clinical trials utilizing genetic diagnosis and stratified therapy are warranted. DisclosuresNo relevant conflicts of interest to declare.

Assessment of circulating microRNA specific for patients with familial adenomatous polyposis.

Circulating microRNAs (miRNAs) are considered promising biomarkers for diagnosis, prognosis, and treatment efficacy of diseases. However, usefulness of circulating miRNAs as biomarkers for hereditary gastrointestinal diseases have not been confirmed yet. We explored circulating miRNAs specific for patients with familial adenomatous polyposis (FAP) as a representative hereditary gastrointestinal disease. Next-generation sequencing (NGS) indicated that plasma miR-143-3p, miR-183-5p, and miR-885-5p were candidate biomarkers for five FAP patients compared to three healthy donors due to moderate copy number and significant difference. MiR-16-5p was considered as an internal control due to minimum difference in expression across FAP patients and healthy donors. Validation studies by real-time PCR showed that mean ratios of maximum expression and minimum expression were 2.2 for miR-143-3p/miR-16-5p, 3.4 for miR-143-3p/miR-103a-3p, 5.1 for miR-183-5p/miR-16-5p, and 4.9 for miR-885-5p/miR-16-5p by using the samples collected at different time points of eight FAP patients. MiR-143-3p/16-5p was further assessed using specimens from 16 FAP patients and 7 healthy donors. MiR-143-3p was upregulated in FAP patients compared to healthy donors (P = 0.04), but not significantly influenced by clinicopathological features. However, miR-143-3p expression in colonic tumors was rare for upregulation, although there was a significant difference by existence of desmoid tumors. MiR-143-3p transfection significantly inhibited colorectal cancer cell proliferation compared to control microRNA transfection. Our data suggested regulation of miR-143-3p expression differed by samples (plasma or colonic tumors) in most FAP patients. Upregulation of plasma miR-143-3p expression may be helpful for diagnosis of FAP, although suppressive effect on tumorigenesis seemed insufficient in FAP patients.

Hearing Status of Children and Adolescents With Familial Adenomatous Polyposis.

Chemopreventative therapeutics may be helpful in familial adenomatous polyposis (FAP) management; however, prospective chemopreventative studies are complicated by potential ototoxicity and pre-existing hearing loss. The aim of this study was to establish and compare baseline hearing status of children and adolescents with FAP and their unaffected siblings. Twenty FAP pediatric patients with documented mutation of the adenomatous polyposis coli (APC) gene and nine unaffected sibling controls underwent baseline hearing evaluation, including audiometry, speech perception testing, and middle and inner ear physiologic measures. Results of the FAP cohort were compared to the unaffected sibling cohort. Two (5%) children with FAP presented with baseline hearing loss of unknown etiology, likely unrelated to their FAP diagnosis. No significant differences were found in any of the hearing measures between groups. Mutation of the APC gene is not necessarily indicative of higher risk for baseline hearing loss in the pediatric population.