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Ileal pouch surgery is the surgical gold standard treatment for patients with ulcerative colitis (UC) and familial adenomatous polyposis (FAP). However, ileal pouch surgery is a technically challenging procedure and is associated with high morbidity. Clinical presentations of pouch complications are often nonspecific but imaging can identify many of these complications and is essential in clinical management. This paper will focus on magnetic resonance imaging (MRI) of the ileal pouch, including recommended MRI protocol and approach to imaging interpretation with an emphasis on those ileal pouch complications particularly well evaluated with MRI., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Fundic gland polyps (FGPs) comprise 66% of all gastric polyps. Although they are usually non-syndromic, they may be associated with various syndromes, including familial adenomatous polyposis (FAP) or gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). We aimed to evaluate how histological features relate to distinct FGP subtypes., Methods and Results: We performed a retrospective analysis of 118 FGPs from 109 patients for the architecture of fundic glands, microcyst lining, parietal cell hyperplasia and surface foveolar epithelial changes. Age, gender and history of FAP or GAPPS were collected. Based on combinations of histological features, three distinct patterns (A, B and C) of FGPs were delineated and correlated to the aetiologies. Non-syndromic FGPs were well-formed polyps composed of disordered fundic glands with intermediate-sized microcysts typically lined by a mixture of oxyntic and mucin-secreting cells (73%). Parietal cell hyperplasia (80%) and foveolar surface hyperplasia (78%) were common. FAP-associated cases demonstrated small microcysts that were predominantly lined by fundic epithelium (77%), with limited parietal cell hyperplasia (27%); foveolar hyperplasia was uncommon. GAPPS-related polyps were the largest, with prominent, mucin-secreting epithelium-lined microcysts (73%). Hyperproliferative aberrant pits were universally present, whereas parietal cell hyperplasia was uncommon. Pattern A was identified in most non-syndromic FGPs (74%) and in a minority of FAP-related FGPs (26%). The majority (82%) of FAP-related FGPs showed pattern B, but only 18% of non-syndromic FGPs did. Pattern C consisted exclusively of GAPPS-associated polyps., Conclusions: We conclude that, although FGPs share similar histomorphology, subtle differences exist between polyps of different aetiology. In the appropriate clinical setting, the recognition of these variations may help to consider syndromic aetiologies., (© 2022 John Wiley & Sons Ltd.)

Introduction: Patients with serrated polyposis syndrome (SPS) and their first-degree relatives (FDRs) have increased colorectal cancer (CRC) risk. Patients with sporadic sessile serrated lesion (SSL) have risk for progression to CRC. Yet familial risks of common extracolonic cancers and even CRC in these cohorts are poorly understood. Our aim was to examine cancer risk for patients with SPS and sporadic SSL and their close and more distant relatives using a large population database., Methods: Patients with SPS (n = 59) from hereditary patient registries were eligible for study. Sporadic SSL (n = 754) and sex- and age-matched normal colonoscopy controls (n = 1,624) were selected from clinical data linked to the Utah Population Database. Cox models adjusting for the number of relatives, degree of relatedness, and person-years at risk were used to estimate CRC, extracolonic, and any-site adenocarcinoma/carcinoma cancer risk in patients and their relatives., Results: Compared with controls, CRC risk was elevated 10-fold in patients with SPS (P = 0.04) and 5-fold in their FDRs (P = 0.001). Any-site adenoma/carcinoma risk was increased 2.6-fold in FDRs of patients with SPS. No elevated risks of other common extracolonic cancers were observed in SPS and family members. The FDRs, second-degree relatives, and third-degree relatives of patients with both SSL and adenomatous polyps exhibited a 50% increased CRC risk., Discussion: Patients with SPS and their FDRs have an increased CRC risk, confirming other reports. Interestingly, patients with SSL were noted to have an increased risk of prostate cancer. Relatives of individuals with both sporadic SSL and adenomas, irrespective of size or dysplasia on examination, may have an elevated CRC risk, suggesting closer colonoscopy surveillance in this population., (Copyright © 2021 by The American College of Gastroenterology.)

Mucosal prolapse syndrome most commonly involves the rectum and presents as solitary rectal ulcer syndrome and proctitis cystica profunda. Symptoms and endoscopic appearances are nonspecific. Histologically, mucosal prolapse is characterized by fibromuscular obliteration of the lamina propria, and displacement of crypts into submucosa and muscularis mucosae. Mucosal prolapse presenting as polyposis is rare and has only been reported involving the rectosigmoid colon. In this report, we describe a case of mucosal prolapse syndrome presenting as diffuse polyposis and colitis cystica profunda involving the hepatic, splenic flexures and descending colon in a teenage boy suffering from refractory fibrostenosing Crohn's disease. This patient was found to have possibly deleterious homozygous single nucleotide polymorphisms in both SULT1A1 and SULT1A2 genes within a unique polygenic variation of altered cell adhesion., (© 2021 by the Association of Clinical Scientists, Inc.)

Germline adenomatous polyposis coli (APC) gene mutation is a cancer-predisposing condition commonly presenting as familial adenomatous polyposis. We describe a patient first diagnosed at the age of 3 years with metastatic hepatoblastoma. With a positive family history, germline testing confirmed maternally inherited APC mutation (p.Thr899Ansfs*13). The patient was subsequently diagnosed at 8 years with colonic adenocarcinoma in the absence of macroscopic polyposis. Total colectomy with adjuvant chemotherapy was delivered and the patient remained disease-free for 5 years since the second diagnosis. This report demonstrates the importance of considering germline APC mutation in children with hepatoblastoma, who may benefit from the early institution of colonoscopic surveillance., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Childhood cancer survivors (CCSs) are at an increased risk for secondary cancers, including colorectal, thyroid, lung, and breast. Treatment with abdominal radiotherapy and/or alkylating agent chemotherapy has been associated with an increased risk for colorectal adenomas and colorectal cancer (CRC) in CCSs. The phenotype of therapy-associated polyposis (TAP) is not well-understood, given the paucity of cases described in the literature. Further defining the phenotype of TAP is important to increase the primary care provider's awareness of when to begin CRC screening in these patients. We present a case of a patient with possible acquired polyposis that seems to meet the criteria identified in the literature for TAP. The purpose of this case study is to add to the body of knowledge related to TAP, further defining the phenotype. Better understanding of therapy-related risks in CCSs and hereditary predisposition will provide primary care providers and their patients with an improved plan for CRC screening.

Turcot syndrome is an association of primary neuroepithelial tumors of the central nervous system with adenomatous polyposis coli. It is a genetic disorder, with two forms; In type I, glioblastomas are usually associated with hereditary nonpolyposis colorectal cancer (HNPC or Lynch). In Type II, medulloblastomas are often associated with familial adenomatous polyposis coli (classical or attenuated). This patient had a medulloblastoma at seven years of age, then 20 years later developed a meningioma which recurred several times. At 36 years old he presented with anemia after digestive bleeding, and an adenomatous polyposis coli with high grade dysplasia was found at colonoscopy. As far as we know, this is the first case of Turcot syndrome described in our country.

Background: The base excision repair gene MUTYH is the causative gene of colorectal polyposis syndrome, which is an autosomal recessive disorder associated with a high risk of colorectal cancer. Since few studies have investigated the genotype-phenotype association in Japanese patients with MUTYH variants, the aim of this study was to clarify the clinicopathological findings in Japanese patients with MUTYH gene variants who were detected by screening causative genes associated with hereditary colorectal polyposis., Methods: After obtaining informed consent, genetic testing was performed using target enrichment sequencing of 26 genes, including MUTYH., Results: Of the 31 Japanese patients with suspected hereditary colorectal polyposis, eight MUTYH variants were detected in five patients. MUTYH hotspot variants known for Caucasians, namely p.G396D and p.Y179D, were not among the detected variants.Of five patients, two with biallelic MUTYH variants were diagnosed with MUTYH-associated polyposis, while two others had monoallelic MUTYH variants. One patient had the p.P18L and p.G25D variants on the same allele; however, supportive data for considering these two variants 'pathogenic' were lacking., Conclusions: Two patients with biallelic MUTYH variants and two others with monoallelic MUTYH variants were identified among Japanese colorectal polyposis patients. Hotspot variants of the MUTYH gene for Caucasians were not hotspots for Japanese patients.

Intestinal tumorigenesis in the ApcMin/+ model is initiated by aberrant activation of Wnt pathway. Increased IL-4 expression in human colorectal cancer tissue and growth of colon cancer cell lines implied that IL-4-induced Stat6-mediated tumorigenic signaling likely contributes to intestinal tumor progression in ApcMin/+ mice. Stat6 also appears to promote expansion of myeloid-derived suppressor cells (MDSCs) cells. MDSCs promote polyp formation in the ApcMin/+ model. Hence, Stat6 could have a broad role in coordinating both polyp cell proliferation and MDSC expansion. We found that IL-4-induced Stat6-mediated proliferation of intestinal epithelial cells is augmented by platelet-derived growth factor-BB, a tumor-promoting growth factor. To determine whether polyp progression in ApcMin/+ mice is dependent on Stat6 signaling, we disrupted Stat6 in this model. Total polyps in the small intestine were fewer in ApcMin/+ mice lacking Stat6. Furthermore, proliferation of polyp epithelial cells was reduced, indicating that Stat6 in part controlled polyp formation. Stat6 also promoted expansion of MDSCs in the spleen and lamina propria of ApcMin/+ mice, implying regulation of antitumor T-cell response. More CD8 cells and reduced PD-1 expression on CD4 cells correlated with reduced polyps. In addition, a strong CD8-mediated cytotoxic response led to killing of tumor cells in Stat6-deficient ApcMin/+ mice. Therefore, these findings show that Stat6 has an oncogenic role in intestinal tumorigenesis by promoting polyp cell proliferation and immunosuppressive mediators, and preventing an active cytotoxic process., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In a large number of patients with multiple gastrointestinal adenomatous polyps, no causal germline mutation can be found. Non-genetic factors may contribute to the development of adenomatous polyps in these unexplained polyposis patients. In the development of gastrointestinal cancer, prior exposure to abdominal radiotherapy has been identified as such a factor, as it increases the gastrointestinal cancer risk in cancer survivors. A relationship of radiotherapy with intestinal polyposis, however, has not yet been described. Despite the increased cancer risk, these cancer survivors do not receive gastrointestinal screening recommendations. This case series describes three patients with adenomatous polyposis after abdominal radiotherapy., Case Presentation: Patient 1 was diagnosed with testicular cancer at the age of 31 and was treated with hemicastration, radiotherapy and chemotherapy. Thirty-nine years later, he was diagnosed with more than 30 colonic adenomas. Additionally, gastroduodenoscopy revealed a well-differentiated adenocarcinoma in the antrum of the stomach. Patient 2 was diagnosed with a nephroblastoma at the age of 10, which was resected and treated with radiotherapy and chemotherapy. At age 36, a rectal adenocarcinoma was diagnosed and treated by radiotherapy and a total mesorectal excision. During 11 years of surveillance endoscopies, 21 colonic adenomas and three duodenal adenomas were detected. Patient 3 was diagnosed with Hodgkin lymphoma at the age of 20 and treated with radiotherapy, followed by chemotherapy for a recurrence 3 years later. At age 62, a subtotal colectomy was performed because of colonic polyposis: 36 adenomas were detected. During screening gastro-duodenoscopy, three duodenal adenomas were detected. In all three patients, germline analysis did not reveal a mutation in the APC and MYH genes. The gastric and rectal cancer were both microsatellite stable., Conclusion: This report describes three patients with adenomatous polyposis, of which two developed a gastrointestinal cancer. The polyposis was not explained by a germline mutation in APC or MYH and all patients received abdominal radiotherapy. Although an etiologic role has not been established, an association between radiotherapy and intestinal adenomatous polyposis and the subsequent development of cancer seems very likely in our patients.

Introduction: Ménétrier disease (MD) is rare that is involved in both the small bowel and entire colon., The Main Symptoms and the Important Clinical Findings: We describe a case of a 76-year-old male patient whose clinical presentations include intermittent diarrhea, epigastric pain, nausea, vomiting, asitia, and weight loss. An endoscopy was performed showing a large number of irregular forms and different sizes of polypoid lesions in the gastrointestinal tract, which is rare for MD., The Main Diagnoses, Therapeutics Interventions, and Outcomes: Herein, this case was diagnosed as MD, mainly dependent on endoscopic evaluation, typical clinical symptoms, and histopathological examination of biopsy. As this patient was also infected with Helicobacter pylori, the eradication of H pylori was administered. Meanwhile, a high-protein diet was enjoined, the aforementioned patient's symptoms were alleviated evidently after 1 month., Conclusion: Although the etiology of MD remained undetermined, we showed that eradication of H pylori in this case might contribute to the disease remission. This study enlarged the present understanding of MD., Competing Interests: The authors have no conflicts of interest to declare.

Background and Goals: Cystic fibrosis (CF) is associated with increased incidence of gastrointestinal cancer. Increasing overall life expectancy of CF patients predicts emergence of colon cancer as a significant clinical problem in the adult CF population. The primary aim of this study was to estimate the incidence of adenomatous colon polyps in patients with CF during systematic screening by colonoscopy., Study: This is a single-center series of 45 CF patients aged 40 years and above (mean age, 47 y) undergoing colonoscopic screening. A fraction of these patients (9/45) had history of organ transplantation. Results from transplant and nontransplant patients were analyzed separately., Results: Adult CF patients have a high incidence of adenomatous polyps identified by colonoscopy. In addition, positive examinations are characterized by multiple polyps and common features of advanced pathology. The incidence of adenomatous colon polyps is greater in male patients, although the 1 patient in this cohort found to have colorectal cancer was female., Conclusions: CF has features of a hereditary colon cancer syndrome. Increasing life expectancy of CF patients suggests that earlier colon screening in this population may be warranted. Optimal criteria for initiation of screening and frequency of surveillance should be subject of further studies.

Aims: Most patients with familial adenomatous polyposis (FAP) develop gastric fundic gland polyps, with many displaying low-grade dysplasia. This study evaluates the natural history and morphological phenotype of dysplasia in FAP-associated fundic gland polyps., Methods and Results: Patients with FAP and dysplastic fundic gland polyps (n = 24) were identified. Twenty-two of 24 FAP-associated dysplastic fundic gland polyps showed a gastric phenotype and two had mixed phenotype. During a mean 6.1-year follow-up (range 0.8-12.6 years) and 5.7 endoscopies (range 2-22), one patient (4%) was diagnosed with a fundic gland polyp with high-grade dysplasia, while 23 patients (96%) in this cohort had either no dysplasia or persistent low-grade dysplasia. Contemporary patients with sporadic fundic gland polyps with low-grade dyplasia had similar morphology and outcomes to the FAP-associated fundic gland polyp cohort. Dysplasia in fundic gland polyps (FAP-associated and sporadic) was associated less frequently with intestinal phenotype, high-grade dysplasia and the finding of concurrent or subsequent carcinoma compared to contemporary patients with sporadic gastric dysplasia not occurring in fundic gland polyps., Conclusions: This cohort of patients with FAP-associated dysplastic fundic gland polyps rarely developed high-grade dysplasia and gastric adenocarcinoma was absent., (© 2014 John Wiley & Sons Ltd.)

Over 1500 adenomatous polyposis coli (APC) gene mutations have already been identified as causative of familial adenomatous polyposis (FAP). However, routine genetic testing fails to detect mutations in about 10% of classic FAP cases. Recently, it has been shown that a proportion of mutation-negative FAP cases bear molecular changes in deep intronic and regulatory sequences. In this study, we used direct sequencing, followed by multiplex ligation-dependent probe amplification (MLPA) of genomic DNA from family members, affected by classic FAP. We first reported the family as mutation negative. With the launch of a new version of MLPA kit, we retested the family and a novel full deletion of promoter 1B was detected. The exact breakpoints of the deletion were determined by array comparative genomic hybridization (CGH) and long range polymerase chain reaction (PCR), followed by direct sequencing. The total APC expression levels were investigated by quantitative polymerase chain reaction (qPCR) assay and allele-specific expression (ASE) analysis. The APC gene expression was highly reduced, which indicates causative relationship. We suggest that there is a significant possibility that APC promoter 1B mutations could be found in mutation-negative FAP patients. In the light of our findings it seems reasonable to consider targeted genetic re-analysis of APC promoter 1B region in a larger cohort of unsolved cases., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mutation of tumor suppressor gene adenomatous polyposis coli (APC) is an initiating step in most colon cancers. This review summarizes Apc models in mice and rats, with particular concentration on those most recently developed, phenotypic variation among different models, and genotype/phenotype correlations., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Unlabelled: Intake of trans fatty acids from hydrogenated fish oils has been related to increased risk of coronary heart diseases. The possible effect on colorectal carcinogenesis is unclear., Materials and Methods: Multiple intestinal neoplasia (Min/+) mice were fed one of four experimental diets: either raw fish oil (FO), low (LHFO)-, high (HHFO)- or fully-hydrogenated fish oil (FFHO), from 0 to 9 weeks of age. The number and size of intestinal tumors were recorded., Results: There was no difference between the intervention groups in the numbers of developed intestinal tumors. The tumor size was statistically significantly lower in HHFO vs. the FO-group in male Min/+ mice. The HHFO and FHFO groups had lower weight gain than did the FO group (p=0.008 and p=0.04, respectively), but gender differences, due to effect of dietary intervention on weight gain, were found in Min/+ mice., Conclusion: When compared with raw fish oil, different degrees of hydrogenation of the fish oil had no effect on intestinal carcinogenesis in Min/+ mice.

Few causes of hepatoblastoma have been conclusively identified, mainly due to the extreme rarity of the disease. Inherited conditions including Familial Adenomatous Polyposis and Beckwith-Wiedemann Syndrome dramatically raise risk of hepatoblastoma but account for few cases overall. A small number of case-control studies investigating risk factors for sporadic hepatoblastoma have been conducted to date. Although most of these studies feature fewer than 200 cases, several clues have emerged. Most notably there is a roughly 20-fold increased risk of hepatoblastoma among children with very low birth weight (<1,500 g) and a doubling of risk among those with moderately low birth weight (1,500-2,500 g). A modicum of evidence points to a possible role of parental tobacco use prior to or during pregnancy in the causation of hepatoblastoma as well., (Copyright © 2012 Wiley Periodicals, Inc.)

Crohn's disease and ulcerative colitis are progressive diseases associated with a high risk of complications over time including strictures, fistulae, perianal complications, surgery, and colorectal cancer. Changing the natural history and avoiding evolution to a disabling disease should be the main goal of treatment. In recent studies, mucosal healing has been associated with longer-term remission and fewer complications. Conventional therapies with immunosuppressive drugs are able to induce mucosal healing in a minority of cases but their impact on disease progression appears modest. Higher rates of mucosal healing can be achieved with anti-tumor necrosis factor therapies that reduce the risk of relapse, surgery and hospitalization, and are associated with perianal fistulae closure. These drugs might be able to change the natural history of the disease mainly when introduced early in the course of the disease. Treatment strategy in inflammatory bowel diseases should thus be tailored according to the risk that each patient could develop disabling disease.

Objective: Genetic predisposition to cancer in Peutz-Jeghers syndrome (PJS) and the role of germline serine-threonine kinase (LKB1) mutations are poorly understood. The authors studied the effect of germline LKB1 mutations on intestinal stem cell dynamics in unaffected flat PJS mucosa. Recent research has documented that the intestinal crypt houses multiple equipotent stem cell lineages. Lineages continuously compete through random drifts, while somatically inherited methylation patterns record clonal diversity., Design: To study the effect of germline LKB1 mutations on clonal expansion, the authors performed quantitative analyses of cardiac-specific homeobox methylation pattern diversity in crypts isolated from unaffected colonic mucosa obtained from archival PJS patient material. The authors compared methylation density and methylation pattern diversity in patients with PJS to those in patients with familial adenomatous polyposis and age-matched controls., Results: The percentage of total methylation is comparable between groups, but the number of unique methylation patterns is significantly increased for patients with familial adenomatous polyposis and patients with PJS compared to control subjects., Conclusions: Monoallelic LKB1 loss is not silent and provokes a protracted clonal evolution in the crypt. The increased methylation pattern diversity observed in unaffected PJS mucosa predicts that premalignant lesions will arise at an accelerated pace compared to the general population.

Obesity is an established risk factor for several malignancies. However, the specific measurement of obesity most relevant to colon neoplasia is still debated, and evidence has suggested gender and racial differences in this measurement. In this study, we sought to compare which measurement--BMI, waist circumference (WC), waist-to-hip ratio (WHR) or waist-to-height ratio (WHtR)--is most strongly associated with development of colon adenomas, a precursor of colon cancer, and to investigate differences in this association between racial groups. We confirmed the strong association between WHR, as a measure of central obesity, and development of colon neoplasia. In our overall analysis, patients in the highest WHR quartile showed a substantial increase in risk of colon adenomas compared to patients in the lowest WHR quartile (odds ratio (OR) = 1.82, 95% confidence interval (CI): 1.12-2.71, P(trend) = 0.0017). In stratified analyses, we noted that strongly associated obesity measures in European Americans were WC (OR = 2.38, 95% CI = 1.45-3.92, P(trend) = 0.0004) and BMI (OR = 2.18, 95% CI = 1.37-3.49, P(trend) = 0.0015), whereas in African Americans, WHR was the strongest and the only obesity measure statistically significantly associated with adenoma risk (OR = 2.12, 95% CI = 1.05-4.30, P(trend) = 0.025). Our data highlight the importance of obesity in the development of early colon neoplasia and suggest substantial racial differences in the measures of obesity most strongly associated with risk of colon adenomas.

Alterations in mitochondrial oxidative phosphorylation have long been documented in tumors. Other types of mitochondrial dysfunction, including altered reactive oxygen species (ROS) production and apoptosis, also can contribute to tumorigenesis and cancer phenotypes. Furthermore, mutation and altered amounts of mitochondrial DNA (mtDNA) have been observed in cancer cells. However, how mtDNA instability per se contributes to cancer remains largely undetermined. Mitochondrial transcription factor A (TFAM) is required for expression and maintenance of mtDNA. Tfam heterozygous knock-out (Tfam(+/-)) mice show mild mtDNA depletion, but have no overt phenotypes. We show that Tfam(+/-) mouse cells and tissues not only possess less mtDNA but also increased oxidative mtDNA damage. Crossing Tfam(+/-) mice to the adenomatous polyposis coli multiple intestinal neoplasia (APC(Min/+)) mouse cancer model revealed that mtDNA instability increases tumor number and growth in the small intestine. This was not a result of enhancement of Wnt/β-catenin signaling, but rather appears to involve a propensity for increased mitochondrial ROS production. Direct involvement of mitochondrial ROS in intestinal tumorigenesis was shown by crossing APC(Min/+) mice to those that have catalase targeted to mitochondria, which resulted in a significant reduction in tumorigenesis in the colon. Thus, mitochondrial genome instability and ROS enhance intestinal tumorigenesis and Tfam(+/-) mice are a relevant model to address the role of mtDNA instability in disease states in which mitochondrial dysfunction is implicated, such as cancer, neurodegeneration, and aging., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Taste perception may influence dietary preferences and nutrient intakes contributing to diet-related disease susceptibility. This study examined bitter taste genetics and whether variation in the TAS2R38 gene at three polymorphic loci (A49P, V262A and I296V) could alter dietary and systemic folate levels and dietary vitamin C intake, and whether a nutrigenetic circuit existed that might link bitter taste, folate/antioxidant status and risk for a colonic adenomatous polyp. TAS2R38 diplotype predicted bitter taste (PROP) phenotype (p value <0.00001) and red cell folate status (p=0.0179) consistent with the diplotype that has the broadest range of bitter perception (AVI/PAV) also possessing the highest average red cell folate value. However, TAS2R38 diplotype did not predict dietary intake of methylfolic acid, pteroylmonoglutamic acid or total folic acid. Neither did it predict dietary intake of vitamin C. Despite this, intake of dietary folate predicts red cell folate with analysis pointing to a key nutrient-nutrient interaction between vitamin C intake and systemic folate status. Analysis of 38 patients with an adenomatous polyp and 164 controls showed that individually, dietary nutrient intake, nutrient status and taste diplotype did not influence polyp risk. However, red cell folate status (in individuals below the population median value) did interact with bitter taste diplotype (AVI/PAV) to predict polyp risk (p=0.0145). Furthermore, synthetic folic acid (below median intake) was statistically associated with adenoma occurrence (p=0.0215); individuals with adenomatous polyps had a 1.77× higher intake than controls. Additionally, stepwise regression taking account of all dietary nutrients showed a tight relationship between methylfolic acid (but not pteroylmonoglutamic acid) intake and red cell folate level in those with a low folate status and occurrence of an adenomatous polyp (p=0.0039). These findings point to a role for folate in the pathoaetiology of adenomatous polyps, with the natural and synthetic vitamers not necessarily having the same biological effect., (This journal is © The Royal Society of Chemistry 2011)

Major efforts to sequence cancer genomes are now occurring throughout the world. Though the emerging data from these studies are illuminating, their reconciliation with epidemiologic and clinical observations poses a major challenge. In the current study, we provide a mathematical model that begins to address this challenge. We model tumors as a discrete time branching process that starts with a single driver mutation and proceeds as each new driver mutation leads to a slightly increased rate of clonal expansion. Using the model, we observe tremendous variation in the rate of tumor development-providing an understanding of the heterogeneity in tumor sizes and development times that have been observed by epidemiologists and clinicians. Furthermore, the model provides a simple formula for the number of driver mutations as a function of the total number of mutations in the tumor. Finally, when applied to recent experimental data, the model allows us to calculate the actual selective advantage provided by typical somatic mutations in human tumors in situ. This selective advantage is surprisingly small--0.004 ± 0.0004--and has major implications for experimental cancer research.

In 100 primary colorectal carcinomas, we demonstrate by array comparative genomic hybridization (aCGH) that 33% show DNA copy number (DCN) loss involving PARK2, the gene encoding PARKIN, the E3 ubiquitin ligase whose deficiency is responsible for a form of autosomal recessive juvenile parkinsonism. PARK2 is located on chromosome 6 (at 6q25-27), a chromosome with one of the lowest overall frequencies of DNA copy number alterations recorded in colorectal cancers. The PARK2 deletions are mostly focal (31% approximately 0.5 Mb on average), heterozygous, and show maximum incidence in exons 3 and 4. As PARK2 lies within FRA6E, a large common fragile site, it has been argued that the observed DCN losses in PARK2 in cancer may represent merely the result of enforced replication of locally vulnerable DNA. However, we show that deficiency in expression of PARK2 is significantly associated with adenomatous polyposis coli (APC) deficiency in human colorectal cancer. Evidence of some PARK2 mutations and promoter hypermethylation is described. PARK2 overexpression inhibits cell proliferation in vitro. Moreover, interbreeding of Park2 heterozygous knockout mice with Apc(Min) mice resulted in a dramatic acceleration of intestinal adenoma development and increased polyp multiplicity. We conclude that PARK2 is a tumor suppressor gene whose haploinsufficiency cooperates with mutant APC in colorectal carcinogenesis.

Familial adenomatous polyposis (FAP) is characterized by the development of many tens to thousands of adenomas in the rectum and colon during the second decade of life. FAP has an incidence at birth of about 1/8,300, it manifests equally in both sexes, and accounts for less than 1% of colorectal cancer (CRC) cases. In the European Union, prevalence has been estimated at 1/11,300-37,600. Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Generally, cancers start to develop a decade after the appearance of the polyps. Nonspecific symptoms may include constipation or diarrhea, abdominal pain, palpable abdominal masses and weight loss. FAP may present with some extraintestinal manifestations such as osteomas, dental abnormalities (unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts and odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoid tumors, and extracolonic cancers (thyroid, liver, bile ducts and central nervous system). A less aggressive variant of FAP, attenuated FAP (AFAP), is characterized by fewer colorectal adenomatous polyps (usually 10 to 100), later age of adenoma appearance and a lower cancer risk. Some lesions (skull and mandible osteomas, dental abnormalities, and fibromas on the scalp, shoulders, arms and back) are indicative of the Gardner variant of FAP. Classic FAP is inherited in an autosomal dominant manner and results from a germline mutation in the adenomatous polyposis (APC) gene. Most patients (~70%) have a family history of colorectal polyps and cancer. In a subset of individuals, a MUTYH mutation causes a recessively inherited polyposis condition, MUTYH-associated polyposis (MAP), which is characterized by a slightly increased risk of developing CRC and polyps/adenomas in both the upper and lower gastrointestinal tract. Diagnosis is based on a suggestive family history, clinical findings, and large bowel endoscopy or full colonoscopy. Whenever possible, the clinical diagnosis should be confirmed by genetic testing. When the APC mutation in the family has been identified, genetic testing of all first-degree relatives should be performed. Presymptomatic and prenatal (amniocentesis and chorionic villous sampling), and even preimplantation genetic testing is possible. Referral to a geneticist or genetic counselor is mandatory. Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome). Cancer prevention and maintaining a good quality of life are the main goals of management and regular and systematic follow-up and supportive care should be offered to all patients. By the late teens or early twenties, colorectal cancer prophylactic surgery is advocated. The recommended alternatives are total proctocolectomy and ileoanal pouch or ileorectal anastomosis for AFAP. Duodenal cancer and desmoids are the two main causes of mortality after total colectomy, they need to be identified early and treated. Upper endoscopy is necessary for surveillance to reduce the risk of ampullary and duodenal cancer. Patients with progressive tumors and unresectable disease may respond or stabilize with a combination of cytotoxic chemotherapy and surgery (when possible to perform). Adjunctive therapy with celecoxib has been approved by the US Food and Drug Administration and the European Medicines Agency in patients with FAP. Individuals with FAP carry a 100% risk of CRC; however, this risk is reduced significantly when patients enter a screening-treatment program.

Introduction: Attenuated adenomatous polyposis coli (AAPC) is a variant of the familial adenomatous polyposis (FAP) characterized by the occurrence of sparse polyps in the colon, stomach, and duodenum with a late onset of colorectal cancer. The AAPC syndrome is associated with mutations at the 5' region of the APC gene. Until recently, the fragment encompassing codons 157 and 170 was considered as boundary for the described cases of AAPC and FAP syndromes., Materials and Methods: This study describes a case of the AAPC syndrome caused by a CCTT deletion at codon 173, with polyps diagnosed at the age of 17. The father and grandfather of the proband died of colorectal cancer (CRC), which developed from untreated polyps, at the age 35 and 40, respectively., Results and Discussions: In the case of the proband's father, the untreated polyps led to death after 12 years. The proband revealed a low number of polyps and an extra colon feature characteristic of AAPC, but the polyps onset and the death of CRC of two family members, who refused colectomy, was very early and characteristic for FAP. An atypical course of AAPC must be taken into consideration both in genetic counseling and in qualifying the patients with AAPC for the surgical treatment.

K-ras mutation-positive (K-ras+) and -negative (K-ras-) colorectal adenomas may differ clinically and pathologically. As environmental compounds may cause mutations in the growth-related K-ras oncogene or affect clonal selection depending on mutational status, we evaluated whether the aetiology of K-ras+ and K-ras- adenomas differs. K-ras mutations in codons 12 and 13 were assessed in colorectal adenoma tissue (K-ras+: n = 81, K-ras-: n = 453). Dietary and lifestyle data were collected through questionnaires that were also administered to 709 polyp-free controls. Multiple logistic regression analyses showed that intake of vitamin B2 and monounsaturated fat were differently associated with risk of K-ras+ and K-ras- adenomas; vitamin B2 was inversely associated with K-ras- (highest vs. lowest tertile: odds ratio (OR) = 0.70, 95% confidence interval (CI) = 0.50-0.97, p trend = 0.020), but not with K-ras+ adenomas, and a positive association with monounsaturated fat was confined to K-ras- adenomas (OR = 1.57, 95% CI = 1.06-2.34, p trend = 0.029). Besides, potential, not statistically significant, differences in risk arose because red meat was distinctly positively associated with K-ras+ adenomas (OR = 1.70, 95% CI = 0.94-3.09, p trend = 0.061); total dietary and polyunsaturated fat tended to be inversely associated with risk of K-ras+ but not of K-ras- adenomas; inverse associations with dairy products, calcium, protein and tea were confined to K-ras- adenomas, and smoking was more markedly positively associated with K-ras- adenomas. No differences in risk of K-ras+ and K-ras- adenomas could be detected for other factors. In conclusion, dietary and lifestyle factors may influence risk of K-ras+ and K-ras- adenomas differently. However, epidemiological literature on diet, lifestyle and colorectal K-ras mutations is inconsistent., (2006 Wiley-Liss, Inc.)

SMAD4 (MAD homologue 4 (Drosophila)), also known as DPC4 (deleted in pancreatic cancer), is a tumour suppressor gene that encodes a central mediator of transforming growth factor-beta signalling. Germline mutations in SMAD4 are found in over 50% of patients with familial juvenile polyposis, an autosomal dominant disorder characterized by predisposition to hamartomatous polyps and gastrointestinal cancer. Dense inflammatory cell infiltrates underlay grossly normal appearing, non-polypoid colonic and gastric mucosa of patients with familial juvenile polyposis. This prominent stromal component suggests that loss of SMAD4-dependent signalling in cells within the epithelial microenvironment has an important role in the evolution of intestinal tumorigenesis in this syndrome. Here we show that selective loss of Smad4-dependent signalling in T cells leads to spontaneous epithelial cancers throughout the gastrointestinal tract in mice, whereas epithelial-specific deletion of the Smad4 gene does not. Tumours arising within the colon, rectum, duodenum, stomach and oral cavity are stroma-rich with dense plasma cell infiltrates. Smad4(-/-) T cells produce abundant T(H)2-type cytokines including interleukin (IL)-5, IL-6 and IL-13, known mediators of plasma cell and stromal expansion. The results support the concept that cancer, as an outcome, reflects the loss of the normal communication between the cellular constituents of a given organ, and indicate that Smad4-deficient T cells ultimately send the wrong message to their stromal and epithelial neighbours.

Colorectal adenomas and possibly some hyperplastic polyps are precursors of colorectal cancer. Tobacco use is associated in epidemiologic studies with these polyps, although links between smoking and colorectal cancer are less consistent. To characterize the role of tobacco in early colorectal carcinogenesis, we compared tobacco use among 4,383 subjects with histologically verified benign (hyperplastic or adenomatous) polyps of the distal colon (descending colon, sigmoid, and rectum) with tobacco use among 33,667 subjects who were endoscopy negative for distal colon tumors, in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Trial, a randomized trial of flexible sigmoidoscopy. Risks, estimated by the odds ratio (OR), associated with current cigarette use were OR = 4.4 [95% confidence interval (95% CI), 3.7-5.2] for hyperplastic polyps only, OR = 1.8 (95% CI, 1.5-2.1) for adenomas only, and OR = 6.2 (95% CI, 4.7-8.3) for subjects with both hyperplastic and adenomatous polyps concurrently. Effects were weaker among ex smokers; the smoking-associated ORs remained consistently higher for hyperplastic polyps. This pattern was also seen in relation to cigarettes smoked per day, smoking duration, and pack-years. Tobacco-associated risks for multiple polyps were also stronger when hyperplastic disease was involved. In conclusion, tobacco use, particularly recent use, increases risk for both adenomatous and hyperplastic polyps, but the risks are substantially greater for hyperplastic lesions.

The contribution of cigarette smoking to sporadic colorectal cancer may differ according to molecular aspects of the tumor or according to glutathione S-transferase M1 (GSTM1) or glutathione S-transferase T1 (GSTT1) genotype. In the prospective Netherlands Cohort Study on Diet and Cancer, adjusted incidence rate ratios for 1986-1993 were computed for overall colorectal cancer, tumors with and without adenomatous polyposis coli (APC) mutations, and tumors with and without human mut-L homologue 1 (hMLH1) expression, according to cigarette smoking characteristics (661 cases, 2,948 subcohort members). Case-only analyses were performed to estimate odds ratios for interaction between cigarette smoking and GSTM1 and GSTT1 genotypes. In comparison with never smokers, a high smoking frequency increased the risk of colorectal cancer (for a five-cigarette/day increment, incidence rate ratio (IRR) = 1.07, 95% confidence interval (CI): 1.03, 1.12), and this association was stronger in 371 tumors without a truncating APC mutation (IRR = 1.11, 95% CI: 1.05, 1.17). Long-term smoking was associated with lack of hMLH1 expression in 56 tumors (for a 10-year increment, IRR = 1.17, 95% CI: 1.00, 1.37). No statistically significant interactions between smoking and GSTM1 or GSTT1 genotype were observed. These results indicate that cigarette smoking is associated with risk of colorectal cancer, and this association may depend on molecular characteristics of the tumor as defined by APC mutation and hMLH1 expression status.

The principal Mendelian disorders predisposing to colorectal cancer are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). FAP is caused by mutations in the adenomatous polyposis coli (APC) gene. HNPCC is caused by a mutation in one of at least five mismatch repair genes. It is important to identify individuals with these conditions because colon cancer will occur in at least 80% and onset is earlier than in the general population. Potential benefits of identification include improved compliance with recommended surveillance, early detection of polyps, reduction in cancer mortality, and reassurance for relatives found to be negative with attendant savings in the time and expense of surveillance. For classic FAP, the large number of polyps readily identifies affected persons. For HNPCC, identification of individuals meriting DNA sequencing requires either recognition of a suspect family history or finding high microsatellite instability in a tumor. Individuals accepting the offer of genetic counseling and DNA testing often have more cancers in their family, are motivated to inform relatives, have a larger social network, and have more confidence in their coping ability. Individuals who decline are often concerned about their own or their family's emotional reaction or fear discrimination.

Introduction: Previous studies have investigated the possibility that specific mutations may be related to specific clinicopathological features. However, most previous investigations included only an average age (40-80 years) group of sporadic colorectal cancers and, moreover, studied only a single gene in isolation. Therefore, the influence of age on these mutation frequencies remains unclear, despite age being considered a risk factor for genetic mutation., Materials and Methods: This study included 122 sporadic colorectal cancers from three different age groups and analyzed mutation frequencies of adenomatous polyposis coli (APC), K-ras, and p53 genes and microsatellite instability to determine their mutation frequencies and relationships with clinicopathological features., Results: Significantly lower p53 mutation frequencies were observed among young (32 years old or younger) and old (86 years old or older) patient groups compared with an average age (39-85 years old) patient group (14.3% and 19.2% versus 51.5%, P<0.001). APC mutation frequency (11.8%) was significantly lower in highly aggressive (Dukes' stage D) tumors ( P=0.003) than in the other stage tumors (Dukes' stage A, B, and C). Additionally, simultaneous occurrence of all three genetic alterations in an individual tumor was rare (below 5%). Statistical analysis further confirmed that mutation number in Dukes' D tumors occurred less frequently than expected in other stage tumors ( P=0.008)., Conclusions: Genetic alterations of sporadic colorectal cancers have different relationships with age or tumor stage. Additionally, most sporadic colorectal tumors do not necessarily require following the widely accepted genetic model, because the three key genetic mutations, APC, K-ras, and p53, rarely occur simultaneously.

In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome, juvenile intestinal polyposis and Cowden disease, respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways. The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number.

Biallelic germ-line variants of the 8-hydroxyguanine repair gene MYH have been associated with multiple colorectal adenomas that display somatic G:C-->T:A transversions in APC. However, the effect of single germ-line variants has not been widely studied. To examine the relationship between monoallelic MYH variants and susceptibility to sporadic colorectal cancer (CRC), 92 cases of sporadic CRC, 19 cases of familial CRC not meeting the Bethesda guidelines, 17 cases with multiple adenomas, and 53 normal blood donors were screened for 8 potentially pathogenic germ-line MYH variants. Loss of heterozygosity (LOH) at 1p adjacent to the MYH locus, microsatellite instability (MSI) status, and somatic mutations in KRAS2 and APC were analyzed in sporadic cancers. Neither homozygote nor compound heterozygote MYH variants were observed in the germ-line of any subjects with sporadic CRC. There was no difference in the incidence of monoallelic variants between this group (20 of 92, 22%) and cancer-free controls (14 of 53, 26%). However, the presence of monoallelic germ-line MYH variants was negatively associated with an MSI-high (MSI-H) tumor phenotype, with an incidence of only 1 of 23 (4%) MSI-H CRCs as contrasted with 19 of 69 (28%) non-MSI-H (P=0.02). Further, 4 of 5 tumors with 1p LOH contained monoallelic MYH variants compared with 15 of 53 without 1p LOH (P=0.04) and the normal population (P=0.03). The presence of G:C-->T:A transversions in KRAS2 or APC was significantly more common in single MYH variant tumors (9 of 12) than in MYH wild-type tumors (11 of 33; P=0.02). These results suggest that single germ-line variants of MYH may influence genetic pathways in CRC., (Copyright 2004 Wiley-Liss, Inc.)

The impact that modern molecular biology has had on elucidating the genetic basis of neoplasia is best illustrated by the paradigm of sporadic and hereditary colon cancer. The clinical and hereditary picture of the familial adenomatous polyposis syndrome (FAP) implied the existence of a single gene that regulates the formation of adenomatous polyps, the precursor for most colorectal cancers. The identification of an interstitial deletion on chromosome 5q in a patient with Gardner's variant of FAP combined with classic linkage analysis facilitated the positional cloning of the adenomatous polyposis coli (APC) gene in 1991. FAP is caused by germline mutations in the APC gene. Somatic mutations in the APC gene are an early event in colorectal tumorigenesis, and can be detected in the majority of colorectal tumors. APC consists of 8,535 bp spanning 21 exons (16 translated exons) and encodes a 2,861 amino acid protein that is expressed in specific epithelial and mesenchymal cells of several fetal and adult human tissues. The APC protein is a large multidomain protein with a molecular mass of 300 kD. The best-known function of the APC protein is the Wnt-1 signaling pathway. Binding Wnt to its receptor, frizzled), leads to the inactivation of the glycogen synthase kinase 3 beta in a cytoplasmic complex with APC, beta-catenin, axin and components of the ubiquitin ligation machinery. This leads to a decrease in beta-catenin phosphorylation and inhibits its proteasomal degradation. As a consequence, increased beta-catenin is available to bind transcription factors leading to the activation of proliferative genes. In addition, APC has recently emerged as a multifunctional protein that can affect a variety of fundamental cellular processes, in particular cytoskeletal regulation and chromosomal stability. Improved understanding of both the genetics and biology of APC may, in time, culminate in preventive or therapeutic strategies specifically targeted at reducing the burden of colorectal cancer.

Introduction: While the association between family history of colorectal cancer in first-degree relatives and risk of developing colon cancer has been well defined, the association with rectal cancer is much less clear. The purpose of this study is to define rectal cancer risk associated with family history of colorectal cancer in first-degree relatives. We also evaluate diet and lifestyle factors associated with developing colorectal cancer among participants with a positive family history., Methods: Data were available from two population-based case--control studies of colon and rectal cancer. Participants were members of the Kaiser Permanente Medical Care Program (KPMCP) or residents of the state of Utah. Cases were first primary colon cancer diagnosed between 1991 and 1994 (n = 1308 cases and 1544 controls) or rectal cancer diagnosed between 1997 and 2001 (n = 952 cases and 1205 controls)., Results: A family history of colorectal cancer in any first-degree relatives slightly increased risk of rectal cancer (OR: 1.37 95% CI: 1.02-1.85). Family history of colorectal cancer was associated with the greatest risk among those diagnosed at age 50 or younger (OR: 2.09 95% CI: 0.94-4.65 for rectal tumors; OR: 3.00 95% CI: 0.98-9.20 for distal colon tumors; and OR: 7.88 95% CI: 2.62-23.7 for proximal colon tumors). Factors significantly associated with cancer risk among those with a family history of colorectal cancer, included not having a sigmoidoscopy (OR: 2.81 95% CI: 1.86-4.24): a diet not Prudent, i.e. high in fruits, vegetables, whole grains, fish and poultry, (OR: 2.79 95% CI: 1.40-5.56); smoking cigarettes (OR: 1.68 95% CI: 1.12-2.53), and eating a Western diet, i.e. a diet high in meat, refined grains, high-fat foods, and fast foods, (OR: 2.15 95% CI: 1.06-4.35). Physical inactivity was not associated with increased cancer risk among those with a positive family history of colorectal cancer., Summary: These results confirm observations reported by others that a family history of colorectal cancer increases risk of cancer among those diagnosed at a younger age. Associations with family history are weakest for rectal cancer and strongest for proximal colonic tumors. Since several diet and lifestyle factors influence development of cancer among those with a family history of the disease, there appears to be practical approaches for individuals with a family history of colorectal cancer to reduce their cancer risk.

In recent years, there have been major advances regarding the understanding of the pathogenesis of sporadic and hereditary colorectal cancer on the basis of molecular research. The clinical implications of this knowledge differ for the sporadic and hereditary forms. In sporadic colorectal cancer, gene mutations occur in colorectal cells but not as germline mutations. Even though molecular data currently do not influence the clinical management of this form of colorectal cancer, promising molecular approaches exist for the assessment of prognosis, early detection, prevention, and therapy. Germline mutations are the cause of hereditary colorectal cancers, in which molecular methods have a major impact on diagnosis and therapy. Prophylactic surgery is accepted for patients with familial adenomatous polyposis (FAP), but not for patients with hereditary non-polyposis colorectal cancer (HNPCC), the second main form of hereditary colorectal cancer. Further studies will have to clarity this issue.

Adenomatous polyposis coli (APC) is an important tumour suppressor in the intestinal epithelium. Its function in reducing nuclear beta-catenin and T-cell factor (TCF)-mediated transcription is conserved from Drosophila to mammals. But APC proteins are also associated with the plasma membrane. Here, we show that mutational inactivation of Drosophila E-APC causes delocalization of Armadillo (the Drosophila beta-catenin) but not DE-cadherin from adhesive plasma membranes. Extensive gaps between these membranes are visible at the ultrastructural level. The oocyte is also mislocalized in E-APC mutant egg chambers, a phenotype that results from a failure of cadherin-based adhesion. These results indicate that Drosophila APC functions in cellular adhesion; these results could have implications for colorectal adenoma formation and tumour progression in humans.

We describe a sporadic case with familial adenomatous polyposis, multiple endocrine neoplasia type 1 (MEN1)-related tumors (an endocrine cell tumor of the pancreas and bilateral parathyroid tumors), and a papillary thyroid carcinoma. To clarify how mutations of the adenomatous polyposis coli ( APC ) gene and the MEN1 gene, responsible for familial adenomatous polyposis and MEN1, respectively, might have contributed to tumorigenesis in this case, we studied germline mutations in both genes and loss of heterozygosity at their genetic loci in multiple lesions. In addition, we performed immunohistochemistry for beta-catenin, associated with the function of the APC gene. A germline mutation was found in the APC gene but not in the MEN1 gene. Normal allelic loss at the APC gene locus was observed in bilateral parathyroid tumors. Immunohistochemical staining of beta-catenin demonstrated accumulation in the cytoplasm in addition to membrane staining in all analyzed tumors and a strong nuclear reaction in the endocrine cell tumor of the pancreas. The presence of normal allelic deletions of the APC gene in bilateral parathyroid tumors and nuclear staining of beta-catenin in the pancreatic tumor in addition to the germline mutations suggests that functional loss of the APC gene played an important role not only in familial adenomatous polyposis but also in the MEN1-related tumors in this case.