Hearing Status of Children and Adolescents With Familial Adenomatous Polyposis.

BACKGROUND/AIM: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: Mutation of the APC gene is not necessarily indicative of higher risk for baseline hearing loss in the pediatric population.

A further study on a disturbance of intestinal epithelial cell population and kinetics in APC1638T mice.

Adenomatous polyposis coli (APC), a well-known anti-oncogene, is considered to have multiple functions through its several binding domains. We have continuingly studied APC1638T/1638T mice (APC1638T mice) to elucidate the functions of APC other than tumor suppression. A distinctive feature of the APC1638T mice is they are tumor free and live as long as APC+/+ mice (WT mice). Previously, we found the length of crypt-villus axis in the jejunum was significantly elongated in APC1638T mice compared with that of WT mice. The populations of goblet cells, Paneth cells, and enteroendocrine cells were also disordered in APC1638T mice. Here, we further analyzed the intestinal dyshomeostasis in APC1638T mice, focusing on the proliferation and differentiation of intestinal stem cell (ISC) lineages, and apoptotic cell shedding at the villus tips. We found that the proliferation of ISC lineages was normally controlled; however, the shedding process of apoptosis cells was significantly delayed in the APC1638T mouse jejunum. Furthermore, the number of microfold cells (M cells) was significantly increased in the APC1638T mouse jejunum. Our data suggested both differentiation process of ISCs and turnover process of intestinal epithelia were disturbed in APC1638T mice, and that contributed to the villus elongation in the APC1638T mouse jejunum.

Possible acquired gastrointestinal polyposis in a childhood cancer survivor.

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.

Acarbose improved survival for Apc+/Min mice.

Acarbose blocks the digestion of complex carbohydrates, and the NIA Intervention Testing Program (ITP) found that it improved survival when fed to mice. Yet, we do not know if lifespan extension was caused by its effect on metabolism with regard to the soma or cancer suppression. Cancer caused death for ~80% of ITP mice. The ITP found rapamycin, an inhibitor to the pro-growth mTORC1 (mechanistic target of rapamycin complex 1) pathway, improved survival and it suppressed tumors in Apc+/Min mice providing a plausible rationale to ask if acarbose had a similar effect. Apc+/Min is a mouse model prone to intestinal polyposis and a mimic of familial adenomatous polyposis in people. Polyp-associated anemia contributed to their death. To address this knowledge gap, we fed two doses of acarbose to Apc+/Min mice. Acarbose improved median survival at both doses. A cross-sectional analysis was performed next. At both doses, ACA fed mice exhibited reduced intestinal crypt depth, weight loss despite increased food consumption and reduced postprandial blood glucose and plasma insulin, indicative of improved insulin sensitivity. Dose-independent and dose-dependent compensatory liver responses were observed for AMPK and mTORC1 activities, respectively. Only mice fed the high dose diet exhibited reductions in tumor number with higher hematocrits. Because low-dose acarbose improved lifespan but failed to reduced tumors, its effects seem to be independent of cancer. These data implicate the importance of improved carbohydrate metabolism on survival.

SATB1 Expression of Colorectal Adenomatous Polyps is Higher than that of Colorectal Carcinomas.

"Special AT-rich sequence-binding protein-1" (SATB1) is a global genome organizer and is found to have effects on carcinogenesis and progression of various malignancies including colorectal carcinoma (CRC). We aimed to investigate the expression of SATB1 in CRC and colorectal adenomatous polyps (CAP), the correlation between clinicopathologic parameters, and overall survival. We examined 227 CRCs and 129 CAPs. SATB1 protein expression was evaluated by immunohistochemistry. We found higher SATB1 expression in adenomatous epithelium than in CRC tissues (55.0% vs. 42.7%, respectively) (P<0.05). None of the adjacent normal colorectal mucosa stained positive in CRC cases, and only one of the adjacent normal mucosa of the CAP cases was positive. SATB1 expression of left-sided CRC was higher than that of right-sided CRC (46.3% vs. 28.6%, respectively) (P<0.05), and SATB1 expression of conventional adenocarcinomas was higher than that of mucinous carcinomas (45.5% vs. 6.3%, respectively) (P<0.05). SATB1 expression was higher in CAPs consisting of high-grade dysplasia than in polyps with low-grade dysplasia (77.8% vs. 51.4%) (P<0.05). SATB1 expression did not correlate with patients' overall survival. In conclusion, due to the higher expression of SATB1 in CAP than in CRC, we think SATB1 may have a role in the early stages of carcinogenesis of CRCs. This is the first study investigating SATB1 expression in CAPs. Besides this is the first report that shows different SATB1 expressions in conventional colorectal adenocarcinoma and mucinous carcinoma, and also in right-sided and left-sided CRC. Our results, with supporting new studies, can provide SATB1 as a possible candidate for targeted therapy for CRC patients.

PLK1 has tumor-suppressive potential in APC-truncated colon cancer cells.

The spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). The expression of APC-ΔC in colon cells reduces the accumulation of mitotic cells upon PLK1 inhibition, accelerates mitotic exit and increases the survival of cells with enhanced chromosomal abnormalities. The inhibition of PLK1 in mitotic, APC-∆C-expressing cells reduces the kinetochore levels of Aurora B and hampers the recruitment of SAC component suggesting a compromised mitotic checkpoint. Furthermore, Plk1 inhibition (RNAi, pharmacological compounds) promotes the development of adenomatous polyps in two independent Apc Min/+ mouse models. High PLK1 expression increases the survival of colon cancer patients expressing a truncated APC significantly.

Ovarian function's role during cancer cachexia progression in the female mouse.

Cachexia is a debilitating condition that occurs with chronic disease, including cancer; our research has shown that some regulation of cancer cachexia progression is affected by sex differences. The ApcMin/+ mouse is genetically predisposed to develop intestinal tumors; IL-6 signaling and hypogonadism are associated with cachexia severity in the male. This relationship in the female warrants further investigation, as we have shown that the ability of IL-6 to induce cachexia differs between the sexes. Since ovarian reproductive function relies on a complex system of endocrine signaling to affect whole body homeostasis, we examined the relationship between ovarian reproductive function and progression of cancer cachexia in the female ApcMin/+ mouse. Our study of ovarian reproductive function in female ApcMin/+ mice showed disease-related cessation of estrous cycling (acyclicity) in 38% of mice. Acyclicity, including morphological and functional losses and enhanced muscle inflammatory gene expression, was associated with severe cachexia. Interestingly, ovariectomy rescued body weight and muscle mass and function but increased muscle sensitivity to systemic IL-6 overexpression. In conclusion, our results provide evidence for a relationship between ovarian reproductive function and cachexia progression in female ApcMin/+ mice.

Childbirth after surgery for familial adenomatous polyposis in Japan.

PURPOSE: Familial adenomatous polyposis (FAP) is a genetic disorder. Some female patients with FAP can become pregnant. However, the current state of childbirth after surgery for FAP is unclear in Japan. METHODS: The study investigated 303 patients (147 female) who had undergone surgery for FAP at the 23 institutions between 2000 and 2012. RESULTS: Eighty female patients had information available on childbirth after surgery for FAP. Eight patients (10 %) gave birth after surgery. The mean age at surgery for FAP was 27 (range 20-41) years and 37 years in patients with and without childbirth after surgery, respectively (P = 0.044). The rate of childbirth after surgery was 17 % in women ≤30 years of age and 13 % in those ≤40 years of age. Although only one patient with invasive cancer (2.9 %) gave childbirth after surgery, seven patients without cancer (15.6 %) gave birth (P = 0.045). CONCLUSIONS: This study clarified the current state of childbirth after surgery for FAP in Japan. It is important to use these data to determine the best therapeutic approach for female FAP patients.

Aldosterone-Producing Adenoma With a Somatic KCNJ5 Mutation Revealing APC-Dependent Familial Adenomatous Polyposis.

CONTEXT: Recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 have been identified in aldosterone-producing adenomas (APAs). The question as to whether they are responsible for both nodulation and aldosterone production is not solved. CASE DESCRIPTION: We describe the case of a young patient who was diagnosed with severe arterial hypertension due to primary aldosteronism at age 26 years, followed by hemorrhagic stroke 4 years later. Abdominal computed tomography showed bilateral macronodular adrenal hyperplasia. Identification of lateralized aldosterone secretion led to right adrenalectomy, followed by normalization of biochemical and hormonal parameters and amelioration of blood pressure. The resected adrenal showed three nodules, one of them expressing aldosterone synthase and harboring a somatic KNCJ5 mutation. A Weiss revisited index of 3 of the APA prompted us to perform a second 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography after surgery, which revealed abnormal rectal activity despite the absence of clinical symptoms. Gastrointestinal exploration showed multiple polyps with severe dysplasia, and the diagnosis of familial adenomatous polyposis was established in the presence of a germline heterozygous APC gene mutation. Sequencing of somatic DNA from the APA and a second adrenal nodule revealed biallelic APC inactivation due to loss of heterozygosity in both nodules. CONCLUSIONS: This case report underlines the need for establishing the frequency of germline APC variants in patients with primary aldosteronism and bilateral macronodular adrenal hyperplasia because their presence may predispose to APA development and severe hypertension well before the first familial adenomatous polyposis symptoms appear. From a mechanistic point of view, it supports a two-hit model for APA development, whereby the first hit drives increased cell proliferation whereas the second hit specifies the pattern of hormonal secretion.

Impact of Screening on Survival in Familial Adenomatous Polyposis.

GOALS: Our aim was to determine whether the screening of family members of familial adenomatous polyposis (FAP) patients significantly influences survival, and to gauge the extent of FAP-related causes of death. BACKGROUND: The screening of families with FAP has been shown to be profitable in reducing colorectal cancer-related mortality, but conclusions about the screening effect on overall survival has been controversial. STUDY: This is a nationwide population-based retrospective cohort study, and the primary outcome of interest was overall mortality and survival. A total of 154 families with at least 1 clinically diagnosed FAP patient between 1963 and 2015 were included. There were altogether 194 probands and 225 call-ups. During the follow-up period, 2639 person-years with 92 deaths among probands were observed and 3634 person-years and 30 deaths among call-ups. We report crude mortality rates and standardized mortality ratios together with descriptive statistics. We compared the survival of probands and call-ups to the population by relative survival method. RESULTS: The crude mortality rate among probands was 34.9 per 1000 person-years and 8.3 among call-ups. The standardized mortality ratios for call-ups was 2.47 (confidence interval, 1.69-3.46) and for probands 4.07 (confidence interval, 3.29-4.96) (P=0.014). The relative survival of probands was significantly lower than call-ups (P=0.0018), and 20-year relative survival for call-ups was 94% (88% to 100%). Over two thirds of all deaths were FAP related. CONCLUSIONS: Survival of screened family members of FAP patients is comparable to the general population within 20 years after diagnosis. Therefore, participation in surveillance should not be delayed when a family member with FAP has been detected.

Problems after restorative proctocolectomy: assessment and therapy.

PURPOSE OF REVIEW: Restorative proctocolectomy with ileal pouch-anal anastomosis is the surgical treatment of choice for patients with ulcerative colitis or familial adenomatous polyposis who require colectomy. Although the surgical procedure significantly improves the patients' quality of life, complications are common. Mechanical or structural complications related to surgical techniques as well as chronic pouchitis are common after the procedure. RECENT FINDINGS: Recent literature has suggested some of those mechanical complications, along with chronic pouchitis, may share similar risk factors, particularly between anastomotic leak or sinus and chronic pouchitis. Those factors include male gender, obesity, weight gain, and Clostridium difficile infection. SUMMARY: Mounting clinical evidence suggests that ischemia or excessive fat deposition plays an important role in the development of the surgical procedure-associated mechanical complication as well as chronic antibiotic-refractory pouchitis. Those findings along with the theory of ischemia/fat deposition will shed some light on the pathogenesis of the complex pouch disorders, providing the guidance for the risk stratification, prevention, diagnosis, and management.

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

El cáncer colorrectal es la neoplasia más frecuente en ambos sexos en España. Entre el 20-25% de los casos presentan historia familiar de dicho tumor y un 5-6% se presentan en el contexto de una mutación germinal, es decir, en el contexto de un síndrome hereditario. La importancia de identificar a los pacientes con síndromes hereditarios que predisponen a cáncer colorrectal radica en la posibilidad de poder aplicar medidas preventivas, de cribado y un manejo más adecuado tanto para ellos como para sus familiares. A continuación se detallan los estudios más relevantes sobre el cáncer colorrectal hereditario que fueron presentados este año en el congreso de la American Gastroenterological Association

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

ß-Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis.

Mutations in Adenomatous polyposis coli (APC) underlie familial adenomatous polyposis (FAP), an inherited cancer syndrome characterized by the widespread development of colorectal polyps. APC is best known as a scaffold protein in the ß-catenin destruction complex, whose activity is antagonized by canonical Wnt signaling. Whether other effector pathways mediate APC's tumor suppressor function is less clear. Here we report that activation of YAP, the downstream effector of the Hippo signaling pathway, is a general hallmark of tubular adenomas from FAP patients. We show that APC functions as a scaffold protein that facilitates the Hippo kinase cascade by interacting with Sav1 and Lats1. Consistent with the molecular link between APC and the Hippo signaling pathway, genetic analysis reveals that YAP is absolutely required for the development of APC-deficient adenomas. These findings establish Hippo-YAP signaling as a critical effector pathway downstream from APC, independent from its involvement in the ß-catenin destruction complex.

Quality of life, social impact and functional outcome following ileal pouch-anal anastomosis for ulcerative colitis and familial adenomatous polyposis.

This study aims to assess quality of life (QoL), functional outcome, and social impact following ileal pouch anal anastomosis (IPAA) for ulcerative colitis (UC) and familial adenomatous polyposis (FAP) since Indian data is limited. Data was collected prospectively from patients who underwent IPAA for UC or FAP from 2004 to 2013. QoL and functional outcome at 1, 3, and 5 years after surgery, return to work, and change of job (social impact) were documented. QoL was assessed using the validated Cleveland Global Quality of Life (CGQL) score, the normal score being 1.0. Twenty-five patients were analyzed. Mean CGQL scores before surgery and at 1, 3, and 5 years were 0.5, 0.63, 0.73, and 0.8, respectively. FAP patients had better scores at 3 and 5 years. Only 40 % returned to same job. Sixty-four percent returned to work within a year. The median number of bowel movements per 24 h was less for FAP patients at 3 and 5 years. UC patients on long-term steroids had poorer function at 3 years. Long-term QoL and functional outcomes following IPAA are acceptable. Initial deterioration in QoL, mainly in FAP and long-term adverse social impact in both groups should not be underestimated. UC patients on long-term steroids showed delayed improvement in pouch function.

HMGA1 drives metabolic reprogramming of intestinal epithelium during hyperproliferation, polyposis, and colorectal carcinogenesis.

Although significant progress has been made in the diagnosis and treatment of colorectal cancer (CRC), it remains a leading cause of cancer death worldwide. Early identification and removal of polyps that may progress to overt CRC is the cornerstone of CRC prevention. Expression of the High Mobility Group A1 (HMGA1) gene is significantly elevated in CRCs as compared with adjacent, nonmalignant tissues. We investigated metabolic aberrations induced by HMGA1 overexpression in small intestinal and colonic epithelium using traveling wave ion mobility mass spectrometry (TWIMMS) in a transgenic model in which murine Hmga1 was misexpressed in colonic epithelium. To determine if these Hmga1-induced metabolic alterations in mice were relevant to human colorectal carcinogenesis, we also investigated tumors from patients with CRC and matched, adjacent, nonmalignant tissues. Multivariate statistical methods and manual comparisons were used to identify metabolites specific to Hmga1 and CRC. Statistical modeling of data revealed distinct metabolic patterns in Hmga1 transgenics and human CRC samples as compared with the control tissues. We discovered that 13 metabolites were specific for Hmga1 in murine intestinal epithelium and also found in human CRC. Several of these metabolites function in fatty acid metabolism and membrane composition. Although further validation is needed, our results suggest that high levels of HMGA1 protein drive metabolic alterations that contribute to CRC pathogenesis through fatty acid synthesis. These metabolites could serve as potential biomarkers or therapeutic targets.

Características fenotípicas de los pacientes con síndrome de poliposis serrada de colon: estudio de 23 casos / Phenotype characteristics of patients with colonic serrated polyposis syndrome: a study of 23 cases

INTRODUCCIÓN: El síndrome de poliposis serrada (SPS) es una entidad rara caracterizada por la presencia de múltiples pólipos de histología hiperplásica en el colon y un riesgo aumentado de presentar y desarrollar cáncer colorrectal (CCR). OBJETIVO: Evaluar las características clínicas y fenotípicas de los sujetos que reúnen alguno de los 3 criterios de la OMS para el diagnóstico de SPS, diagnosticados y seguidos en nuestro hospital. PACIENTES Y MÉTODOS: Se revisan los pacientes con SPS durante 2005-2012, periodo en el que se realizan 24.208 colonoscopias. Se analizan edad, sexo, historia familiar de CCR (APC/MYH), fenotipo proximal/mixto/distal, indicación de colonoscopia, número, tamaño, localización de los pólipos hiperplásicos, presencia de pólipos mixtos/adenomatosos, CCRI, seguimiento y tratamiento endoscópico/quirúrgico. RESULTADOS: Se han recogido 23 casos (19 hombres). El promedio de edad fue 51 años. El 34% presentaba antecedentes familiares de CCR o pólipos. El fenotipo distal (48%) fue más frecuente. El 73% presentaba pólipos adenomatosos sincrónicamente, y el 26% un CCR. El 57% eran pacientes asintomáticos. Se realizó cirugía en 9 casos (6 por cáncer y 3 por poliposis, y 14 con polipectomías sucesivas y observación). Un total de 11 pacientes (47%) presentaron lesiones recurrentes/persistentes tras el tratamiento quirúrgico/endoscópico inicial. CONCLUSIÓN: El SPS es un síndrome heterogéneo, variable en tipo, tamaño, distribución y número de pólipos, siendo más frecuente en varones fumadores con fenotipo distal. La mayoría de los pacientes presentan además pólipos adenomatosos de manera sincrónica. Estos pacientes requieren una evaluación organizada multidisciplinary

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

Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones.

It recently has been recognized that men develop colonic adenomas and carcinomas at an earlier age and at a higher rate than women. In the Apc(Pirc/+) (Pirc) rat model of early colonic cancer, this sex susceptibility was recapitulated, with male Pirc rats developing twice as many adenomas as females. Analysis of large datasets revealed that the Apc(Min/+) mouse also shows enhanced male susceptibility to adenomagenesis, but only in the colon. In addition, WT mice treated with injections of the carcinogen azoxymethane (AOM) showed increased numbers of colonic adenomas in males. The mechanism underlying these observations was investigated by manipulation of hormonal status. The preponderance of colonic adenomas in the Pirc rat model allowed a statistically significant investigation in vivo of the mechanism of sex hormone action on the development of colonic adenomas. Females depleted of endogenous hormones by ovariectomy did not exhibit a change in prevalence of adenomas, nor was any effect observed with replacement of one or a combination of female hormones. In contrast, depletion of male hormones by orchidectomy (castration) markedly protected the Pirc rat from adenoma development, whereas supplementation with testosterone reversed that effect. These observations were recapitulated in the AOM mouse model. Androgen receptor was undetectable in the colon or adenomas, making it likely that testosterone acts indirectly on the tumor lineage. Our findings suggest that indirect tumor-promoting effects of testosterone likely explain the disparity between the sexes in the development of colonic adenomas.

[Clinical and genetic features of APC- and MYH-mutation-negative patients with multiple polyposis of large bowel that tested by conventional methods].

The genealogic analysis, molecular and clinical investigations has been carried out in 19 probands with multiple colorectal adenomas (approximately 100 or more). Twelve of these patients (63.1%) were APC and MYH mutation-negative. Three (25%) probands have positive family history. The median of the disease manifestation age in APC-negative patients was intermediate between the median of the disease manifestation age in APC- and MYH-positive patients. Extraintestinal manifestations in the APC-negative probands are more rare than in APC-positive patients. A half of APC- and MYH-negative probands with multiple polyposis had colorectal cancer. APC- and MYH-negative patients formed a genetically heterogenous group.

Cell and tissue polarity in the intestinal tract during tumourigenesis: cells still know the right way up, but tissue organization is lost.

Cell and tissue polarity are tightly coupled and are vital for normal tissue homeostasis. Changes in cellular and tissue organization are common to even early stages of disease, particularly cancer. The digestive tract is the site of the second most common cause of cancer deaths in the developed world. Tumours in this tissue arise in an epithelium that has a number of axes of cell and tissue polarity. Changes in cell and tissue polarity in response to genetic changes that are known to underpin disease progression provide clues about the link between molecular-, cellular- and tissue-based mechanisms that accompany cancer. Mutations in adenomatous polyposis coli (APC) are common to most colorectal cancers in humans and are sufficient to cause tumours in mouse intestine. Tissue organoids mimic many features of whole tissue and permit identifying changes at different times after inactivation of APC. Using gut organoids, we show that tissue polarity is lost very early during cancer progression, whereas cell polarity, at least apical-basal polarity, is maintained and changes only at later stages. These observations reflect the situation in tumours and validate tissue organoids as a useful system to investigate the relationship between cell polarity and tissue organization.