Features Of Familial Adenomatous Polyposis Research Articles

A differential diagnosis of a head and neck bony lesion: Review of a case series with 18 patients with extraintestinal features of familial adenomatous polyposis.

A differential diagnosis of a head and neck bony lesion: Review of a case series with 18 patients with extraintestinal features of familial adenomatous polyposis.

Abstract IA01: Recent advances in studying EGFR and its ligands in colorectal cancer

Abstract At Vanderbilt, we have fashioned a three-pronged approach to study colorectal cancer (CRC): from in vitro studies to those both in mouse and humans. In vitro, we have analyzed trafficking and cell-surface delivery of EGFR and its ligands in a battery of CRC cell lines that retain the ability to form uniform polarizing monolayers on Transwell filters. In the mouse, we have discovered that the pan-ERBB inhibitor, LRIG1, marks a largely quiescent population of colonic stem cells distinct from LGR5 and that administration of tamoxifen to Lrig1-CreET2;Apcfl/+ mice eliminates one allele of Apc and results in highly penetrant, multiple, histologically advanced adenomas in the distal colon 50-100 days later; these adenomas show the expected loss of the 2nd Apc allele. Later this month, we will submit the 4th renewal of our GI Specialized Programs of Research Excellence (SPORE) that focuses on CRC. An advance in each of these areas will be discussed. Based on our trafficking studies, we have discovered that EGFR ligands can be released in endosome-derived small vesicles called exosomes. The ligands are signaling competent and bind to EGFR on recipient cells. We have termed this new mode of signaling, Exosomal Targeted Receptor Activation (ExTRAcrine). We have recently advanced this work to studying EGFR in exosomes isolated from mouse and human plasma using a method we have developed, fluorescence-based vesicle sorting (FAVS). Second, a limitation to studying EGFR in the mouse is the lack of robust reagents to monitor EGFR by immunohistochemistry. To circumvent this limitation, we have used CRISPR gene editing to target the endogenous mouse locus to create a chimeric EGFR-Emerald (green) reporter mouse. We will present data showing the value of this mouse in monitoring EGFR in the normal colon and in colonic tumors generated in our Lrig1-CreERT2;Apcfl/+ mouse model. Finally, we have developed a new 3D system to study CRC. Using this system, we have discovered a novel mode of cetuximab resistance and will show its relevance to human CRC. 1. Singh B, Coffey RJ. Trafficking of epidermal growth factor receptor ligands in polarized epithelial cells. Annu Rev Physiol 76: 275-300, 2014. PMC4180094. 2. Higginbotham JN, Demory Beckler M, Gephart JD, Franklin JL, Bogatcheva G, Kremers GJ, Piston DW, Ayers GD, McConnell RE, Tyska MJ, Coffey RJ. Amphiregulin exosomes increase cancer cell invasion. Curr Biol 21: 779-86, 2011. PMC3417320. 3. Higginbotham JN, Zhang Q, Jeppesen DK, Scott AM, Manning HC, Ochieng J, Franklin JL, Coffey RJ. Identification and characterization of EGF receptor in individual exosomes by fluorescence-activated vesicle sorting. J Extracell Vesicles 5: 29254, 2016. PMC4921784. 4. Powell AE, Wang Y, Li Y, Poulin EJ, Means AL, Washington MK, Higginbotham JN, Juchheim A, Prasad N, Levy SE, Guo Y, Shyr Y, Aronow BJ, Haigis KM, Franklin JL, Coffey RJ. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149: 146-58, 2012. PMCPMC3563328. 5. Powell AE, Vlacich G, Zhao ZY, McKinley ET, Washington MK, Manning HC, Coffey RJ. Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis. Am J Physiol Gastrointest Liver Physiol 307: G16-23, 2014. PMC4080164. 6. Wang Y, Shi C, Lu Y, Poulin EJ, Franklin JL, Coffey RJ. Loss of Lrig1 leads to expansion of Brunner glands followed by duodenal adenomas with gastric metaplasia. Am J Pathol 185: 1123-34, 2015. PMC4380843. 7. Poulin EJ, Powell AE, Wang Y, Li Y, Franklin JL, Coffey RJ. Using a new Lrig1 reporter mouse to assess differences between two Lrig1 antibodies in the intestine. Stem Cell Res 13: 422-430, 2014. PMC638408. 8. Kondo J, Powell AE, Wang Y, Musser MA, Southard-Smith EM, Franklin JL, Coffey RJ. LRIG1 Regulates Ontogeny of Smooth Muscle-Derived Subsets of Interstitial Cells of Cajal in Mice. Gastroenterology 149: 407-19 e8, 2015. PMC4527342. Citation Format: Robert J. Coffey. Recent advances in studying EGFR and its ligands in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA01.

Clinicopathological features of familial adenomatous polyposis in Korean patients.

To identify prognostic factors and to correlate APC mutations with clinical features, including extracolic manifestations. One hundred thirty-five patients who underwent surgical procedures for familial adenomatous polyposis (FAP) were included. FAP was diagnosed when the number of adenomatous polyps was > 100. Data related to patient, extracoloic manifestations, cancer characteristics, operative procedure, follow up and surveillance were collected. APC mutation testing was performed in the 30 most recent patients. DNA was extracted from peripheral blood and polymerase chain reaction products using 31 primer pairs on APC gene were sequenced. A retrospective study was performed to investigate a causal relationship between prognosis and feature of patient. The mean age of the 51 patients with colorectal cancer (CRC) was older than that of those without CRC (30.5 vs 36.9, P = 0.002). Older individuals were more likely to have colon cancer at the time of FAP diagnosis [odds ratio, 4.75 (95%CI: 1.71-13.89) and 5.91(1.76-22.12) for 40-49 years and age > 50 vs age < 30). The number of confirmed deaths was 13 and the median age at death was 40 years (range, 27 to 85 years). Ten of the deaths (76.9%) were from CRC. Another cause of two cases of death were desmoid tumors (15.4%). Development of cancer on remnant rectal or ileal mucosa after surgery was not observed. The APC mutation testing revealed 23 pathogenic mutations and one likely pathogenic mutation, among which were four novel mutations. The correlation between mutational status and clinical manifestations was investigated. Mutations that could prodict poor prognosis were at codon 1309 which located on mutation cluster region, codon 1465 and codon 1507. Identification of APC mutations should aid in the diagnosis and counseling of family members in terms of early diagnosis and management of FAP.

Abstract 58: Highly tractable stem cell-driven mouse model of colonic neoplasia with features of familial adenomatous polyposis

Abstract The ApcMin mouse, which harbors a germline mutation in Apc, is the most widely utilized mouse model of colorectal neoplasia; a major drawback to this model is that the tumors arise mainly in the small intestine. In addition, tumorigenesis occurs randomly within the epithelium, complicating examination of the precise tumor cell-of-origin and local environmental cues that promote tumorigenesis. Given the growing importance of stem cells in tumor initiation, it is desirable to build models that target this population. To this end, it is surprising that elimination of one Apc allele in Lgr5+ stem cells does not result in subsequent loss of heterozygosity (LOH) and tumor formation. We recently reported that Lrig1, a pan-ErbB inhibitor, marks a population of stem cells at the base of colonic crypts. To examine the dynamics of colonic tumor initiation and progression, and to compare our disease model with human patients, we examined tamoxifen-induced Lrig1-CreERT2/+;Apcfl/+ mice where Apc LOH occurs in the Lrig1+ stem cells yielding high-grade lesions, faithfully recapitulating this key genetic event in human colon cancer (CRC) initiation. Colonic lesions grow into the luminal space over the span of 50-100 days and can be visualized by both colonoscopic and FDG-PET non-invasive imaging. This inducible mouse model also harbors extra-colonic features of human Familial Adenomatous Polyposis (FAP), an autosomal dominant variant of CRC caused by germline mutations in APC. With stochastic LOH, affected individuals develop colonic adenomas that invariably progress to CRC and many patients develop peri-ampullary tumors, gastric abnormalities, desmoid and soft tissue tumors, along with characteristic eye findings. To further examine the molecular parallels between the mouse and human colonic tumors, we performed RNA-Seq analysis and validated selected targets with immunofluorescence. Interestingly, a number of genes were found to be differentially regulated in the Lrig1-CreERT2/+;Apcfl/+ colonic tumors compared to ApcMin colonic tumors, despite both models being driven by the Wnt/β-catenin pathway. This model is the closest mimic of FAP to-date and represents a tractable system to test the efficacy of innovative therapeutic interventions whose efficacy can be monitored over time by colonoscopy and non-invasive imaging modalities. Our inducible system also allows a detailed dissection of the pre-neoplastic spatiotemporal events that occur following removal of one Apc allele in the mouse colon. To complement these studies, we are currently examining both Lgr5+ and Lrig1+ stem cell participation in colonic tumor initiation both in vivo and ex vivo at super resolution, using our newly developed Lrig1-Apple and Lrig1-Apple/+;Lgr5-EGFP fluorescent reporter mice. Citation Format: Anne E. Powell, Gregory Vlacich, Zhen-Yang Zhao, Eliot McKinley, Rebekah Karns, Mary Kay Washington, Henry Charles Manning, Bruce Aronow, Robert Coffey. Highly tractable stem cell-driven mouse model of colonic neoplasia with features of familial adenomatous polyposis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 58. doi:10.1158/1538-7445.AM2014-58

Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis.

Individuals with familial adenomatous polyposis (FAP) harbor a germline mutation in adenomatous polyposis coli (APC). The major clinical manifestation is development of multiple colonic tumors at a young age due to stochastic loss of the remaining APC allele. Extracolonic features, including periampullary tumors, gastric abnormalities, and congenital hypertrophy of the retinal pigment epithelium, may occur. The objective of this study was to develop a mouse model that simulates these features of FAP. We combined our Lrig1-CreERT2/+ mice with Apcfl/+ mice, eliminated one copy of Apc in leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1)-positive (Lrig1(+)) progenitor cells with tamoxifen injection, and monitored tumor formation in the colon by colonoscopy and PET. Initial loss of one Apc allele in Lrig1(+) cells results in a predictable pattern of preneoplastic changes, culminating in multiple distal colonic tumors within 50 days of induction, as well as the extracolonic manifestations of FAP mentioned above. We show that tumor formation can be monitored by noninvasive PET imaging. This inducible stem cell-driven model recapitulates features of FAP and offers a tractable platform on which therapeutic interventions can be monitored over time by colonoscopy and noninvasive imaging.

A case of pneumatosis cystoides intestinalis mimicking familial adenomatous polyposis

In rare cases the diagnosis of Familial Adenomatous Polyposis (FAP) may not be simple or straightforward. We describe the case of a 54-year man in whom endoscopic and histological features of FAP led to proctocolectomy with ileoanal anastomosis. At anatomical examination, air-filled cystic formations in the submucosa and subserosa of the entire large bowel led to the diagnosis of "Pneumatosis Cystoides Intestinalis", a rare clinical condition featured by the infiltration (or the production) of gas within the intestinal wall. In this case the disease was associated with a long-lasting ingestion of acarbose; as suggested by previous reports, it is possible that gas produced by the fermentation of this unabsorbable carbohydrate penetrates the bowel wall giving origin to cystic formation and to the endoscopic appearance of several polypoid lesions in the large bowel. This report indicates that in rare occasions Pneumatosis Intestinalis can lead to a wrong diagnosis of FAP.

Inherited Polyposis Syndromes: Molecular Mechanisms, Clinicopathology, and Genetic Testing

The inherited polyposis syndromes are a group of conditions in which multiple gastrointestinal polyps occur in the lumen of the gastrointestinal tract, most exhibit an increased risk of colon cancer. Benign and malignant extraintestinal tumors might also be observed. Recent elucidation of the underlying gene mutations has contributed to our understanding of the cell biology and molecular mechanisms associated with gastrointestinal tumorigenesis. Developments have also allowed genetic testing to become an integral component in accurate diagnosis, categorization, and management of inherited polyposis syndromes. In this review, we will focus on familial adenomatous polyposis, mutY human homologue-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis, and Cowden syndrome. It is essential that both physician and patient understand the benefits and limitations of genetic testing before submission of samples to the laboratory. There are many issues accompanying molecular diagnosis of cancer syndromes, and genetic counseling is an essential prelude to genetic testing.

The use and interpretation of commercial APC gene testing for familial adenomatous polyposis.

The use of commercially available tests for genes linked to familial cancer has aroused concern about the impact of these tests on patients. Familial adenomatous polyposis is an autosomal dominant disease caused by a germ-line mutation of the adenomatous polyposis coli (APC) gene that causes colorectal cancer if prophylactic colectomy is not performed. We evaluated the clinical use of commercial APC gene testing. We assessed indications for APC gene testing, whether informed consent was obtained and genetic counseling was offered before testing, and the interpretation of the results through telephone interviews with physicians and genetic counselors in a nationwide sample of 177 patients from 125 families who underwent testing during 1995. Of the 177 patients tested, 83.0 percent had clinical features of familial adenomatous polyposis or were at risk for the disease-both valid indications for being tested. The appropriate strategy for presymptomatic testing was used in 79.4 percent (50 of 63 patients). Only 18.6 percent (33 of 177) received genetic counseling before the test, and only 16.9 percent (28 of 166) provided written informed consent. In 31.6 percent of the cases the physicians misinterpreted the test results. Among the patients with unconventional indications for testing, the rate of positive results was only 2.3 percent (1 of 44). Patients who underwent genetic tests for familial adenomatous polyposis often received inadequate counseling and would have been given incorrectly interpreted results. Physicians should be prepared to offer genetic counseling if they order genetic tests.

Extracolonic features of familial adenomatous polyposis in patients with sporadic colorectal cancer.

We have investigated the occurrence of attenuated extracolonic manifestations (AEMs) of familial adenomatous polyposis (FAP) in patients with non-polyposis colorectal cancer. In a prospective case-control study, we observed that significantly more colorectal cancer patients exhibited AEM than did age and sex-matched controls (19.5% vs 7.5%, P < 0.004). However patients with AEMs do not have occult FAP, as we found no heterozygous adenomatous polyposis coli (APC) gene mutations despite extensive analysis of constitutional DNA. Genome-wide DNA replication errors (RERs) occur in a proportion of colorectal cancers, particularly right-sided lesions and in almost all tumours from hereditary non-polyposis colorectal cancer (HNPCC) patients. As AEMs have been reported in familial colon cancer cases, we investigated the relationship of AEMs to tumour RER phenotype. There was indeed an excess of AEMs in patients with right-sided tumours (30.2% of 53 patients vs 14.7% of 116 patients, P < 0.03) and in those with RER tumours (3 out of 12 patients with RER tumours vs none out of 21 patients with non-RER tumours, P < 0.05). Two patients with AEM were from HNPCC families compared with none of those without AEM (P < 0.05). The association of AEMs with colorectal cancer is intriguing, and we speculate that it may be a manifestation of mutational mosaicism of the APC gene, perhaps associated with a constitutional defect in DNA mismatch pair.