Familial Adenomatous Polyposis

Division of Gastroenterology, Department of Medicine, The Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
The American Journal of Gastroenterology (Impact Factor: 10.76). 03/2006; 101(2):385-98. DOI: 10.1111/j.1572-0241.2006.00375.x
Source: PubMed


Familial adenomatous polyposis (FAP) is an autosomal-dominant colorectal cancer syndrome, caused by a germline mutation in the adenomatous polyposis coli (APC) gene, on chromosome 5q21. It is characterized by hundreds of adenomatous colorectal polyps, with an almost inevitable progression to colorectal cancer at an average age of 35 to 40 yr. Associated features include upper gastrointestinal tract polyps, congenital hypertrophy of the retinal pigment epithelium, desmoid tumors, and other extracolonic malignancies. Gardner syndrome is more of a historical subdivision of FAP, characterized by osteomas, dental anomalies, epidermal cysts, and soft tissue tumors. Other specified variants include Turcot syndrome (associated with central nervous system malignancies) and hereditary desmoid disease. Several genotype-phenotype correlations have been observed. Attenuated FAP is a phenotypically distinct entity, presenting with fewer than 100 adenomas. Multiple colorectal adenomas can also be caused by mutations in the human MutY homologue (MYH) gene, in an autosomal recessive condition referred to as MYH associated polyposis (MAP). Endoscopic screening of FAP probands and relatives is advocated as early as the ages of 10-12 yr, with the objective of reducing the occurrence of colorectal cancer. Colectomy remains the optimal prophylactic treatment, while the choice of procedure (subtotal vs proctocolectomy) is still controversial. Along with identifying better chemopreventive agents, optimizing screening of extracolonic cancers and applying new radiological and endoscopic technology to the diagnosis and management of extracolonic features are the major challenges for the future.

    • "TherearealsoseveralhumangeneticsyndromesthatpredisposetoCRC.Familialadenomatous polyposis(FAP)patientshavegerm-lineAPCmutations,leavingthemwithonlyonefunctionalcopyof thiscrucialtumorsuppressorprotein(Fearon2011).Thus,thelikelihoodoflossofheterozygosityatthe APClocusisdramaticallyincreasedinFAPpatients,andnearly100%ofcasesdevelopCRCby36years ofage(GaliatsatosandFoulkes2006).TypicaltreatmentforFAPinvolvesresectionofthecoloninearly adulthoodtopreventdevelopmentofmetastaticCRC(LynchanddelaChapelle2003).AlthoughFAP accountsforonly0.5%ofCRCcases(Fearon2011),itsgeneticbasishasmadeitanattractiveforusein modelorganisms.TheApcMin/+mousemodelisbasedonthehumanFAPsyndrome,andisthemain modelforstudiesofCRCdevelopmentandprogression(Suetal.1992).TumorsinApcmin/+miceareApc- negative,demonstratingthatlossofheterozygosity(LOH)isrequiredfortumordevelopment(Luongoet al.1994).Interestingly,ApcMin/+miceformtumorspredominantlyinthesmallintestine,asopposedto humanFAP,whichdevelopsadenomasinthecolon(Suetal.1992).Thecauseforthisdifferent anatomicalsiteisnotwellunderstood,althoughithasbeennotedthatseveralmarkersofhumanCRC, suchastheCBCstemcellmarkerOlfm4,arenotexpressedinthemurinecolonicepithelium(vander Flieretal.2009).Nevertheless,ApcMin/+micehaveproventobeausefultoolinunderstandingboth intestinalandcolorectaltumorigenesis. "
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    ABSTRACT: The intestinal epithelium is an ideal model system for the study of normal and pathological differentiation processes. The mammalian intestinal epithelium is a single cell layer comprising proliferative crypts and differentiated villi. The crypts contain both proliferating and quiescent stem cell populations that self-renew and produce all the differentiated cell types, which are replaced every 3-5 days. The genetics of intestinal development, homeostasis, and disease are well defined, but less is known about the contribution of epigenetics in modulating these processes. Epigenetics refers to heritable phenotypic traits, including gene expression, which are independent of mutations in the DNA sequence. We have known for several decades that human colorectal cancers contain hypomethylated DNA, but the causes and consequences of this phenomenon are not fully understood. In contrast, tumor suppressor gene promoters are often hypermethylated in colorectal cancer, resulting in decreased expression of the associated gene. In this review, we describe the role that epigenetics plays in intestinal homeostasis and disease, with an emphasis on results from mouse models. We highlight the importance of producing and analyzing next-generation sequencing data detailing the epigenome from intestinal stem cell to differentiated intestinal villus cell.
    No preview · Article · Jul 2015 · Cellular and Molecular Life Sciences CMLS
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    • "Dento-osseous anomalies such as osteomas, dense bone island, odontomas, and supernumerary and impacted teeth are also proliferative benign lesions related to dento-osseous development and they are well documented in familial adenomatous polyposis (FAP) [20,21]. To our knowledge, dento-osseous alterations have not been previously reported in individuals with HNPCC. "
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    ABSTRACT: Introduction Hereditary nonpolyposis colorectal cancer is a colorectal cancer syndrome characterized by the development of colorectal cancer and extracolonic tumors, and this syndrome has an autosomal dominant mode of inheritance. To our knowledge, our study was the first to find dento-osseous anomalies and the second to observe Fordyce granules in a family with individuals with hereditary nonpolyposis colorectal cancer. Case presentations Twenty members of one Brazilian family with individuals with hereditary nonpolyposis colorectal cancer were analyzed according to the presence of colorectal cancer and the occurrence of Fordyce granules and dento-osseous anomalies. Their average age was 29.6 (range 7 to 53 years) years. Medical examinations of this family with hereditary nonpolyposis colorectal cancer were performed at the Coloproctology Division of our hospital. Then, all individuals were referred to our Oral Care Center for Inherited Diseases for intraoral examinations to verify the presence of Fordyce granules. Dental panoramic radiographs were done in order to describe dento-osseous anomalies on applying the Dental Panoramic Radiograph System. Of the 20 family members, four were diagnosed with hereditary nonpolyposis colorectal cancer and all four presented Fordyce granules in their upper lip, but only one of these four patients (Case 2) had a significant dento-osseous anomaly. Conclusions Our familial study verified the presence of Fordyce granules in all individuals diagnosed with hereditary nonpolyposis colorectal cancer, and the presence of significant dento-osseous anomalies in one of these cases. However, the relationship between oral manifestations and hereditary nonpolyposis colorectal cancer should be further investigated.
    Full-text · Article · Jul 2014 · Journal of Medical Case Reports
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    • "Colorectal cancer (CRC) represents one of the most important causes of cancer-related death, and is the second most frequent type of cancer after lung cancer [1] [2] [3]. While CRC is mostly identified in the sporadic form, a significant portion can also occur in the context on inflammatory bowel disease (IBD) [4] [5] or genetic syndromes, such as familial adenomatous polyposis (FAP) [6] [7] and Lynch syndrome [8]. The development of sporadic CRC is caused by the accumulation of genetic and epigenetic changes, which can be generally categorized into two types: (I) Approximately 80% of CRC patients undergo a well-characterized series of molecular events, described as adenoma–carcinoma sequence [9] [10] [11], involving chromosomal aberrations and mutations in several genes, such as APC, KRAS, P53 and DCC [12] [13] [14] [15] [16] [17]. "
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    ABSTRACT: Systemic mining of cancer exoproteome/secretome has emerged as a pivotal strategy for delineation of molecular pathways with mechanistic importance in cancer development, as well as the discovery of diagnostic/prognostic biomarkers. Although major advances in diagnostic and therapeutic management of colorectal cancer have been underscored in the last decade, this cancer still remains the second leading cause of cancer-related deaths in developed world. Despite previous studies on deciphering the colorectal cancer exoproteome, such studies lack adequate depth and robustness due to technological limitations. Here, using a well-established LC-MS/MS method on an LTQ-Orbitrap mass spectrometer, we extensively delineated the exoproteome of 12 colon cancer cell lines. In total, 2,979 non-redundant proteins were identified with minimum of two peptides, of which ~62% were extracellular or cell membrane-bound, based on prediction software. To further characterize this dataset and identify clinical opportunities, first, we investigated overrepresented molecular concepts of interest via enrichment map analysis and second, we demonstrated translational importance of certain proteins, such as olfactomedin-4 and kallikrein-related peptidases-6 and -10, by investigating their expression levels in patient tissues and/or fluids. Overall, the present study details a comprehensive colorectal cancer exoproteome dataset, and may be used as future platform for biomarker discovery, and hypothesis-generating studies. This article represents one of the most extensive and comprehensive proteomic datasets regarding the secreted/extracellular proteome of colorectal cancer cell lines. The reported datasets may form a platform for a plethora of future, discovery-based or hypothesis-generating studies, attempting to either delineate putative cancer biomarkers for CRC, or elucidate questions of mechanistic importance (e.g. investigation of deregulated pathways for CRC progression).
    Full-text · Article · Mar 2014 · Journal of proteomics
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