Familial adenomatous polyposis
Encyclopedia
Familial adenomatous polyposis (FAP) is an inherited condition in which numerous polyp
s form mainly in the epithelium
of the large intestine
. While these polyps start out benign
, malignant transformation
into colon cancer
occurs when not treated.
due to gradually developing iron deficiency. If malignancy develops, this may present with weight loss
, altered bowel habit, or even metastasis
to the liver
or elsewhere.
The genetic determinant in familial polyposis may also predispose carriers to other malignancies, e.g., of the duodenum
and stomach
. Other signs that may point to FAP are pigmented lesions of the retina
("CHRPE - congenital hypertrophy of the retinal pigment epithelium"), jaw cysts, sebaceous cyst
s, and osteoma
ta (benign bone tumors). The combination of polyposis, osteomas, fibroma
s and sebaceous cyst
s is termed Gardner's syndrome
(with or without abnormal scarring).
and virtual colonoscopy
can suggest the diagnosis of FAP.
Once the diagnosis of FAP is made, close colonoscopic
surveillance with polypectomy
is required. Prophylactic colectomy
is indicated if more than a hundred polyps are present, if there are severely dysplastic polyps, or if multiple polyps larger than 1 cm are present. When a partial colectomy is performed, colonoscopic surveillance of the remaining colon is necessary as the individual still carries significant risk of developing colon cancer.
Ultrasound
of the abdomen and blood test
s evaluating liver function
are often performed to rule out metastasis
to the liver.
Genetic testing
provides the ultimate diagnosis in 95% of cases; genetic counseling
is usually needed in families where FAP has been diagnosed. Testing may also aid in the diagnosis of borderline cases in families that are otherwise known to p34.3 and p32.1 (1p34.3-p32.1).
APC
is a tumour suppressor gene, acting as a "gatekeeper" to prevent development of tumours. Mutation of APC also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer.
Although the polyps are inherently benign, the first step of the two-hit hypothesis
has already taken place: the inherited APC mutation. Often, the remaining "normal" allele
is mutated or deleted, accelerating generation of polyps. Further mutations (e.g. in p53
or kRAS) to APC-mutated cells are much more likely to lead to cancer than they would in non-mutated epithelial
cells.
The normal function of the APC gene product is still being investigated; it is present both the cell nucleus
and the membrane. The canonical tumor-suppressor function of Apc is suppression of the oncogenic protein beta-catenin
. However, other tumor-suppressor functions of Apc may be related to cell adherence and cytoskeleton
organization.
MUTYH
encodes DNA repair
enzyme MYH glycosylase. During normal cellular activities, guanine
sometimes becomes altered by oxygen
, which causes it to pair with adenine
instead of cytosine
. MYH glycosylase fixes these mistakes by base excision repair
, such that mutation
s do not accumulate in the DNA
and lead to tumor formation. When MYH glycosylase does not function correctly, DNA errors may accrue to initiate tumorigenesis with a clinical presentation similar to that in patients with Apc mutations.
Mutations in the MUTYH gene are inherited in an autosomal recessive pattern, which means two copies of the gene must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene.
Prenatal testing is possible if a disease-causing mutation is identified in an affected family member; however, prenatal testing for typically adult-onset disorders is uncommon and requires careful genetic counseling
.
Because of the genetic nature of FAP, polyposis registries have been developed around the world. The purpose of these registries is to increase knowledge about the transmissibility of FAP, but also to document, track, and notify family members of affected individuals. One study has shown that the use of a registry to notify family members (call-ups) significantly reduced mortality when compared with proband
s. The St. Mark's polyposis registry is the oldest in the world, started in 1924, and many other polyposis registries
now exist.
.
In 2007, the "ApcPirc" rat model was isolated with a stop codon at position 1137. In contrast to the mouse models where >90% of tumors form in the small intestine, the Pirc rat forms tumors preferentially (>60%) in the large intestine, similar to the human clinical presentation.
By age 35 years, 95% of individuals with FAP have polyps. Without colectomy, colon cancer is virtually inevitable. The mean age of colon cancer in untreated individuals is 39 years (range 34–43 years).
(permanent stoma where stool goes into a bag on the abdomen) or have an ileo-anal pouch
reconstruction.
Various medications are being investigated for slowing malignant degeneration of polyps, most prominently the non-steroidal anti-inflammatory drug
s (NSAIDs). The NSAIDS have been shown to significantly decrease the number of polyps but do not usually alter management since there are still too many polyps to be followed and treated endoscopically.
Polyp (medicine)
A polyp is an abnormal growth of tissue projecting from a mucous membrane. If it is attached to the surface by a narrow elongated stalk, it is said to be pedunculated. If no stalk is present, it is said to be sessile. Polyps are commonly found in the colon, stomach, nose, sinus, urinary bladder...
s form mainly in the epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
of the large intestine
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
. While these polyps start out benign
Benign
A benign tumor is a tumor that lacks the ability to metastasize. Common examples of benign tumors include moles and uterine fibroids.The term "benign" implies a mild and nonprogressive disease. Indeed, many kinds of benign tumors are harmless to human health...
, malignant transformation
Malignant transformation
Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor....
into colon cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
occurs when not treated.
Signs and symptoms
From early adolescence and onwards, patients with this condition develop hundreds to thousands of polyps. These may bleed, leading to blood in the stool. If the blood is not visible, it is still possible for the patient to develop anemiaAnemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
due to gradually developing iron deficiency. If malignancy develops, this may present with weight loss
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
, altered bowel habit, or even metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
to the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
or elsewhere.
The genetic determinant in familial polyposis may also predispose carriers to other malignancies, e.g., of the duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
and stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
. Other signs that may point to FAP are pigmented lesions of the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
("CHRPE - congenital hypertrophy of the retinal pigment epithelium"), jaw cysts, sebaceous cyst
Sebaceous cyst
A sebaceous cyst is a term that loosely refers to either epidermoid cysts or pilar cysts . Because an epidermoid cyst originates in the epidermis and a pilar cyst originates from hair follicles, by definition, neither type of cyst is strictly a sebaceous cyst...
s, and osteoma
Osteoma
An osteoma is a new piece of bone usually growing on another piece of bone, typically the skull. It is a benign tumor.When the bone tumor grows on other bone it is known as "homoplastic osteoma"; when it grows on other tissue it is called "heteroplastic osteoma".Osteoma represents the most common...
ta (benign bone tumors). The combination of polyposis, osteomas, fibroma
Fibroma
Fibromas are benign tumors that are composed of fibrous or connective tissue. They can grow in all organs, arising from mesenchyme tissue. The term "fibroblastic" or "fibromatous" is used to describe tumors of the fibrous connective tissue...
s and sebaceous cyst
Sebaceous cyst
A sebaceous cyst is a term that loosely refers to either epidermoid cysts or pilar cysts . Because an epidermoid cyst originates in the epidermis and a pilar cyst originates from hair follicles, by definition, neither type of cyst is strictly a sebaceous cyst...
s is termed Gardner's syndrome
Gardner's syndrome
Gardner syndrome, also known as familial colorectal polyposis, is an autosomal dominant form of polyposis characterized by the presence of multiple polyps in the colon together with tumors outside the colon...
(with or without abnormal scarring).
Diagnosis
Making the diagnosis of FAP before the development of colon cancer is important not just for the individual, but also for the sake of other family members who may be affected. Colonoscopy is considered the diagnostic test of choice as it can provide not only a quantification of polyps throughout the colon but also a histologic diagnosis. Barium enemaBarium enema
A lower gastrointestinal series, also called a barium enema, is a medical procedure used to examine and diagnose problems with the human colon . X-ray pictures are taken while barium sulfate fills the colon via the rectum.-Procedure:...
and virtual colonoscopy
Virtual colonoscopy
Virtual colonoscopy is a medical imaging procedure which uses x-rays and computers to produce two- and three-dimensional images of the colon from the lowest part, the rectum, all the way to the lower end of the small intestine and display them on a screen...
can suggest the diagnosis of FAP.
Once the diagnosis of FAP is made, close colonoscopic
Colonoscopy
Colonoscopy is the endoscopic examination of the large bowel and the distal part of the small bowel with a CCD camera or a fiber optic camera on a flexible tube passed through the anus. It may provide a visual diagnosis and grants the opportunity for biopsy or removal of suspected...
surveillance with polypectomy
Polypectomy
The method used to perform colonic polypectomies during colonoscopy depends on the size, shape and histological type of the polyp to be removed. Prior to performing polypectomy, polyps can be biopsied and examined histologically to determine the need to perform polypectomy.Gastrointestinal polyps...
is required. Prophylactic colectomy
Colectomy
Colectomy consists of the surgical resection of any extent of the large intestine .-History:Sir William Arbuthnot-Lane was one of the early proponents of the usefulness of total colectomies, although his overuse of the procedure called the wisdom of the surgery into question.-Indications:Some of...
is indicated if more than a hundred polyps are present, if there are severely dysplastic polyps, or if multiple polyps larger than 1 cm are present. When a partial colectomy is performed, colonoscopic surveillance of the remaining colon is necessary as the individual still carries significant risk of developing colon cancer.
Ultrasound
Medical ultrasonography
Diagnostic sonography is an ultrasound-based diagnostic imaging technique used for visualizing subcutaneous body structures including tendons, muscles, joints, vessels and internal organs for possible pathology or lesions...
of the abdomen and blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
s evaluating liver function
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
are often performed to rule out metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
to the liver.
Genetic testing
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
provides the ultimate diagnosis in 95% of cases; genetic counseling
Genetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
is usually needed in families where FAP has been diagnosed. Testing may also aid in the diagnosis of borderline cases in families that are otherwise known to p34.3 and p32.1 (1p34.3-p32.1).
APC
APC (gene)
Adenomatous polyposis coli also known as deleted in polyposis 2.5 is a protein that in humans is encoded by the APC gene. Mutations in the APC gene may result in colorectal cancer....
is a tumour suppressor gene, acting as a "gatekeeper" to prevent development of tumours. Mutation of APC also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer.
Although the polyps are inherently benign, the first step of the two-hit hypothesis
Knudson hypothesis
The Knudson hypothesis is the hypothesis that cancer is the result of accumulated mutations to a cell's DNA. It was first proposed by Carl O. Nordling in 1953, and later formulated by Alfred G. Knudson in 1971. Knudson's work led indirectly to the identification of cancer-related genes...
has already taken place: the inherited APC mutation. Often, the remaining "normal" allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
is mutated or deleted, accelerating generation of polyps. Further mutations (e.g. in p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
or kRAS) to APC-mutated cells are much more likely to lead to cancer than they would in non-mutated epithelial
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
cells.
The normal function of the APC gene product is still being investigated; it is present both the cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
and the membrane. The canonical tumor-suppressor function of Apc is suppression of the oncogenic protein beta-catenin
Beta-catenin
Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
. However, other tumor-suppressor functions of Apc may be related to cell adherence and cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
organization.
MUTYH
MUTYH
MUTYH is a human gene encoding a DNA glycosylase, MUTYH glycosylase, involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA...
encodes DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...
enzyme MYH glycosylase. During normal cellular activities, guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
sometimes becomes altered by oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
, which causes it to pair with adenine
Adenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
instead of cytosine
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
. MYH glycosylase fixes these mistakes by base excision repair
Base excision repair
In biochemistry and genetics, base excision repair is a cellular mechanism that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky...
, such that mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s do not accumulate in the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
and lead to tumor formation. When MYH glycosylase does not function correctly, DNA errors may accrue to initiate tumorigenesis with a clinical presentation similar to that in patients with Apc mutations.
Genetics
Familial adenomatous polyposis can have different inheritance patterns and different genetic causes. When this condition results from mutations in the APC gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene is sufficient to cause the disorder. The incidence of malignancy in these cases approaches 100%. In most cases, an affected person has one parent with the condition.Mutations in the MUTYH gene are inherited in an autosomal recessive pattern, which means two copies of the gene must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene.
Prenatal testing is possible if a disease-causing mutation is identified in an affected family member; however, prenatal testing for typically adult-onset disorders is uncommon and requires careful genetic counseling
Genetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
.
Because of the genetic nature of FAP, polyposis registries have been developed around the world. The purpose of these registries is to increase knowledge about the transmissibility of FAP, but also to document, track, and notify family members of affected individuals. One study has shown that the use of a registry to notify family members (call-ups) significantly reduced mortality when compared with proband
Proband
Proband, or propositus, is a term used most often in medical genetics and other medical fields to denote a particular subject being studied or reported on. On pedigrees, the proband is noted with an arrow and the box or circle shaded accordingly...
s. The St. Mark's polyposis registry is the oldest in the world, started in 1924, and many other polyposis registries
Polyposis registries
Polyposis registries exist for the purpose of understanding the genetic disease familial adenomatous polyposis. The registries provide a service to doctors for identification, surveillance and management of families and individuals with high colorectal cancer risk from Familial Adenomatous...
now exist.
Animal models
The "ApcMin" mouse model was described in 1990 and carries an Apc allele with a stop codon at position 850. Heterozygosity for this mutation results in a fully penetrant phenotype on most genetic backgrounds, with mice on a sensitive background developing over 100 tumors in the intestinal tract. The number and location of the intestinal tumors is modified by unlinked genes. Many other models have since appeared, including a model of attenuated FAP (the 1638N model) and several conditional mutants that allow for tissue-specific or temporal ablation of gene function. For more information see mouse models of colorectal and intestinal cancerMouse models of colorectal and intestinal cancer
Mouse models of colorectal cancer and intestinal cancer are experimental systems in which mice are genetically manipulated or challenged with chemicals to develop malignancies in the gastrointestinal tract...
.
In 2007, the "ApcPirc" rat model was isolated with a stop codon at position 1137. In contrast to the mouse models where >90% of tumors form in the small intestine, the Pirc rat forms tumors preferentially (>60%) in the large intestine, similar to the human clinical presentation.
Epidemiology
The incidence of the mutation is between 1 in 10,000 and 1 in 15,000 births.By age 35 years, 95% of individuals with FAP have polyps. Without colectomy, colon cancer is virtually inevitable. The mean age of colon cancer in untreated individuals is 39 years (range 34–43 years).
Treatment
Treatment for FAP depends on the genotype. Most individuals with the APC mutation will develop colon cancer by the age of 40. Therefore, prophylactic surgery is generally recommended before the age of 25. There are several surgical options that involve the removal of either the colon or both the colon and rectum. The decision to remove the rectum depends on the number of polyps in the rectum as well as the family history. If the rectum has few polyps, the colon is removed and the small bowel (ileum) is connected to the rectum (ileorectal anastomosis). If the rectum is involved then the colon and rectum are removed and a patient may require an ileostomyIleostomy
An ileostomy is a surgical opening constructed by bringing the end or loop of small intestine out onto the surface of the skin. Intestinal waste passes out of the ileostomy and is collected in an external pouching system stuck to the skin...
(permanent stoma where stool goes into a bag on the abdomen) or have an ileo-anal pouch
Ileo-anal pouch
The ileal pouch-anal anastomosis , also known as an ileo-anal pouch, restorative proctocolectomy, ileal-anal pullthrough, or sometimes referred to as a j-pouch, s-pouch, w-pouch or an internal pouch, is an internal reservoir; usually situated where the rectum would normally be...
reconstruction.
Various medications are being investigated for slowing malignant degeneration of polyps, most prominently the non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
s (NSAIDs). The NSAIDS have been shown to significantly decrease the number of polyps but do not usually alter management since there are still too many polyps to be followed and treated endoscopically.
External links
- GeneReviews/NCBI/NIH/UW entry on APC-Associated Polyposis Conditions
- Familial adenomatous polyposis - NIH Genetics Home ReferenceNational Institutes of HealthThe National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
- Cancer.Net: Familial Adenomatous Polyposis
- Familial Adenomatous Polyposis - eMedicine GastroenterologyEMedicineeMedicine is an online clinical medical knowledge base that was founded in 1996 by Scott Plantz and Richard Lavely, two medical doctors. The website is searchable by keyword and consists of approximately 6,800 articles, each of which is associated with one of 62 clinical subspecialty textbooks...
- Colon, Polyposis Syndromes
- www.fapgene.org.uk
- National Cancer Institute: Genetics of Colorectal Cancer information summary
- http://www.polyposisregistry.org.uk/