Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon cancer occurs when they are left untreated. Three variants are known to exist, FAP and attenuated FAP (originally called hereditary flat adenoma syndrome) are caused by APC gene defects on chromosome 5 while autosomal recessive FAP (or MUTYH-associated polyposis) is caused by defects in the MUTYH gene on chromosome 1. Of the three, FAP itself is the most severe and most common; although for all three, the resulting colonic polyps and cancers are initially confined to the colon wall. Detection and removal before metastasis outside the colon can greatly reduce and, in many cases, eliminate the spread of cancer.

The root cause of FAP is understood to be a genetic mutation—a change in the body's tumour suppressor genes that prevent the development of tumours. The change allows numerous cells of the intestinal wall to develop into potentially cancerous polyps when they would usually reach the end of their life; inevitably, one or more will eventually progress and give rise to cancer (7% risk by age 21, rising to 87% by age 45 and 93% by age 50). These gene changes do not trigger cancer, but rather, they reduce the body's ability to prevent cells from becoming cancerous. Even with the gene change, it may still take time before a cell actually does develop that is cancerous one as a result, and the gene may, in some cases, still partially operate to control tumours. Cancer from FAP takes many years to develop and is almost always an adult-onset disease.

The second form of FAP, known as attenuated familial adenomatous polyposis has the APC gene functional but slightly impaired. It is therefore somewhat able to operate as usual. Attenuated FAP still presents a high 70% lifetime risk of cancer (as estimated), but typically presents with far fewer polyps (typically 30) rather than the hundreds or thousands usually found in FAP, and arises at an age when FAP is usually no longer considered likely—typically between 40 and 70 years old (average 55) rather than the more usual 30s upward. Because it has far fewer polyps, management options may be different. pigmented lesions of the retina ("CHRPE—congenital hypertrophy of the retinal pigment epithelium"), jaw cysts, sebaceous cysts, and osteomata (benign bone tumors). The combination of polyposis, osteomas, fibromas and sebaceous cysts is termed Gardner's syndrome (with or without abnormal scarring).

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.

APC gene mutation variants

The APC is a tumour suppressor gene responsible for the production of adenomatous polyposis coli (APC), a large multifunction tumour-suppressing protein which acts as a "gatekeeper" to prevent development of tumours. (APC regulates β-catenin, a protein that plays a crucial role in cell communication, signalling, growth, and controlled destruction, but which, left uncontrolled, also gives rise to numerous cancers 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.

Diagnosis

thumb|right|200px|[[Micrograph of a tubular adenoma, the colorectal cancer precursor most commonly associated with FAP]]

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. Two diagnostic methods exist:

Colonoscopy is the usual diagnostic test of choice as it favours the common right-side location of polyps better than sigmoidoscopy if the mutation is attenuated FAP,

Once the diagnosis of FAP is made, close colonoscopic surveillance with polypectomy is required.

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.

Ultrasound of the abdomen and blood tests evaluating liver function are often performed to rule out metastasis to the liver.

Management

thumb|[[Colectomy specimen showing numerous polyps throughout the large bowel]]

Because of the way familial polyposis develops, it is possible to have the genetic condition and therefore be at risk, but have no polyps or issues so far. Therefore, an individual may be diagnosed "at risk of" FAP, and require routine monitoring, but not (yet) actually have FAP (i.e., carries a defective gene but as yet appears not to have any actual medical issue as a result of this). Clinical management can cover several areas:

Identifying those individuals who could be at risk of FAP: usually from family medical history or genetic testing
Diagnosis (confirming whether they have FAP)—this can be done either by genetic testing, which is definitive, or by visually checking the intestinal tract itself.

:: Visual examination, or monitoring, cannot 'clear' a person of risk. It can only say what their condition is at the time. If at any point in their life, the person develops numerous polyps, this would tend to suggest a diagnosis of FAP. (Absence of polyps does not 'clear' a person, as polyps can develop later in life; also, a few polyps over time are not that uncommon in people without FAP. However, a substantial number or a profusion of polyps would generally tend to suggest a diagnosis of FAP, and histopathology to determine whether or not any polyps are cancerous.)

Screening/monitoring programs involve visually examining the intestinal tract to check its healthy condition. It is undertaken as a routine matter every few years, where there is cause for concern when either (a) a genetic test has confirmed the risk or (b) a genetic test has not been undertaken for any reason, so the actual risk is unknown. Screening and monitoring allow polyposis to be detected visually before it can become life-threatening.
Treatment, typically surgery of some kind, is involved if polyposis has led to a large number of polyps, or a significant risk of cancer, or actual cancer.

Family history

NCBI states that "Although most individuals diagnosed with an APC-associated polyposis condition have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent." Asymptomatic individuals (and therefore asymptomatic family members) are also known to exist.

Prognosis

Before reaching the advanced stages of colorectal cancer, the polyps are confined to the inner wall and thickness of the intestinal tract and do not metastasize or 'spread'. So, provided FAP is detected and controlled either at the pre-cancerous stage or when any cancerous polyps are still internal to the intestinal tract, surgery has a very high success rate of preventing or removing cancer, without recurrence, since the locations giving rise to cancer are physically removed in toto by the surgery.

Following surgery, if a partial colectomy has been performed, colonoscopic surveillance of the remaining colon is necessary as the individual still has a risk of developing colon cancer. However, if this happened, it would be a fresh incident from polyps developing anew in the unremoved part of the colon after surgery, rather than a return or metastasis of any cancer removed by the original surgery.

Desmoid tumors, with their infiltrative nature and potential proximity to vital structures, are the second-highest cause of death.

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 (>100 adenomas) 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).

Attenuated FAP arises when APC is defective but still somewhat functional. As a result, it retains part of its ability to suppress polyps. Therefore, attenuated FAP manifests as colorectal cancer unusually late (age 40–70, average=55 Gastric fundic polyps and duodenal adenomas are also seen. Therefore, polyps and cancers may manifest in the upper portion of the colon or upper gastrointestinal tract rather than the usual locations. || ?

| Typical core diagnostic criteria || (a) 100+ polyps and age under 40, OR (b) polyps and FAP in a relative || Not settled as yet. (a) no family history of 100+ polyps before age 30 PLUS ONE OF 10–99 polyps / 100+ polyps and aged over 35 to 40 / colorectal cancer before age 60 and relatives with multiple adenomatous polyps, OR (b) Family history of 10 to 99 adenomas diagnosed after age 30 years || ?

| Age at which polyps manifest || 7–36 (typ. 16), rapidly increasing thereafter || ? || ?

| Colorectal cancer risk (penetrance) and age if untreated || "inevitable.. virtually 100%": 7% by age 21, 87% by age 45, 93% by age 50. Typical ages: 34–43 (avg.39) || "Lower.. less well known.. estimated 70% by age 80". Sovaria states as of 1998, "average age at CRC diagnosis is ~58 years" || ?

| Variability || Inter- and intrafamilial phenotypic variability are common || See FAP || ?

| Possible non-colon manifestations || "polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors, desmoid tumors, and associated cancers" || As for FAP, but "CHRPE and desmoid tumors are rare," and also thyroid cancer is added. || ?

| Other lifetime risks || "Small bowel [duodenum or periampulla] carcinoma 4–12% [distal to duodenum] Rare; Pancreas Adenocarcinoma ~1%; Papillary thyroid carcinoma 1–2%; CNS [typ. medulloblastoma] <1%; Liver hepatoblastoma 1.6%; Bile ducts adenocarcinoma Low but increased; Stomach adenocarcinoma <1% in Western cultures." || ? || ?

| Inheritance || "inherited in an autosomal dominant manner. Approximately 75%-80% of individuals with APC-associated polyposis conditions have an affected parent. Offspring of an affected individual are at a 50% risk of inheriting the disease-causing mutation." || Same as FAP || Different—recessive (requires 2 parents to be carriers)

| Genetic overview and genetic detection || "Full gene sequencing of all APC exons and intron-exon boundaries appears to be the most accurate clinical test available. Most APC mutations are nonsense or frameshift mutations that cause premature truncation of the APC protein. The likelihood of detecting an APC mutation is highly dependent on the severity of colonic polyposis and on the family history. ◦Approximately 20% of individuals with an apparent de novo APC mutation. The markers used for linkage analysis of APC-associated polyposis conditions are highly informative and very tightly linked to the APC locus; thus, they can be used with greater than 98% accuracy in more than 95% of families with an APC-associated polyposis condition. Linkage testing is not possible for families with a single affected individual, a situation that often occurs when an individual has a de novo gene mutation and no affected offspring.. If no disease-causing APC mutation is found, molecular genetic testing of MUTYH (see Differential Diagnosis) should be considered." || "Fewer than 30% of individuals with attenuated phenotypes are expected to have an identifiable APC mutation" (see also details under FAP)|| ?

| Genotype-Phenotype [Core condition] || Most frequent APC mutation is at codon 1309 and leads to a high number of polyps at an early age (~20). Profuse polyposis (avg=5000) reported with mutations in codons 1250–1464. Most partial and whole APC deletions are associated with 100–2000 colonic adenomas, although attenuated FAP has been seen. Sample typical onset ages: between codon 168 and 1580 (excluding 1309) = 30 years, 5' of codon 168 and 3' of codon 1580 = 52 years. || Attenuated FAP is associated with mutations (typically truncating) in the 5' part of the gene (codons 1–177), exon 9, and the distal 3' end of the gene; interstitial deletions of chromosome 5q22 that include APC; partial and whole-gene deletions; and somatic mosaicism for APC mutations that are generally associated with classic FAP. Sovaria states attenuated FAP is "caused by mutations in three distinct regions of the APC gene—the 5 end in the region spanning exons 4 and 5, exon 9, and the extreme 3 end. Phenotypic expression in these three groups of kindreds is variable but is definitely milder than that in classical FAP" and that rectal polyps are rare in attenuated FAP but not yet confirmed whether this also means rectal cancer risk is lower as well. || ?

| Genotype–Phenotype [Other extra-colonic conditions] || Prominent extracolonic manifestations often correlate (though not completely) with more distal APC mutations. General study of FAP plus extracolonic symptoms showed: mutations in codons 1395–1493 has significantly higher rates of desmoid tumors, osteomas, and epidermoid cysts than those with mutations in codons 177–452; mutations in codons 1395–1493 have significantly higher rates of desmoid tumors and osteomas than those with mutations in codons 457–1309; no individuals with mutations in codons 177–452 developed osteomas or periampullary cancers; only individuals with mutations in codons 457–1309 developed hepatoblastoma and/or brain tumors. Duodenal adenomas: Fourfold increased risk with mutations between codons 976 and 1067. Desmoid tumors: mutations 3' to codon 1399 were associated with desmoid tumor development with an odds ratio of 4.37; desmoid tumors in 20% of individuals with mutations 5' to codon 1444, 49% of individuals with mutations 3' to codon 1444, and 61% of individuals with mutations in codons 1445–1580; several families with severe desmoid tumors had mutations at the extreme 3' end; consistent association of desmoid tumors with mutations distal to codon 1444. CHRPE is associated with mutations between codons 311 and 1444; whole APC gene deletions. Thyroid cancer and FAP: In 24 individuals, the majority of mutations identified were 5' to codon 1220 [Cetta et al. 2000]; 9 of 12 individuals had APC mutations identified proximal to the mutation cluster region (codons 1286–1513). General review of the literature (to August 2006): revealed 89 submicroscopic APC deletions (42 partial and 47 whole-gene deletions). Extracolonic findings were seen in 36% of cases, with no significant differences in those with partial vs. whole-gene deletions. || ? || ?

| Prevalence || "2.29 to 3.2 per 100,000 individuals. APC-associated polyposis conditions historically accounted for about 0.5% of all colorectal cancers; this figure is declining as more at-risk family members undergo successful treatment following early polyp detection and prophylactic colectomy." || "Likely underdiagnosed, given the lower number of colonic polyps and lower risk for colorectal cancer compared to classic FAP" || ?

| Treatment of manifestations || Classic FAP: "Colectomy is recommended after adenomas emerge; colectomy may be delayed depending on the size and number of adenomatous polyps. Colectomy is usually advised when more than 20 or 30 adenomas or multiple adenomas with advanced histology have developed" || "Colectomy may be necessary. In approximately one third of individuals, the colonic polyps are limited enough in number that surveillance with periodic colonoscopic polypectomy is sufficient" || ?

| Surveillance (monitoring) activities once risk is established || "Sigmoidoscopy or colonoscopy every 1–2 years, beginning at age ten to 12 years; colonoscopy, once polyps are detected; annual colonoscopy, if colectomy is delayed more than a year after polyps emerge (Age ten to 20 years with certain milder symptoms, delay in colectomy may be considered); Esophagogastroduodenoscopy (EGD) by age 25 years or prior to colectomy and repeated every 1–3 years; in some cases, endoscopic retrograde cholangiopancreatography (ERCP) to evaluate for adenomas of the common bile duct; small-bowel imaging when duodenal adenomas are detected or prior to colectomy, repeated every 1–3 years depending on findings; screening for hepatoblastoma (optimal interval unknown, one paper recommends "at least every three months"); annual physical examination, including evaluation for extraintestinal manifestations, and palpation of the thyroid with consideration of follow-up ultrasound examination and fine-needle aspiration if thyroid nodules are present" || "Colonoscopy every two to three years, beginning at age 18 to 20 years; esophagogastroduodenoscopy (EGD) beginning by age 25 years or prior to colectomy and repeated every 1–3 years; in some cases, endoscopic retrograde cholangiopancreatography (ERCP) may be necessary to evaluate for adenomas of the common bile duct; annual physical examination with palpation of the thyroid with consideration of follow-up ultrasound examination and fine-needle aspiration if thyroid nodules are present. Colectomy usually advised when more than 20 or 30 adenomas or multiple adenomas with advanced histology have developed." Sovaria states as at 1998 that "colonoscopy, as opposed to sigmoidoscopy, should be advised for endoscopic surveillance, because of the right-side location of colorectal adenomas; UGI endoscopic surveillance is warranted in an attempt to detect premalignant gastric or duodenal tumors; individuals affected with [attenuated FAP] may require total colectomy with ileo-rectal anastomosis only when prophylactic colectomy is advised" || ?

| Decision to monitor || "Early recognition may allow for timely intervention and improved final outcome; thus, surveillance of asymptomatic, at-risk children for early manifestations is appropriate; genetic testing is more cost effective than sigmoidoscopy in determining who in the family is affected; individuals diagnosed with APC-associated polyposis conditions as a result of having an affected relative have a significantly greater life expectancy than those individuals diagnosed on the basis of symptoms.. As colon monitoring for those at risk for classic FAP begins as early as age ten to 12 years, molecular genetic testing is generally offered to children at risk for classic FAP by age ten years. Genetic testing at birth may also be warranted, as some parents and pediatricians may consider hepatoblastoma screening from infancy to age five years in affected offspring. No evidence points to an optimal age at which to begin screening." || See FAP. Also, "Colon screening for those with attenuated FAP begins at age 18 to 20 years; thus, molecular genetic testing should be offered to those at risk for attenuated FAP at approximately age 18 years." || ?

| Inheritance and implications of confirmed diagnosis for other close relatives || APC-associated polyposis conditions are inherited in an autosomal dominant manner. Approximately 20–25% have the altered gene as a result of a de novo gene mutation. Little or no evidence of maternal/paternal bias, or effect related to advanced paternal age, in de novo mutations. Siblings have a classic 50% risk of sharing the condition if inherited and not de novo and a "low" but slightly higher risk than general if de novo, therefore genetic testing should be offered. Offspring each have a 50% chance of inheriting. Other family members are at risk if their parents share the same mutation. Germline mosaicism has been documented in asymptomatic cases. Prenatal testing is possible via fetal extracted DNA. || See FAP || ?

Polyposis registries

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 probands. The St. Mark's polyposis registry is the oldest in the world, started in 1924, and many other polyposis registries now exist.

References

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