Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is rare hereditary predisposition to cancer, generally of the colon and rectum. This type of syndrome is characterized by hundreds to thousands of benign polyps. FAP affects both men and women in equal numbers. Most FAP cases are inherited from parents who are affected by this conditions. However, over a quarter percent of people diagnosed with FAP did not have any history in their family. In general, benign polyps appears in the early teens to early twenties. In a few cases, polyps will not make an appearance until age 40 or later (Dukes, 1952; Reed & Neel, 1955). One or more of the polyps have a tendency to turn cancerous causing early death. The majority of individuals affected by FAP remain asymptomatic until the polyps turn malignant. It is therefore essential to get presymptomatic high risk individuals tested and get their proper diagnosis early on. Appropriate diagnostic tests differentiate people that have the disease from those who do not. In young patients, nonspecific symptoms such as diarrhea, abdominal cramping and pain, discomfort with bowel movement, and blood in stool may be suggestive of FAP (Dukes, 1952; Jasperson, Patel, & Ahnen, 2017).
Early cases of familial adenomatous polyposis (FAP) were accounted by Dr. Niemack (1902), a surgeon from Iowa, in his article. He detailed three cases that he encountered and treated in his practice. The first two cases were of a daughter (deceased) and her father (underwent colectomy), the third was a first degree relatives of the first two. At that time, very little was known about FAP. Dr. Niemack believed, based on his observations, that intestinal polyposis had a “certain contagiousness” and had certain heredity factor involved due to the fact that the patients were from the same family.
Several syndromes are recognized as part of FAP phenotypic spectrum. These conditions have the same germline mutation in the APC gene. These include attenuated adenomatous polyposis coli (AAPC), Gardner syndrome, and Turcot syndrome. AACP is characterized by a fewer number of polyps (less than a 100) involving the proximal colon and develop at a later age. Gardner syndrome is characterized by tumors in the soft tissue and bones, and abnormalities in dentition. Turcot syndrome is characterised by tumors in the central nervous system. There are three variants of FAP: “classic” autosomal dominant FAP, attenuated FAP, and autosomal recessive FAP (MYH-associated polyposis). The first two are caused by defects on chromosome 5, while autosomal recessive FAP is caused by defects on chromosome 1(Soravia et al., 1998; Jasperson, et. al, 2017). This paper will focus mostly on “classic” autosomal dominant FAP, the most common and severe form of the polyposis disorder.
Genetic alteration and mode of inheritance
Familial adenomatous polyposis (FAP), in its classic form, is a cancer predisposition syndrome characterized by formations of thousands of polyps in the colon and rectum. FAP is inherited in an autosomal-dominant manner. It is cause by a germline mutation in the tumor suppressor gene known as adenomatous polyposis coli (APC) (Kerr, Thomas & Thibodeau, 2013). Children of individuals with APC-associated polyposis have a 50% risk of inhereting the disease-causing mutations. For the majority of individuals affected by FAP, about 75% to 80% of cases has a parent affected by this disease. However, approximately 25 to 30 percent of individuals diagnosed, had no family history (Dukes, 1952; Galiatsatos & Foulkes, 2006; Jasperson, et. al., 2017).
The adenomatous polyposis coli (APC) gene is located at chromosome 5q21 and composed of 15 coding exons. The gene encodes a protein of 2843 amino acid. APC is a tumor suppressor gene found in the long (q) arm of chromosome 5. The APC gene produces a large multi-function protein that helps control the rate of cell divisions, intracellular attachment within the tissue, cell movements, and ensuring the correct number of chromosomes during cell division. APC protein regulates beta-catenin, a protein that plays an important role in preventing cell overgrowth and becoming cancerous tumors (Lesko et al., 2015).
The APC protein negatively regulates the beta-catenin oncoprotein by inactivation and degradation. Approximately 80% of truncating germline mutation in APC genes can be detected in classic FAP cases (Kerr et al., 2013). APC is the most common mutated gene in about 60% of carcinomas and adenomas. In families with FAP, more than 1500 mutations have been identified. Approximately 60% of mutations were found in the region located in exon 15 of the APC protein between codons 1284 and 1580. This region of the APC protein is involve in downregulating beta-catenin and function as tumor suppressor. This area is often lost in the mutated APC gene (Majumder, et al., 2018; Kerr et al., 2013). Without APC protein, beta-catenin accumulates in the nucleus up-regulating the transcription of genes involved in the progression of cell division (Kerr et al., 2013).
A profuse phenotype manifested in thousands of polyps is associated with mutations found in the middle part of the APC gene. However, the site of mutation does not exactly predict a certain gene product and a subsequent phenotype. Although very general correlations can be established, inconsistencies and contradictions were reported. This inconsistencies emphasized the limitations of genotype-phenotype relationships (Nieuwenhuis & Vasen, 2007).
The development of benign polyps and progression to malignant tumors occurs in accordance to the two-hit hypothesis. For FAP patients inheriting one germline mutation, a second hit leads to the development of adenomas. Polyps form as the result of mutations in tumor suppressor genes (APC). The “second hit” cause epithelial cells in the colon to undergo abnormal growth. The overgrowth, formation of benign tumors, increased the probability of malignancy or colon cancer (Majumder et al., 2018).
The type of germline mutation appears to determine the nature of the second hit to APC. Patients with germline mutation close to codon 1300 tend to acquire a “second hit” by allelic loss. In this type of mutation, no APC function is left and patients develop severe polyposis. Germline mutation distant from codon 1300 have truncating mutations. This mutation leaves a large portion of APC gene intact, causing only a slightly altered functionality. For example, a mutation on codon 1309 may not necessarily result in phenotype, an early onset of the disease, and/or severe polyposis. In this type of mutation, additional genetic and environmental factors may be needed for phenotype to manifest, in both colon and other areas (Nieuwenhuis & Vasen, 2007).
The majority of FAP affected individuals carry germline mutations of the APC gene. This means that the cells contains one copy each of mutated and normal genes. For FAP patients, the copy of mutated APC allele is inherited from an affected parent. Every epithelial cell in the colon of patients with FAP contain one mutated APC allele. Mutation occurring on the second allele thats inherited from unaffected parent results in the development of adenomas. Mutation or deletion of the APC gene, inactivates the remaining normal copy of the gene. This results in partial or complete removal of the tumor suppressive function of APC protein. Lacking this functioning APC gene, adenomatous polyps grow without restriction. The majority of the inactivation of the second normal APC allele occurs in the colon, resulting in the numerous colonic polyps formations (Galiatsatos & Foulkes, 2006).
The function of APC gene, a tumor suppressor, is to promote normal cell death in the colon. The APC protein controls the stimulatory effects of beta-catenin, a protein that activates growth-associated genes. Mutations of the APC gene results in losing part of a protein deeming it nonfunctional. The loss of APC protein function allows a large amount of beta-catenin to accumulate in the cell. The accumulation of beta-catenin protein stimulates rapid cell growth and results in the development of benign polyps. The rapid cell expansion due to lack of APC functionality, increases the possibility for other growth-related genetic alterations to occur. The changes in various gene expression negatively affect cell growth and multiplication, differentiation, migration, and eventual normal cell death. Allowing multiple genetic events to occur increases the progression of benign polyps to turn malignant in individuals affected with FAP. The APC gene is considered the “gatekeeper” preventing formation of abnormal cell in the colon. Mutation of APC gene results in its functional inactivation which is an initial step leading to the progression from benign growth to colorectal cancer (Waller, Findeis, & Lee, 2016; Burt & Neklason, 2005).
The molecular basis of tumor growth in FAP has not been fully understood despite its high risk for turning cancerous. Mutations responsible have not been identified in approximately 30% of patients affected with FAP that do not have APC germline mutations. For FAP patients with APC germline mutations, the “second hit” against APC gene has not been definitively identified (Takane et al., 2018).
Epidemiology
FAP is a rare condition that equally affects both male and female, and is found in all ethnic groups. Approximately 30% of affected individual do not have any history and the first person in their family with this condition (Takane, Fukuyo, Matsusaka, et. al., 2018). Estimates on the number of people affected by FAP vary from 1 in 2,200 up to 1 in 7,000. The worldwide incidence of FAP is 3 to10 per 100,000. The estimated prevalence is between 1 to 6,850 to 1 to 31,250 live births worldwide (Jasperson et al., 2017; Kerr et al., 2013). Prevalence of FAP in European countries has been estimated at 1/ 11,300-37,600 (Half, Bercovich, & Rozen, 2009).
In classic form of FAP, the average age of polyposis onset is 16 years while average age for colorectal cancer onset is 39 years. For individuals with attenuated FAP who have a fewer polyp count, average onset is about 2 decades later. FAP accounts for approximately 1% of colorectal cancer cases. The risk of progression of FAP to colorectal cancer (CRC) by the age of 35–40 years is approximately 100% if left untreated. (Takane et al., 2018).
Pathophysiology
For individuals with FAP, premalignant and malignant lesions throughout the colon are the most common manifestation. However, other various manifestations were seen in patients with FAP aside from colorectal adenomas. These includes polyps in the upper digestive system, desmoid tumors, congenital hypertrophy of the retinal pigment epithelium (CHRPE), lipomas, dental abnormalities, epidermoid cysts, and other cancers (thyroid, brain and hepatobiliary tract) (Half et al., 2009; Kerr et al., 2013).
Dr. Niemack, a surgeon from Iowa, described in detail several cases that he encountered and treated in his practice in 1900. His first patient was a twelve year old German-American girl who had been having bowel problems since she was nine years old. She was pale, emaciated, and had a very firm, distended abdomen. On examination, he found multiple polyps in the rectum and above. Hundreds of polyps were removed for up to 12 inches up the sigmoid colon in three different times which helped the distention. However, Dr. Niemack realized that hundreds more polyps where remaining in the upper colon, growing larger in both size and number. A month later, the girl died. Post mortem, Dr. Niemack found hundreds of polyps on the colon mucosa and the lower part of the ileum. They ranged from pea size to a large, cauliflower shaped polyps with some of the pedicles up to an inch long. The polyps were microscopically studied by Dr. Bierring of Iowa City who made the diagnosis of “adenoma papillosum” (Niemack, 1902).
Two years later, the girl’s father came to the hospital and had multiple polyps including some big cauliflower shapes. He complained of tenesmus, pain in defecation, and stool with blood and mucus. He was diagnosed with adenocarcinoma. Dr. Niemack estimated the onset around the time that the daughter died. A radical bowel resection was performed. The patient successfully recovered and went home. There is no further accounting whether polyps returned after the operation or not (Niemack, 1902).
A twenty-nine year old nephew of the above mentioned patient came to Dr. Niemack’s attention. He complained of intermittent intestinal hemorrhages. Found on examination were several polyps of varying size. Just like the other two previous cases, some polyps were smooth and some cauliflower shaped. His abdomen had the same glandular induration found on his cousin (the girl who died). No intervention was mentioned related to this case (Niemack, 1902).
Colorectal cancer is the principal cause of mortality in all FAP patients unless they are treated. The second fatal complication of FAP is a desmoid tumor. It cause gastrointestinal obstruction, and constrictions of the ureters, arteries and veins. Approximately 4% to 32% of patients are affected by Desmoid tumors. About 20% of patients develop desmoid tumors even after a colectomy, a surgical treatment of FAP. An estimated 10% to 50% mortality from these tumors (Giardiello, Brensinger, & Petersen, 2001).
There is no current cure for familial adenomatous polyposis (FAP) disorders. Removal of polyps through surgical means remains the mainstay. However, left untreated, polyps often return in number and can turn malignant. Tumor malignancy can progress into colorectal cancer (CRC). Familial adenomatous polyposis (FAP) progressed to CRC in almost 100% of cases by the age of 35 to 40 years, if left untreated. Studies find the estimated overall 5 years survival rate for colorectal cancer from FAP is 54.4% (Majumder et al., 2018).