FAMILIAL ADENOMATOUS POLYPOSIS: ONE GENE. MANY MANIFESTATIONS.
MAKING SENSE OF THE ALPHABET SOUP THAT IS THE GENETIC CODE.
Parts I and II of this series looked at the genetics, diagnosis and treatment of hereditary nonpolyposis colorectal cancer.
Part III will examine familial adenomatous polyposis and the damage caused by this inherited disease. Emphasis is placed on the genetics of the disease and how knowledge of the mutational pattern can help the clinician secure a diagnosis, and begin treatment. Look alike diseases, those looking like familial adenomatous polyposis but arising from a mutation on a different gene will also be considered.
Part IV will evaluate the surveillance and surgical options for patients and family members affected by familial adenomatous polyposis. With an understanding of the genetics underlying familial adenomatous polyposis, the clinician on the frontlines of diagnosis and treatment will be able to help the patient and family members begin to struggle with, and overcome some of the dreaded consequences associated with this virulent disease.
Genotype to Phenotype: From Genetics To Appearance
Familial adenomatous polyposis (FAP), an inherited disorder, is responsible for one percent of all colorectal malignancies. Caused by a mutation in a single gene, the Adenomatosis Polyposis Coli (APC) gene, FAP can lead to a radical change in the structure and functioning of the body. How can a seemingly small change in the genotype so drastically alter the phenotype in such a lethal manner? The answer is in the genetic realm where proteins are produced. A mutant gene produces abnormal proteins which lead to disease.
A nucleotide, is formed by the combination of a five carbon sugar, one or more phosphates and one of the purine or pyrimidine nucleobases guanine, adenine, cytosine, or thymine. A tri-nucleotide sequence, also known as a triplet or codon, codes for and produces a specific amino acid using processes called transcription and translation. A long sequence of codons with a start codon and a stop codon defines a single gene, which codes for many amino acids. These amino acids bond together to form a protein. Proteins participate in every process within the cell. Proteins are the building blocks of enzymes and they also make up the structural or mechanical elements of body cells and tissues. Proteins play integral roles in cellular signaling, cellular division, and cell death or apoptosis. Each protein is considered to be the protein product of its parent gene.
The gene is a long-term storage area for the genetic code, or DNA, and all of the genes form a set of blueprints used by the body to control cellular structure and functioning. Many genes reside on a linear stretch of DNA and the entire length of these genes plus the intervening, non-coding portions form a chromosome. Humans have 46 chromosomes (the common fruit fly has 8 and goldfish have 104). Human chromosome five has between nine hundred and one thousand three hundred genes. One of these is the Adenomatosis Polyposis Coli gene.
In both FAP and sporadic colorectal cancers, a mutation of the APC gene is one of the earliest events leading to polyp formation, and subsequent malignant degeneration. This is known as the adenoma-carcinoma sequence. (1) Six hundred mutations have been discovered in the APC gene. The APC protein is made up of 2,843 amino acids. A mutation in any one of the six hundred APC codons can lead to disease through the production of a defective, malfunctioning, truncated APC protein product. The ubiquitous APC protein belongs to the family of suppressor proteins and is commonly found in the cell cytoplasm. It interacts with several other cytoplasmic proteins, including ß-catenin. ß-catenin may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once an epithelial layer is complete. Normally, the APC protein binds to, and down-regulates ß-catenin through destruction of the ß-catenin. Because of truncation or shortening of the now malfunctioning APC protein, ß-catenin may enter the nucleus and actually stimulate cell proliferation. This begins a neoplastic cascade and malignant transformation through unchecked cellular division. The result of this is polyp and tumor growth. The APC protein is highly concentrated in colonic mucosa. (2)
Different mutant codons within the APC gene may code for different forms of FAP or attenuated familial adenomatous polyposis (AFAP), and also code for the development of extra-colonic tumors. In other words, the mutation at the genotype level is translated into a somatic mutation, deformity or neoplasm at the phenotype level. For example, “mutations between codons 1301 and 2011 are associated with a six fold increase in desmoid tumors relative to the low risk region. Codons 1250-1464 are associated with severe polyposis and earlier onset cancer. Duodenal adenoma risk and extracolonic manifestations are highest between codons 976 and1067.”(3) Mutations associated with AFAP are located on either end of this large APC gene, (figure 1). (4) Mutations found in the APC gene of patients with FAP or AFAP are similar to those found in patients with sporadic colorectal cancer. However, in contradistinction to the acquired sporadic colorectal carcinoma, the APC mutation in the inherited disease is present at birth. (5)
Phenotype To Diagnosis: From Appearance To Discovery
The Phenotype Story: The Many Faces Of FAP
Familial adenomatous polyposis is a rare autosomal dominant disorder characterized by the pancolonic formation of hundreds or thousands of polyps which develop at an early age. It is associated with at least eight other malignancies. The APC gene mutation has a high penetrance rate, meaning that individuals with the mutated gene (the genotype) will almost surely develop polyps (the phenotype).
In the average, untreated patient the natural history of the disease is: (6)
- Age of appearance of adenomas: 23 years
- Age of onset of symptoms: 33 years
- Age of diagnosis of adenomas: 36 years
- Age of diagnosis of carcinomas: 39 years (65 years in the general population)
- Age of death from carcinomas: 42 years (71 years in the general population)
Sixty five percent of patients who present with symptoms of FAP already have a colorectal carcinoma.
There is an almost one hundred per cent risk of developing colon cancer if patients with familial adenomatous polyposis remain untreated. Therefore, early diagnosis and treatment are of paramount importance.
Eighty per cent of patients will have a family history of FAP or AFAP, with a known, precisely located mutation, heightening diagnostic suspicion and making the diagnosis of FAP straightforward. However, twenty per cent of patients will have a de-novo mutation in an unknown gene location. In these patients who are unaware of their disease, symptoms generally begin when the polyposis is complete, at an average age of thirty three years.
Rectal bleeding and diarrhea are the commonest presentations. As the symptoms call attention to the need for evaluation, colonoscopy is the surest way to detect the disease. Extracolonic manifestations of disease (see below) may also be discovered on physical examination and call attention to the diagnosis. The diagnosis is secured with histopathological confirmation of adenomatous polyps. Affected patients have as few as one hundred colonic polyps and may have thousands of polyps carpeting large sections of the colon. Polyp size can range from microscopic to greater than one centimeter; however most of the polyps are small. The smaller adenomas may require the use of indigo carmine or narrow-band imaging to be discovered. In contrast to HNPCC, where the disease is predominantly located proximal to the splenic flexure, FAP commonly affects the left side of the colon. Rectal carcinoma occurs in fifty nine percent of patients. However, the entire colon must be examined as rectal sparing has been reported. (7) Twenty four percent of patients have a sigmoid malignancy, and the remainder of cases shows more proximal disease. (8)
In FAP, there is a lifetime risk of developing associated desmoid tumors (15%), duodenal cancer (4%), thyroid cancer (2%), brain cancer (2%), ampullary cancer (1.7%), pancreatic cancer (1.7%), hepatoblastoma (1.6%), or gastric cancer (0.6%) and early diagnostic questioning and subsequent evaluation must focus on these areas.(9) Esophagogastroduodenoscopy may often disclose fundic gland polyps which might point the clinician to search in the direction of a defective APC gene. Suitable radiographic examinations such as CT scanning or MRI evaluation may be employed in the search for extracolonic disease.
Clinical Variants of Familial Adenomatous Polyposis
Attenuated Familial Adenomatous Polyposis
Attenuated Familial Adenomatous Polyposis (AFAP) is characterized by the formation of fewer, more proximal polyps developed at a later age. (10,11) Clinically, AFAP has been recognized relatively recently. It may be a variant of FAP, or may be a disease in its own right.
Securing a diagnosis of AFAP is more challenging but must be considered in younger patients with between ten and one hundred proximally located colonic polyps. The polyps are often flat. An upper gastrointestinal examination must be performed in patients with FAP or AFAP, as eighty to ninety per cent will develop duodenal or periampullary adenomas. The polyps are commonly flat. They are diagnosed at an average age of forty four years. The carcinomas in AFAP develop at age fifty six compared with FAP in which the average age at diagnosis is ten or fifteen years earlier. It is possible that the differential in age of onset of the polyposis and malignant transformation between FAP and AFAP is due to a lack of earlier recognition of AFAP by physicians and patients, rather than being a true difference in the age of onset. (5)
It is often difficult to distinguish between FAP and AFAP based solely on the number of polyps seen on examination. In a single family with a single mutation, the number of colonic polyps in each family member may vary widely. In fact, there is evidence that AFAP and FAP may not be separate diseases, but different manifestations of a single entity. Extracolonic disease is similar in both forms of polyposis. Genetically, FAP and AFAP are associated with a large number of different APC mutations. Clinically, patients with fewer than one hundred polyps may have FAP, AFAP or HNPCC. In a single family, patients may present with widely differing clinical manifestations. “The definition of AFAP, “multiple, but fewer than one hundred synchronous colorectal adenomas, is one that suffers from an arbitrary imposition of a finite number of polyps combined with a spectrum of subtle variations.”(5) Even though the polyps in AFAP are predominantly right sided and the mutation is usually located on either end of the APC gene, the underlying disease remains FAP. (5) AFAP simply may be a form of FAP with mild expression.
Turcot’s Syndrome:
Turcot’s Syndrome describes the association of colorectal adenomatous polyposis with central nervous system tumors, specifically, cerebellar medulloblastomas. Two thirds of patients have an APC gene mutation and one third have a mutation in a mismatch repair gene. Mismatch repair genes are commonly associated with hereditary nonpolyposis colorectal cancer, and Turcot’s Syndrome may be a disease that has several underlying genetic etiologies.
APC I1307K
Three hundred sixty thousand American Ashkenazy Jews are carriers of a mutant gene located on codon 1307 of the APC gene. This represents five percent of the Ashkenazy population. People carrying this mutation, known as APC I1307K, are at a 1.7 times greater risk of colorectal neoplasia compared with those who do not have this mutation. Additionally there are greater numbers of adenomas and colorectal cancers in this group, with a younger age at diagnosis. It is estimated that APC I1307K is responsible for up to four percent of all Ashkenazy Jewish colorectal cancers. Although the impact of this mutation is not fully understood at this time, it is thought that genetic testing of this entire population, irrespective of a family history of colorectal cancer, followed by appropriate clinical screening and surveillance might benefit the mutation carriers who are expected to develop colorectal cancer. (12)
Gardner’s Syndrome.
Gardner’s Syndrome is the association of FAP with epidermoid cysts, osteomas and fibromas (now called desmoid tumors). Colorectal polyposis was later added to the syndrome. Gardner’s Syndrome is thought to be FAP with an extraintestinal feature. As this seems to be the case in most clinical presentations of FAP, Gardner’s Syndrome is no longer considered to be a distinct entity.
MYH mutations: A Look Alike, But A Different Gene.
MYH polyposis is a condition resembling FAP on a phenotypic level but which results from a mutation on a gene other than the APC gene. The MYH gene is located on the short arm of chromosome one. Being inherited in an autosomal recessive manner means that both alleles, or both copies of the MYH gene must be mutant to cause the phenotypic expression of disease. MYH is usually associated with a smaller number of colorectal polyps, but some cases have been reported presenting with hundreds of colorectal adenomatous polyps; hence, the inclusion of MYH polyposis in the family of inheritable colonic polyposis syndromes. In patients with clinical disease, in whom no APC mutation is identified, a diagnosis of MYH polyposis should be considered and should be evaluated using gene analysis of a whole blood sample. Although malignant transformation of the polyps does occur, the exact incidence of this transformation is unknown. Treatment and surveillance is as for patients with FAP.
Other Look Alikes: Rare But Troublesome
Peutz-Jeghers Syndrome, Juvenile Polyposis, Cowden Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, and Metaplastic Polyposis are all rare inherited syndromes with varying presentations, varying types of polyps and variable degrees of risk for the development of a malignancy. The common phenotypic disorder linking them together is the development of gastrointestinal polyposis. The polyps become manifest at differing ages and have differing malignant potentials. The key point for the clinician to keep in mind is that the polyps’ histopathological features must be identified so as to appropriately guide surveillance and treatment. Genetic counseling is an integral part of the care in these patients.
Extracolonic Manifestations of Familial Adenomatous Polyposis
Endoderm Derived Disease
FAP affects the entire body and may give rise to extracolonic neoplasms derived from the embryologic endoderm, ectoderm or mesoderm. (Table 1) (13) The etiology of the extracolonic manifestations is not clear and may involve the APC gene, other genes or environmental factors. There is inconclusive data that suggests that the codon location of the APC mutation may have a phenotypic effect. (14) Death from extracolonic disease in patients with FAP is now more common than death from colorectal carcinoma. (15)
The prevalence of gastric polyps ranges from thirty four percent to one hundred percent. Most are hyperplastic polyps and a few are adenomatous and are located in the antrum. Malignant transformation rarely occurs. There is evidence that the adenomatous polyps are located in areas that have been exposed to bile through reflux. (16,17,18)
Duodenal polyps are found in over ninety percent of FAP patients. They are often located in the periampullary region. They vary in number, size and morphology. However, they are almost always adenomas. The concern in these patients relates to the potential for malignant transformation of these adenomas. Up to thirty five percent of patients with FAP have been found to have a duodenal or periampullary carcinoma. However, other studies have reported a much lower incidence of carcinoma (9)After desmoid tumors, periampullary carcinoma is the second leading cause of death in patients with FAP. (15)
Small intestinal adenomas and carcinomas occur rarely and the risk of developing a malignant lesion is small.
Mesoderm Derived Disease
Desmoid tumors arise from benign fibroaponeurotic tissue. They are thought to be true neoplasms as opposed to a fibroblastic reaction. They are locally invasive. Commonly, they cause pressure on surrounding structures and erosions of adjacent tissue. Small bowel obstructions are common and are also the result of local growth. The most common symptom in patients with an intraabdominal desmoid tumor is a painful mass, with pain being secondary to a small bowel obstruction. Desmoid tumors have been observed in fourteen percent of patients undergoing laparotomy for FAP (19). They are even more common in patients undergoing a repeat laparotomy. (20) Growth rates range from indolent to rapid. Although rare, spontaneous regression has been noted. In up to thirty eight percent of cases of laparotomy, a desmoid tumor interfered with the planned procedure. Treatment is controversial, empirical and difficult, especially with desmoid involvement with abdominal vessels, the ureters or the mesentery. Because of a high rate of recurrence, it is felt that a conservative approach, including the use of combinations of non-steroidal anti-inflammatory drugs and/or anti-neoplastic agents is warranted, with operative treatment reserved for patients having life threatening complications such as local invasion into vital structures. (21) Death as a result of desmoid disease is from local invasion into a vascular structure, sepsis resulting from an enteric fistula or as the result of the attempted therapeutic operation. (22)
Osteomas may occur in any bone, particularly in the facial bones. They are benign, cause symptoms due to local growth and are sometimes identified prior to the diagnosis of FAP. Dental abnormalities such as unerupted or supernumerary teeth, dentigerous cysts or odontomas occur often in FAP and their appearance is diagnostically useful. (21,23)
Ectodermal Disease
Ectodermal lesions associated with a mutated APC gene involve the eye, the skin or the brain.
Congenital hypertrophy of retinal pigment epithelium (CHRPE) is considered to be a marker for FAP, and is restricted to a mutation in codons 463 to 1444. The lesion is a hamartoma, which is a collection of cellular elements normally found at the site, but presenting as a disordered mass of histologically normal tissue. CHRPE is asymptomatic and benign. It is best viewed on indirect ophthalmoscopy through a dilated pupil. As a marker for FAP, it has a seventy nine percent sensitivity rate and a ninety five percent specificity rate. (24,25) In other words, patients presenting with CHRPE will most likely have FAP.
Epidermoid cysts are found on the limbs, face and scalp. They may be found in up to half of patients with FAP. They are rarely found in children except in FAP, and may appear even prior to the development of colorectal polyps. The association is strong enough such that any child with an epidermoid cyst should undergo a sigmoidoscopy after age fourteen. Histologically, the cyst is made up of a thin layer of squamous cells and may be asymptomatic or may present as a painful nodule.
Although also found in patients with hereditary nonpolyposis colorectal cancer, medulloblastomas are more often found in FAP. This association bears the name of Turcot’s syndrome, after Jacques Turcot, the Canadian surgeon who discovered this new extracolonic manifestation of FAP. Although rare, Turcot’s syndrome is usually fatal, with death occurring at an average age of twenty. In two studies, seventy five percent of patients died from the medulloblastoma and sixteen percent died from colorectal cancer. (26,27)
Part IV of this series will evaluate the surveillance and surgical options for patients and family members affected by familial adenomatous polyposis.
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