Germline mutations in the adenomatous polyposis coli gene (APC) cause the most common form of hereditary polyposis syn- dromes termed familial adenomatous polyposis (FAP). The inci- dence is approximately one in 8300 to one in 13,000 live births.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Autosomal dominant with high penetrance (80–
100%)
b. Spontaneous mutations account for approximately 30% of cases
2. Caused by germline mutations in the adenomatous poly- posis coli (APC) gene on chromosome 5q21
a. More than 300 different disease-causing mutations of the APC gene are currently identified
b. Nonsense or frameshift mutations that result in a trun- cated protein in nearly all of the germline mutations in APC
c. Nearly 80% of FAP families have identifiable germline mutations in one allele of APC in affected individuals
d. Similar high incidence of germline mutations is seen in the FAP variant, Gardner syndrome
3. APC gene
a. A large gene consisting of approximately 6 kilobases in length
b. A tumor suppressor gene encoding for a 2843-amino acid protein with a putative role in:
i. Cell adhesion ii. Signal transduction iii. Transcriptional activation
c. The causative germline defect of APC gene predis- pose to the following conditions:
i. FAP
ii. Nearly obligatory colorectal cancers
d. Loss of second APC allele either by somatic mutation or loss of heterozygosity in the earliest premalignant lesions:
i. Dysplastic aberrant crypt foci ii. Small adenomatous polyps e. Adenoma formation
i. Beginning with loss of function of the APC tumor suppressor gene
ii. Followed by activation of the K-ras oncogene iii. Subsequent loss of function of genes on chromo-
some 18q and inactivation of p53 ushers in malignant degeneration
4. Colorectal carcinogenesis: involves two principal path- ways:
a. Chromosomal instability
i. Deletion of portions of a chromosome results in loss of specific genes and abnormal amounts
of DNA per cell (aneuploidy): This pathway accounts for:
a) All cases of colorectal cancers associated with FAP
b) Nearly 85% of sporadic colorectal cancers ii. The pathway of c-myc and β-catenin as down-
stream targets appears to impact on the kineto- chore and microtubule attachment
iii. Mutations in APC interfere with the way that epithelial cells divide and distribute their nuclear DNA
b. Microsatellite instability
i. Produced by defects of the DNA base mismatch repair system
ii. This pathway accounts for:
a) 15% of sporadic colorectal cancers
b) Most cases of hereditary nonpolyposis col- orectal cancer
5. Genotype–phenotype correlation
a. FAP phenotype expressed in an individual depends in part on the site of the germline APC mutation
i. Attenuated familial adenomatous polyposis coli occurs when there is a truncating mutation in the extreme ends of the APC coding sequence ii. Mutations between codons 169 and 1393 result-
ing in classic FAP
iii. Mutations between codons 1250 and 1464, espe- cially around codon 1300, resulting in profuse colorectal polyposis and earlier onset of gas- trointestinal polyps
iv. Retinal lesions (congenital hypertrophy of the retinal pigment epithelium, a condition present at any age in 60% of FAP families) occur only with mutations between codons 457 and 1444 v. Up to 60% of patients with mutations between
codons 1445 and 1580 result in desmoids b. Limited clinical application of genotype–phenotype
correlation: considerable phenotypic variability exists even among individuals and families with identical genotypic mutations
CLINICAL FEATURES
1. Spectrum of disease activity a. Attenuated FAP (AFAP)
i. The number of adenomatous polyps is less than 100
ii. A later age of onset for colorectal cancers b. Fulminant FAP
i. With hundreds to thousands of polyps at a young age
ii. A nearly 100% risk of developing colorectal cancers by the age of 40
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2. Usually asymptomatic until puberty when colonic polyps begins to develop
3. Average age of onset of polyps: 25 years 4. Presenting symptoms
a. Rectal bleeding: the most common symptom b. Diarrhea
c. Anemia d. Abdominal pain
e. Change in bowel habits occurring approximately 8 years later
5. Congenital hypertrophy of retinal pigment epithelium a. Multiple and bilateral lesions: a sensitive phenotypic
marker that can direct clinical screening tests prior to or in lieu of genetic screening in an at-risk member of a FAP kindred
b. Generally a benign condition but low-grade adenocar- cinoma of the retina has been reported in several indi- viduals with this condition
6. Extracolonic features
a. Duodenal or periampullary polyps (5–10% lifetime risk) i. May progress to cancer
ii. 5% of these patients develop malignant transfor- mation within 20 years after the onset of polyps b. Other small intestinal tract polyps: rare
c. Adenomas of the ileal pouch may follow proctocolec- tomy
d. Pancreatic (2%) and biliary tract cancers: rare e. Adrenal adenomas: rare
f. Gastric polyps
i. Typically benign fundic gland polyps ii. Adenomatous in rare cases
iii. An increased rate of gastric cancer in some kindreds
iv. Gastric cancer occur more frequently than duo- denal cancer in Japanese FAP kindreds (Opposite is true for FAP kindreds with European Caucasian descent)
v. Gastric adenomas occur in 50% of Japanese FAP kindreds
g. Papillary thyroid carcinomas
i. Affect about 1–2% of patients with FAP ii. One-hundred fold increased risk in the women
with FAP
iii. Activation of ret/ptc1 oncogene in FAP-associated thyroid papillary carcinomas
h. Hepatoblastomas: a 1–3% risk of developing hepato- blastomas from birth until 6 years of age in infants and children who are at risk or known APC mutation carriers
i. Brain (medulloblastoma) (<1%) 7. Desmoid tumors
a. Also known as mesenteric fibromatosis b. A relatively common complication of FAP
i. A lifetime risk for men: 8%
ii. A lifetime risk for women: 13%
c. No metastatic potential but can be both life-threatening or problematic in treatment when the lesions slowly expand:
i. To involve the intra abdominal cavity ii. To surround the nervous or vascular systems
d. Conditions which may accelerate the growth i. Surgery
ii. Estrogen receptor antagonnists iii. Radiation
iv. Chemotherapy e. Common recurrence 8. FAP variants
a. Gardner syndrome
i. Refers to FAP with additional extra intestinal phenotypic manifestations accompanying colonic polyposis
a) Osteomas b) Sebaceous cysts c) Lipomas d) Desmoids
e) Dental abnormalities
ii. Caused by mutations in the APC gene b. Attenuated FAP
i. Characterized by the development of significantly fewer colonic adenomas (<100)
ii. Typically right-sided polyps
iii. 70% of patients develop colorectal cancers by age 65 if polypectomy is not performed
iv. Presence of fundic gland polyps, a clue to the possible diagnosis of AFAP
c. Turcot syndrome
i. Characterized by medulloblastoma in association with colonic polyposis and colorectal cancers ii. Caused by germline APC mutations
iii. Variable inter- and intrafamilial phenotypic expression
9. Differential diagnosis with two other main polyposis syn- dromes and one nonpolyposis syndrome, all of which are associated with an increased risk of GI cancer, especially colorectal cancer
a. Juvenile polyposis
i. An autosomal dominant disorder ii. Caused by at least two separate genes
a) SMAD4/DPC4 in chromosome 18q21 b) BMPR1A/Alk3 in chromosome 10q21-22 iii. Characterized by multiple juvenile polyps of the
colorectum
iv. Also involves the stomach and the small intestine v. Large polyps
a) Commonly lobulated
b) Adenomatous dysplasia in 50% of cases, giving rise to the increased risk of colorectal cancer
b. Peutz-Jeghers polyposis
i. An autosomal dominant disorder
ii. Caused by mutations of the LKB1 gene on 19p13.3
iii. Characteristics
a) Mucocutaneous melanin pigmentation b) Harmatomatous intestinal polyposis iv. Sites of polyps
a) Affect small intestine preferentially b) Also affect stomach and large intestine c. Hereditary non-polyposis colorectal cancer syndrome
(Lynch syndrome)
i. An autosomal dominant disorder
ii. Caused by mutations of three DNA mismatch repair genes
a) MSH2 (2p21-23) b) MLH1 (3p21) c) MSH6 (2p16)
iii. More common than the polyposis syndromes iv. Predominant tumors
a) Colorectal cancer b) Endometrial cancer
v. Other cancer types: cancers of the stomach, ovary, ureter and renal pelvis, bile ducts, kidney, small intestine, and brain tumors
DIAGNOSTIC INVESTIGATIONS
1. Detection of FAP in known kindreds
a. Retinoscopy: presence of more than three pigmented ocular fundic lesions confirms the diagnosis of FAP b. Flexible sigmoidoscopy
c. Presymptomatic APC gene testing i. Indications
a) Children and siblings of affected individuals with FAP or AFAP: usually delayed until the early teenage years (10 year or older) when screening by flexible sigmoidoscopy would normally commence
b) Patients with an unusually high number of colorectal adenomas for their age but not enough to be clinically diagnostic of classical FAP ( ≥20 cumulative colorectal adenomas, suspected AFAP)
c) ≥100 colorectal adenomas ii. Methods
a) Protein truncation testing of peripheral blood lymphocytes: detects APC mutation in more than 80–90% of affected families b) Conformation strand gel electrophoresis c) Single-strand conformation polymorphism d) Direct sequencing
e) Linkage analysis to markers on chromo- some 5q
iii. Germline APC testing: the most efficient means for identifying gene carriers within an FAP kindred
iv. Direct sequencing targeted at the known region of the APC gene if a mutation has already been detected within one member of a kindred a) Cost effective
b) Nearly 90% accurate means of APC testing 2. Screening in FAP
a. Colonoscopic examination for at-risk and APC muta- tion carriers, initiate at 10–12 years of age
b. Flexible sigmoidoscopy for at-risk individuals with unknown mutation status
i. Annually from age 10–15 ii. Biennially from age 26–35 iii. Every third year from age 36–50
c. Upper GI tract endoscopy for at-risk individuals with colorectal polyps and known gene carriers
d. Annual physical examination to assess thyroid nodules e. Hepatoblastoma screening in children with FAP (at-
risk or mutation-positive carriers until age 6) i. Annual screening by liver ultrasonography ii. Annual serum α-fetoprotein levels
f. Medulloblastoma screening: brain imaging for symp- tomatic or known Turcot syndrome kindreds
g. Imagings
i. CT scan for desmoid tumors of the mesentery ii. MRI to delineate vascular involvement and to
predict desmoid growth 3. Screening in AFAP
a. Colonoscopy required for individual at risk for AFAP b. Continued screening in the individual with AFAP
because of the later age of onset of polyps
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Not increased in a de novo case ii. 50% if a parent is affected
b. Patient’s offspring: a 50% risk of inheriting the con- dition and virtually all children who inherit the condi- tion will develop polyposis
2. Prenatal diagnosis
a. Molecular genetic testing of the APC gene on fetal DNA obtained from amniocentesis or CVS for fetuses at 50% risk for FAP if a clinically diagnosed rela- tive has an identified disease-causing APC gene alteration
b. Linkage analysis if the family is informative for linked markers
3. Management a. FAP
i. Prophylactic surgery remains the best means to minimize the risk of developing colorectal cancers.
ii. Consider colectomy
a) By late teen years for cancer prophylaxis for both gene carriers and at-risk individuals with polyposis
b) Without colectomy, colorectal cancer is inevitable, appearing approximately 10–15 years after the onset of polyposis
iii. Specific surgical recommendation a) Proctocolectomy with mucosectomy b) Ileal pouch anal anastomoses c) Ileorectal anastomosis
iv. Surgical removal of osteomas for cosmetic reasons v. Treatments for desmoid tumors
a) Surgical excision: associated with high rates of recurrence
b) Nonsteroidal anti-inflammatory drugs (sulin- dac, celecoxib) (use before colectomy): remains experimental
c) Antiestrogens
d) Cytotoxic chemotherapy e) Radiation
vi. Celecoxib, a selective cyclooxygenase-2 (pros-
taglandin synthetase) inhibitor
a) Reduces by 28% the mean number of polyps in adult patients with FAP
b) Potential use of this class of drugs as chemo- preventive and therapeutic agents: subject of intense current investigation
b. AFAP
i. Endoscopy and polypectomy
ii. Surgery: ileorectostomy rather than ileal pouch anal anastomosis is recommended because the rectum is relatively spared by polyposis
a) For recurrent, numerous polyposis
b) For the presence of aggressive histologic features
iii. Continued need for annual endoscopic evalua- tion of the rectal remnant
c. Pre- and post-test genetic counseling i. A pretest counseling session covering:
a) The nature of the disease itself b) The genetic aspects
c) The implications of positive and negative test results on future screenings
d) On insurability and family relationships ii. A posttest counseling session
a) Disclosure of the results
b) Addressing psychological consequences d. Potential consequences of genetic testing for heredi-
tary colorectal cancer (Trimbath and Giardiello, 2002) i. Positive consequences if the result is gene posi-
tive (the disease-causing mutation detected) a) Removal of uncertainty
b) Early detection of polyps and prevention of cancer
c) Greater ability to plan the future including family and career decisions
d) Increased compliance with colonic screen- ing/surveillance
e) Greater choice of surgical and medical management
ii. Negative consequences if the result is gene posi- tive (the disease-causing mutation detected) a) Psychological distress, including anxiety,
depression, anger, or denial
b) Changes in family psychosocial dynamics c) Stigmatization
d) Increased fear about surgery or death e) Children at 50% risk of disease
f) Guilt/worry about children
g) Colon surgery and possible lifestyle changes iii. Positive consequences if the result is gene nega- tive (truly negative for gene mutation identified in family)
a) Removal of uncertainty b) Children not at risk
c) Fewer medical exams and costs d) Better insurability
iv. Negative consequences if the result is gene neg- ative (truly negative for gene mutation identified in family)
a) Survival guilt (guilt about being unaffected when other family members are affected) b) Changes in family psychosocial dynamics
v. Negative consequences if the result is inconclu- sive (no pedigree mutation found or variant of unknown significance)
a) False sense of security
b) Does not rule out risk for disease c) Need for continued screening d) Confusion/anxiety
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Fig. 1. Colon of an 8-year-old girl with familial adenomatous polypo- sis. Numerous small polyps were present on the mucosal surface of the entire colon. The polyps measured up to 3 mm in size. Occasional polyps had a slender stalk, up to 2 mm in length. Histologically, the polyps were of tubular (adenomatous) type.
Fig. 2. A segment of colon showing juvenile polyposis. The polyps are large and lobulated. Stalk are present in some of them. The number of polyps is not as numerous as seen in Fig. 1 (AFP).
