Learning Objectives
1) Explain the epidemiology and prevalence of Famlial Adenomatous Polyposis
(FAP)
2) Describe the typical presentation of FAP
3) Describe the prognosis and treatment for FAP
4) Name the genes involved and mode of inheritance for FAP
5) Name and describe the variations of FAP
6) Create a genetic counseling plan for a patient and the family members of
a person with FAP
Pretest Questions
1) Which tumor maker correlates with progression and regression colorectal
tumors?
a.) CEA
b.) CA-125
c.) PSA
d.) AFP (alpha-fetoprotein)
e.) HCG
2) In the United States, what percentage of the total colorectal cancer risk
does Familial Adenomatous Polyposis account?
a) 15%
b) 80
c) 1%
d) 45%
e) 7%
3) By the age of 35, what percentage of FAP patients will develop colorectal
adenomas?
a) 66%
b) 95%
c) 50%
d) 85%
e) 7%
4) Parents with FAP should be counseled that their children need to be carefully
screened for which disease from infancy up to 5 years of age?
a) CNS tumors (usually medulloblastomas)
b) Hepatoblastoma
c) Follicular or Papillary thyroid cancer
d) Duodenal ampullary carcinoma
e) Gastric Carcinoma
5. Which of the following genes plays a role in the development of Familial
Adenomatous Polyposis?
a) ApoA2
b) BA4
c) ApoE4
d) NF2
e) APC
Answers: 1) a 2) c 3) b 4) b 5) e
Case Study
A 26 year old male is seen at clinic for the evaluation of blood visualized
in his stool over the last two months. He reports intermittently visualizing
blood on the tissue over the last two years, but the amount has recently significantly
increased. The patient denies fevers, chills, nausea, vomiting, gastro-esophageal
reflux, hematemesis, melena, or a change in bowel habits. He denies diarrhea,
constipation, or a history of hemorrhoids. He reports a five pound weight loss
over the last two months, but he has been on a diet and exercise regimen over
this period of time. The patient reports that his mother died from colon cancer
at 42 years of age. The patient reports both his sister (age 31) and brother
(age 35) have been diagnosed with colon cancer as well. Physical exam is significant
only for flat pigmented lesions located within the lower portion of the retina.
Explain the epidemiology and prevalence of FAP:
Colorectal cancer is the third leading cause of cancer
and the second leading cause of cancer related deaths in the United States.
There are an estimated 136,000 new cases and over 56,000 deaths expected from
the disease this year alone. The etiology of colon cancer appears to
be heterogenous with 80% of patients diagnosed with sporadic disease and no
evidence of an inherited disorder. In the remaining 20% of cases, family history
and certain genetic predisposition places patients at increased risk for developing
colon cancer. One such disease is familial adenomatous polyposis, which
occurs in approximately 1/10,000 to 1/30,000 births. It accounts for less than
1% of the total colon cancer risk in the United States. It affects males and
females equally and has an equal, worldwide distribution.
What is the typical presentation of FAP?
A diagnosis of Familial Adenomatous Polyposis is given
to any individual with more than 100 adenomatous polyps distributed equally
throughout the colon. If an individual has a relative with Familial Adenomatous
Polyposis, a diagnosis can be made even if the patient has less than 100 adenomatous
polyps. The mean age of polyposis development in FAP patients is 16. Other
benign clinical manifestations that hint towards a diagnosis of FAP include:
pigmented ocular fundic lesions (congenital hypertrophy of the retinal pigment
epithelium), extracolonic polyps found in the small intestine or stomach, cutaneous
lesions such as lipomas, sebaceous, and epidermoid cysts, occult radiopaque
jaw lesions, dental abnormalities, and nasopharyngeal angiofibromas.
What is the prognosis and treatment for FAP?
The mean age of polyposis development in FAP patients is
16. By the age of 15 years old, 50% of FAP patients will develop adenomas.
By 35, 95% of patients will have adenomas. Thus, the development of colorectal
cancer in patients with FAP is inevitable. Treatment is a total colectomy recommended
at the time of diagnosis. Because colorectal cancer can occur in the
rectal segment of the colon, usually either a proctocolectomy with mucosal
protectomy and ileoanal pullthrough or total proctocolectomy with Brooke ileostomy
are recommended.
Is FAP genetic? If so what genes are involved with inherited forms of FAP?
FAP is acquired through autosomal dominant inheritance. Almost all cases of
FAP are caused by a mutation in the APC tumor suppressor gene located on chromosome
5q21-q22. Usually, the mutation leads to either frame shift mutations or premature
stop codons, both leading to a truncated protein. There have been over 800
different mutations on the APC gene discovered that lead to some form of FAP.
Mutations between codons 169-1393 are associated with the classic form of FAP.
What genetic counseling could you offer FAP patients and their family
members?
“At risk relatives” are considered to be first degree relatives
of a known individual with FAP that are greater than 10 years of age. Before
evaluation of individuals at risk, a family member with known FAP should first
be tested to assess for a detectable mutation. Usually, protein truncation
testing is performed. If there is no identifiable mutation, testing at risk
relatives will be inconclusive and should therefore not be recommended. If
a mutation is found, then physicians should proceed with genetic testing of
all relatives at risk. This way, true positive and true negative results will
be obtained.
Special screening should be considered in the children of patients with FAP.
Childhood hepatoblastoma occurs in approximately 1 in 300 persons at risk for
FAP under 5 years of age. Thus, in children with a parent with FAP, regular
imagery of the liver along with alpha-fetoprotein levels should be conducted
from infancy to 5 years of age.
What diseases or medical problems does FAP place a patient at increased
risk?
1) CNS tumors (usually medulloblastomas)
2) Childhood hepatoblastoma
3) Follicular or Papillary thyroid cancer
4) Duodenal ampullary carcinoma
5) Gastric Carcinoma
What are the different variations of FAP?
- Attenuated FAP- Mutations in the 5’ (5’ to
codon 158) and 3’ (3’ to codon 1596) ends of the APC gene have
been associated with a less severe form of FAP. These patients have been
found to have less than 100 adenomatous polyps and a more delayed progression
from polyp to colorectal cancer (average of 12 year longer delay in comparison
to classic FAP).
- Turcot’s Syndrome-An association between both HNPCC
and FAP and brain tumors has been observed. Brain tumors in patients with
concurrent FAP are usually medulloblatomas but gliomas sometimes occur.
- Gardner’s Syndrome-patients have
a predominance of extra-intestinal lesions including: mandible osteomas,
desmoid tumors, sebaceous or epidermoid cysts, lipomas, gastric polyps, juvenile
nasopharyngeal angiofibromas, and supernumerary teeth.
What tumor markers are used for evaluation of the recurrence of colorectal
cancer?
Carcinoembryonic Antigen is an oncofetal glycoprotein
that is expressed in mucosal cells and overexpressed in adenocarcinoma, especially
colorectal cancer. Because the glycoprotein is only elevated in 25% of patients
with colorectal cancer confined to the colon, it should not be used as a screening
method for colon cancer. It is also elevated in benign disease such as: inflammatory
bowel disease, pancreatitis, hypothyroidism, biliary obstruction, peptic ulcer
disease, and cirrhosis. Usually, levels greater than 10 ng/mL are rarely caused
by benign disease. However, it is a useful tool in screening patients who are
at higher risk for developing colorectal recurrence after surgical resection,
usually defined as stage II or above at time of diagnosis. CEA levels typically
return to normal 6 weeks after surgical resection. Thus, a CEA level should
be ordered every 2-3 months in patients for at least 2 years after surgery
to monitor for colorectal cancer recurrence.
FAP Patient Internet Resources:
- FAP SUPPORT GROUP www.fapsupportgroup.org
- FAP PATIENT FACT INFORMATION http://cancer.stanford.edu/information/geneticsAndCancer/types/fap/
RESOURCES:
- Wee, CC, McCathy EP, Phillips RS. Factors associated with colon cancer
screening: the role of patient factors and physician counseling. Preventative
Medicine. 2005;41(1):23-29.
- Burt, RW, DiSario JA, Cannon-Albright, L. Genetics of Colon Cancer: Impact
of inheritance on colon cancer risk. Annu Rev Med 1995; 46:371.
- Moisio AL, Jarvinen, H, Peltomaki P. Genetic and clinical characterization
of FAP: a population based study. Gut 2002; 50:845
- Lindor, NM, Green MH, and the Mayo Familial Cancer Program. The concise
handbook of family cancer syndromes. J Natl Cancer Inst 1998; 90:1039
- Giardiello FM, Krush AJ, Petersen GM, et al. Phenotypic variability of
familial adenomatous polyposis coli gene. Ann Intern Med 1997;126:514.
- Solomon, C and Burt RW. Associated Polyposis Conditions. Gene Reviews.
Posted December 18, 1998 and updated October 21, 2005. Retrieved from www.genetests.org on
August 17, 2006.
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