Confirmation of FAP diagnosis for patients with clinical features  

This test should be ordered only for individuals with symptoms

suggestive of FAP. Asymptomatic patients with a family history

of FAP should not be tested until a mutation has been identified

in an affected family member.

Familial adenomatous polyposis (FAP) is an autosomal dominant

condition caused by mutations in the APC gene located on the long arm

of chromosome 5 (5q21). The incidence of FAP may demonstrate ethnic

variability, however most reports estimate a panethnic incidence

somewhere between 1 in 6,000 to 1 in 18,000 individuals. Approximately

25% (1 in 4) of affected individuals are the de novo case in their family.

Therefore, FAP is inherited from an affected parent approximately 75%

of the time.

Classic FAP is clinically characterized by the progressive development

of hundreds to thousands of adenomatous colon polyps, some of which

inevitably progress to carcinoma if the colon is not surgically removed.

Polyps may develop during the first decade of life and the majority of

untreated FAP patients will develop colon cancer by age 40. Typically,

there is a predominance of polyps on the left side of the colon, however

other areas of the colon my also be affected. The presence of

extracolonic manifestations is variable and includes gastric and

duodenal polyps, ampullary polyps, congential hypertrophy of the

retinal pigment epithelium (CHRPE), desmoids tumors, thyroid cancer,

hepatoblastoma (most commonly diagnosed before the age of 4 years),

and rarely jejunal, adenal, pancreatic, and biliary tract malignancies.

Common constellations of colonic and extracolonic manifestations have

resulted in the designation of 3 clinical variants: Gardner syndrome,

Turcot syndrome, and hereditary desmoid disease.

In addition to the typical colonic manifestations of classic FAP, Gardner

syndrome is characterized by the presence of soft tissue tumors (thyroid),

osteomas (typically of mandible, but not always), tooth abnormalities

(supernumerary) and skin tumors (epidermoid cysts, lipomas, fibromas,

leiomyomas).

Individuals with Turcot syndrome show central nervous system (CNS)

tumors in addition to adenomatous polyps. Turcot syndrome is an

unusual clinical variant of FAP, as it is also considered a clinical variant

of hereditary nonpolyposis colorectal cancer (HNPCC). The types of

CNS tumor observed helps to distinguish Turcot-FAP variant patients

from Turcot-HNPCC variant patients. The predominant CNS tumor

associated with the Turcot -FAP variant is medulloblastoma, while

glioblastoma is the predominant CNS tumor associated with Turcot-

HNPCC.

Hereditary desmoid disease (HDD) is a variant of FAP where multiple

desmoids tumors is the predominant feature. Many patients with HDD may

not even show colonic manifestations of FAP. APC germline testing may

assist clinicians in distinguishing a sporadic desmoid tumor, from that

associated with FAP.

Attenuated FAP (AFAP) is characterized by later onset of disease and a

milder phenotype (typically <100 adenomatous polyps and

fewer extraclonic manifestations) than classic FAP (typically 100s to

1,000s of adenomatous polyps). Typically individuals with AFAP develop

symptoms of the disease at least 10 to 20 years later than classically

affected individuals. Individuals with AFAP often lack a family history of

colon cancer and/or multiple adenomatous polyps. Of note, clinical

overlap is observed between AFAP and MYH-associated polyposis

(MAP), an autosomal recessive polyposis syndrome typically associated

with fewer than 100 polyps. Although the clinical phenotype of MAP

remains somewhat undefined, extracolonic manifestations, including

CHRPE have been described in affected patients. Given the phenotypic

overlap of AFAP and MAP, these tests are commonly ordered together

or in a reflex fashion (example:  if MYH germline testing is negative,

proceed with APC germline testing). Mayo Medical Laboratories does

not offer a formal reflex test for FAP and MYH, however, reflex testing can

be arranged by contacting the on-call genetic counselor for the molecular

genetics laboratory at 800-533-1710.

The APC gene is quite large. It is composed of 15 exons and has an

8,538 bp reading frame. A variety of technologists must be employed

when analyzing each specimen to ensure accurate results within an

efficient, clinically helpful, turnaround time. The Mayo Molecular

Genetics Laboratory utilizes multiplex ligation probe amplification

(MLPA) to investigate for large genomic deletions/duplications within

the APC gene. In addition, DNA sequencing is performed to investigate

for mutations within exons 1-14. Protein truncation with follow-up

site-specific DNA sequencing is performed to investigate for mutations

within exon 15.

Detection of a disease causing mutation in the APC gene can be used to

confirm a diagnosis of FAP and to predict carrier status for at-risk family

members of an affected individual. Patients diagnosed with FAP benefit

from genetic counseling, prophylactic surgery, and cancer surveillance.

For at-risk individuals, molecular genetic studies can be useful to refine

risk estimates and to determine an appropriate cancer surveillance

regimen.

See "Colorectal Adenomatous Polyposis Algorithm" in Special Instructions

for additional information. Also see "Hereditary Colorectal Cancer:

Adenomatous Polyposis Syndromes" (September 2004 Communique')

in publications for additional information.

An interpretive report will be provided.

An interpretive report will include specimen information, pedigree

(when appropriate), assay information, and whether or not results

are consistent with a diagnosis of FAP, or indicate a risk to

develop FAP.

DNA sequence analysis is able to identify mutations in the coding regions

and exon/intron junctions (splice site mutations) of the APC gene. This

test does not identify mutations in the promoter region or other

noncoding regions. Thus, we predict that some individuals who have a

clinical diagnosis of FAP may have a mutation that is not identified by

this method.

Because not all affected individuals have a detectable mutation, a

negative test result does not rule out the diagnosis of HNPCC.

In rare cases, DNA alterations of undetermined significance may be

found.

Because the test does not have 100% clinical sensitivity and because

some families with a clinical diagnosis of FAP do not have mutations

in APC; it is important to first document the presence of a mutation

in an affected family member prior to performing testing.

Linkage analysis (available as a separate test) may provide an

alternative approach for predictive testing when a mutation has not been

identified in an affected family member. Intragenic and closely linked

extragenic markers are used with recombination rates of <1%. Blood from

several family members is required for linkage analysis. Consultation with

the Molecular Genetics Laboratory is required prior to sending specimens

for linkage analysis.

We strongly recommend that patients undergoing predictive testing

receive genetic counseling both prior to testing and after results are

available.

In addition to disease-related probes, the MLPA technique utilizes probes

localized to other chromosomal regions as internal controls. In certain

circumstances, these control probes may detect other diseases or

conditions for which this test was not specifically intended. Results of the

control probes are not normally reported. However, in cases where

clinically relevant information is identified, the ordering physician will be

informed of the result and provided with recommendations for any

appropriate follow-up testing.

1.   American Society of Clinical Oncology. American Society of

      Clinical Oncology policy statement update: genetic testing for

      cancer susceptibility Clin Oncol. 2003;21:2397-406.

2.   Mandl M, Paffenholz R, Friedl E, et al:  Frequency of common

      and novel inactivation APC mutations in 202 families with

      adenomatous polyposis.  Hum Molec Genet 1994;3:181-184

3.   Galiatsatos P, Foulkes WD:  Familial adenomatous polyposis.

      Am J Gastroenterol 2006;101:385-398

4.   Croner RS, Brueckl WM, Reingruber B, et al:  Age and manifestation

      related symptoms in familial adenomatous polyposis. BMC Cancer

      2005 Mar 2;5:24