Confirmation of FAP diagnosis

Predictive testing for FAP when 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 may also be affected. The presence of

extracolonic manifestations is variable and includes gastric and

duodenal polyps, ampullary polyps, congenital hypertrophy of the retinal

pigment epithelium (CHRPE), desmoid tumors, thyroid cancer,

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

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

Common constellations of colonic and extracolonic manifestations have

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

Turcot syndrome, and Hereditary desmoid disease.

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 type 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 are 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 desmoids 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 extracolonic 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 compressed of 15 exons and has an

8,538 base pair (bp) open reading frame. A variety of technologies 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 "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 occasional cases, DNA alterations of undetermined significance may

be identified.

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.

Because of the previous cautions, it is important to first document

the presence of a mutation in an affected family member prior to

performing predictive testing.

We strongly recommend that patients undergoing predictive testing

receive genetic counseling both prior to testing and after results are

available.

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;Feb;101(2):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