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APC-Associated Polyposis Conditions

[Includes: Familial Adenomatous Polyposis, Gardner Syndrome, Turcot Syndrome, Attenuated FAP]

Summary

Disease characteristics.   APC-associated polyposis conditions include familial adenomatous polyposis (FAP), attenuated FAP, Gardner syndrome, and Turcot syndrome. FAP is a colon cancer predisposition syndrome in which hundreds to thousands of precancerous colonic polyps develop, beginning at a mean age of 16 years (range 7-36 years). By age 35 years, 95% of individuals with FAP have polyps; without colectomy, colon cancer is inevitable. The mean age of colon cancer diagnosis in untreated individuals is 39 years (range 34-43 years). Extracolonic manifestations are variably present and include polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors, desmoid tumors, and associated cancers. Attenuated FAP is characterized by a significant risk for colon cancer, but fewer colonic polyps (average of 30) than classic FAP, more proximally located polyps, and diagnosis of colon cancer at a later age; management may be substantially different. Gardner syndrome is characterized by colonic polyposis typical of FAP together with osteomas and soft tissue tumors. Turcot syndrome is the association of colonic polyposis and CNS tumors; the phenotypic features of Gardner syndrome and Turcot syndrome relate to the location of the APC mutation and are generally expressed in families with FAP.

Diagnosis/testing.   APC-associated polyposis conditions are caused by mutations in the APC gene. The diagnosis of APC-associated polyposis conditions relies primarily upon clinical findings. Molecular genetic testing of APC detects disease-causing mutations in up to 95% of probands with typical FAP. Such testing is clinically available. Molecular genetic testing is most often used in the early diagnosis of at-risk family members and in the confirmation of the diagnosis of FAP or attenuated FAP in individuals with equivocal findings (e.g., fewer than 100 adenomatous polyps).

Management.  Colectomy is advised in individuals with classic FAP when more than 20 or 30 adenomas or multiple adenomas with advanced histology have occurred. NSAIDs, especially sulindac, celecoxib, and rofecoxib, have caused regression of adenomas in FAP and decreased the number of polyps requiring ablation in the remaining rectum of persons with a subtotal colectomy. Endoscopic or surgical removal of duodenal adenomas is considered if polyps exhibit villous change or severe dysplasia, exceed one centimeter in diameter, or cause symptoms. Osteomas may be removed for cosmetic reasons. Desmoid tumor treatments include surgical excision, nonsteroidal anti-inflammatory drugs (NSAIDs), anti-estrogens, cytotoxic chemotherapy, and radiation. Recommended surveillance of individuals who are known to have FAP or an APC disease-causing mutation and individuals who are at risk for FAP include screening for hepatoblastoma by ultrasound examination and measurement of serum alpha-fetoprotein concentration, sigmoidoscopy, colonoscopy, esophagogastroduodenoscopy, small bowel X-ray, and regular physical examinations. Use of molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited the disease-causing mutation.

Genetic counseling.   APC-associated polyposis conditions are inherited in an autosomal dominant manner. Approximately 75-80% of individuals with APC-associated polyposis conditions have an affected parent. Offspring of an affected individual have a 50% risk of inheriting the altered APC gene. Prenatal testing is possible if a disease-causing mutation is identified in an affected family member; however, prenatal testing for typically adult-onset disorders is uncommon and requires careful genetic counseling.

Diagnosis

Clinical Diagnosis

The APC-associated polyposis conditions include (1) the overlapping, often indistinguishable phenotypes of familial adenomatous polyposis (FAP), Gardner syndrome, and Turcot syndrome and (2) attenuated FAP, which has a lower colonic polyp burden and lower cancer risk.

Familial adenomatous polyposis (FAP) is diagnosed clinically in an individual with:

• More than 100 colorectal adenomatous polyps OR
• Fewer than 100 adenomatous polyps AND a relative with FAP

Gardner syndrome is the association of colonic adenomatous polyposis, osteomas, and soft tissue tumors (epidermoid cysts, fibromas, desmoid tumors) [Gardner & Richards 1953].

Turcot syndrome is the association of colonic adenomatous polyposis and CNS tumors, usually medulloblastoma.

Attenuated FAP (AFAP) is considered in an individual with:

• Many colonic adenomatous polyps OR
• A family history of colon cancer in individuals younger than age 60 years with multiple adenomatous polyps

Note: Variable features not included in the diagnostic criteria but potentially helpful in establishing the clinical diagnosis of an APC-associated polyposis condition include: gastric polyps, duodenal adenomatous polyps, osteomas, dental abnormalities (especially supernumerary teeth and/or odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors (specifically epidermoid cysts and fibromas), desmoid tumors, and associated cancers.

Histology of adenomatous polyps

• Dysplasia.  Adenomatous polyps (often referred to as adenomas) are precancerous growths in which the surface epithelium of the gastrointestinal tract exhibits features of dysplasia. Dysplasia is characterized by branching of the microscopic glands, loss of goblet cells, and the following cellular features: loss of basilar polarity of the nucleus, increased nuclear/cytoplasmic ratio, increased basophylia of the cytoplasm, and loss of cytoplasmic glycogen. Dysplasia is graded as mild, moderate, or severe. Severe dysplasia is more likely to have cancer found somewhere within it, and is more likely to progress to cancer.

• Villous changes.  In addition to the dysplastic features of an adenomatous polyp, villous changes, characterized by elongated villi at the surface of the polyp, may develop.

  • Villous adenoma.  When the majority of the polyp surface exhibits villous change, the polyp is called a villous adenoma. A greater risk of cancer is associated with villous features within an adenomatous polyp.

  • Tubular adenoma.  If no villous features are present, the adenomatous polyp is called a tubular adenoma.

  • Tubulovillous adenoma.  If some villous features are present, the adenomatous polyp is called a tubulovillous adenoma.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.   APC is the gene associated with APC-associated polyposis conditions.

Molecular genetic testing: Clinical uses

• Confirmatory diagnosis
• Predictive testing
• Prenatal diagnosis

Molecular genetic testing: Clinical methods

• Full gene sequencing.  Mutation detection rate is up to 90%.

• Mutation scanning.  A variety of mutation scanning methods are used. Mutation detection rate is approximately 80-90%.

• PTT alone.  Most mutations in the APC gene cause premature truncation of the APC protein. A test based on this finding [Powell et al 1993] is positive in about 80% of individuals with FAP.

• Duplication/deletion analysis.  Among individuals with an APC-associated polyposis condition and more than 100 polyps, approximately 8-12% have an APC duplication or large deletion [Sieber et al 2002 , Bunyan et al 2004 , Aretz et al 2005 , Michils et al 2005]. Methods currently used to identify duplications/deletions include Southern blot analysis, multiplex ligation-dependent probe amplification (MLPA), and quantitative PCR.

Table 1. Molecular Genetic Testing Used in APC-Associated Polyposis Conditions Test Method Mutations Detected Mutation Detection Rate  1 Test Availability Sequence analysis APC sequence alteration Up to 90% Clinical Mutation scanning ~80-90% Protein truncation testing (PTT) Premature truncation of APC protein ~80% Duplication/deletion analysis Duplication/deletion of one or more exons ~8-12%  2

1. Detection of mutations using all methods listed below appears to be higher in typical FAP than in attenuated FAP [Sieber et al 2002 , Aretz et al 2005 , Michils et al 2005]. 2. Sieber et al 2002 , Bunyan et al 2004 , Aretz et al 2005 , Michils et al 2005

• Linkage analysis.  Linkage analysis can be considered in families with more than one affected family member who belong to different generations. Linkage studies are based upon an accurate clinical diagnosis of an APC-associated polyposis condition in the affected family members and accurate understanding of genetic relationships in the family. Linkage analysis is dependent on the availability and willingness of family members to be tested. The markers used for linkage analysis of APC-associated polyposis conditions are highly informative and very tightly linked to the APC locus; thus, they can be used in more than 95% of families with an APC-associated polyposis condition with greater than 98% accuracy [Petersen et al 1991 , Burt et al 1992]. Linkage testing is not available to families with a single affected individual, a situation that often occurs when an individual has a de novo gene mutation and no affected offspring.

Table 2. Linkage Analysis in APC-Associated Polyposis Conditions

% of Families	Genetic Mechanism	Test Type	Test Availability
95%	Markers linked to the APC gene	Linkage analysis	Clinical

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy for a Proband

• If the purpose of genetic testing is to determine the status of at-risk family members, it is most appropriate to test an affected family member using one of the molecular genetic test methods. Cost and detection rates differ; the clinician should determine with the individual the best option to pursue initially. Only if an APC mutation is detected can testing relying on these methods be offered to at-risk family members.
• In some instances, families may opt for linkage analysis as the initial test if appropriate samples are available. In other families linkage analysis can be considered if no alteration in the APC gene is identified in an affected family member using one of the molecular genetic tests.

Genetically Related (Allelic) Disorders

Colon cancer and/or polyps

• I1307K mutation in the APC gene.  A mutation in the APC gene at codon 1307 appears to create a hypermutable region that does not lead to classic FAP, but causes an increased risk of colon cancer [Laken et al 1997]. It is thought that 6% of all individuals of Ashkenazi Jewish ancestry have the I1307K mutation. Individuals with the I1307K mutation are predisposed to developing colon polyps but do not develop hundreds to thousands of polyps as in typical FAP. Individuals with the I1307K mutation have an approximate 10-20% lifetime risk of developing colon cancer. Individuals of Ashkenazi Jewish ancestry who have a family history of colon cancer or polyps, a personal history of colon cancer or polyps, or a heightened concern for colon cancer may be offered genetic testing for the I1307K mutation. The test is not appropriate for individuals who are not of Ashkenazi Jewish ancestry. While studies assessing the effectiveness of screening for colon polyps in individuals with the I1307K mutation have not been performed, some experts recommend that individuals who test positive for the mutation have a colonoscopy every two years starting at age 35 years or five to ten years earlier than the earliest colon cancer diagnosis in the family, while others recommend colonoscopy every three to five years starting at age 35 years or five to ten years earlier than the earliest colon cancer diagnosis in the family.

• E1317Q mutation.  Another missense variant in the APC gene, E1317Q, may be associated with a predisposition to colon adenomas and/or colon cancer [Frayling et al 1998 , Lamlum et al 2000 , Popat et al 2000 , Hahnloser et al 2003]; however, data are conflicting [Michils et al 2002]. The role of the E1317Q variant in colon cancer is uncertain and testing for this specific variant alone is not currently available on a clinical basis.

Deletion 5q22.  Interstitial deletions of chromosome 5q22, which includes the APC gene, have been reported in individuals with adenomatous polyposis and mental retardation [Pilarski et al 1999]. Large deletions are only rarely cytogenetically visible and are sometimes detectable using fluorescence in situ hybridization (FISH).

Clinical Description

Natural History

APC-associated polyposis conditions include classic FAP and two overlapping phenotypes, Gardner syndrome and Turcot syndrome, and attenuated FAP.

Classic FAP

Colorectal adenomatous polyps begin to appear at an average age of 16 years (range 7-36 years) [Petersen et al 1991]. By age 35 years, 95% of individuals have polyps. Once they appear, the polyps rapidly increase in number; when colonic expression is fully developed, hundreds to thousands of colonic adenomatous polyps are typically observed. Without colectomy, colon cancer is inevitable. The average age of colon cancer diagnosis in untreated individuals is 39 years (range 34-43 years). Seven percent of untreated individuals with FAP develop colon cancer by age 21 years, 87% by 45 years, and 93% by 50 years [Bussey 1975]. Although rare, asymptomatic individuals in their 50s have been reported [Evans et al 1993]. Interfamilial and intrafamilial phenotypic variability is common [Giardiello et al 1994 , Rozen et al 1999].

Other features that are variably present in FAP:

• Gastric polyps.  Gastric polyps can either be fundic-gland or adenomatous [Bulow et al 1995].

  • Gastric fundic-gland polyps are hamartomatous. They occur in approximately half of individuals with FAP [Offerhaus et al 1999], and are located in the fundus and body of the stomach. Although gastric fundic-gland polyps are considered to have little malignancy potential, several reports of gastric adenocarcinoma and high-grade dysplasia have been reported [Zwick et al 1997 , Hofgartner et al 1999 , Attard et al 2001]. For a complete review of gastric fundic gland polyps and their relationship to FAP and attenuated FAP, see Burt 2003 .
  • Gastric adenomatous polyps occur in about 10% of individuals with FAP [Bulow et al 1995 , Wallace & Phillips 1998] and are usually confined to the gastric antrum [Offerhaus et al 1999]. The risk for gastric cancer is small.

• Adenomatous polyps of the small bowel.  A classification system for duodenal polyps based on number and size of polyps, histology, and degree of dysplasia has been developed [Spigelman et al 1989]. The presence and number of adenomatous polyps are dependent upon the specific location in the small bowel [Wallace & Phillips 1998]. Adenomatous polyps of the duodenum are observed in 50-90% of individuals with FAP, and are commonly found in the second and third portions of the duodenum [Kadmon et al 2001]. No clear association has been identified between the number of colonic polyps and the number of upper gastrointestinal polyps [Kadmon et al 2001]. The lifetime risk of small bowel malignancy is 4-12%; the majority occur in the duodenum.

  Adenomatous polyps of the periampullary region (including the duodenal papilla and ampulla of Vater) are seen in at least 50% of individuals. Polyps in this area can cause obstruction of the pancreatic duct resulting in pancreatitis, which occurs at increased frequency in FAP. These polyps are often small and require a side-viewing endoscope for visualization. Some theorize that pancreaticobiliary secretions, such as bile, affect the development of adenomas and cancer in this area [Wallace & Phillips 1998 , Kadmon et al 2001]. The risk of malignancy of polyps in the periampullary region is higher than that of adenomas in other parts of the duodenum [Kadmon et al 2001].

• Extraintestinal manifestations.  Mutations in certain locations of the APC gene appear to favor the occurrence of extraintestinal manifestations that tend to run true in families.

  • Osteomas.  Osteomas are bony growths found most commonly on the skull and mandible; however, they may occur in any bone of the body. Osteomas do not usually cause clinical problems and do not become malignant. Osteomas may appear in children prior to the development of colonic polyps.

  • Dental abnormalities.  Unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts, and odontomas have been reported in approximately 17% of individuals with FAP compared to 1-2% of the general population [Brett et al 1994].

  • Congenital hypertrophy of the retinal pigment epithelium (CHRPE).  CHRPE are discrete, flat, pigmented lesions of the retina that do not cause clinical problems. It is thought that CHRPE are present at birth. Observation of multiple or bilateral CHRPE may be an indication that an at-risk family member has inherited FAP, whereas isolated or unilateral lesions may be seen in the general population. Visualization of CHRPE may require examination of the ocular fundus with an indirect ophthalmoscope through a dilated pupil.

  • Benign cutaneous lesions.  These lesions include epidermoid cysts and fibromas that may be found on any part of the body, including the face, and are mainly of cosmetic concern.

  • Desmoid tumors.  Approximately 10% of children and adults with FAP develop desmoid tumors [Gurbuz et al 1994 , Clark & Phillips 1996]. The risk of desmoid tumors in individuals with FAP is 852 times the risk in the general population [Gurbuz et al 1994]. These poorly understood benign fibrous tumors are clonal proliferations of myofibroblasts that are locally invasive but do not metastasize [Clark et al 1999]. A pathologically distinct fibromatous lesion called a Gardner-associated fibroma (GAF) is hypothesized to be a precursor lesion [Wehrli et al 2001]. Desmoid tumors form predominantly within the abdomen or in the abdominal wall, but may also occur extra-abdominally. Desmoid tumors may compress abdominal organs or complicate abdominal surgery. About 5% of individuals with FAP experience morbidity and/or mortality from desmoid tumors. Abdominal desmoid tumors may occur spontaneously or following abdominal surgery, pregnancy, and oral contraceptive use [Bertario et al 2001]. Independent predictors for desmoid tumor development include an APC mutation 3' of codon 1444, family history of desmoids, female gender, and the presence of osteomas [Bertario et al 2001]. Desmoid tumors are best evaluated by CT scan [Clark & Phillips 1996] or MRI. A CT scoring system for desmoids in FAP has been developed [Middleton et al 2003].

  • Adrenal masses.  Although not thoroughly studied, a statistically significant association between adrenal masses and FAP has been reported. Adrenal masses are found in 1-3% of the general population; a retrospective analysis identified adrenal masses in 7.4% of individuals with FAP [Marchesa et al 1997] and a prospective study of 107 individuals with FAP found 13% with an adrenal mass greater than or equal to 1.0 cm on abdominal CT scan [Smith et al 2000]. Most of these masses appeared to be adrenocortical adenomas without endocrinopathy or hypertension. Smith et al (2000) found no evidence to warrant screening for adrenal masses.

• Extracolonic cancers.  Several extracolonic cancers occur with a higher incidence in individuals with FAP than in the general population (Table 3) [Burt 2000].

Duodenal adenocarcinoma has been reported between ages 17 and 81 years, with the mean age of diagnosis between 45 and 52 years [Wallace & Phillips 1998 , Kadmon et al 2001]. It occurs most commonly in the periampullary area. Small bowel cancer past the duodenum has been reported, but is rare.

Among individuals with FAP, gastric adenocarcinoma occurs in 0.5% living in Western cultures, and with greater frequency in Japanese and Korean cultures [Offerhaus et al 1999]. Gastric adenocarcinoma is believed to arise most often from adenomas, but may also develop from fundic-gland polyps.

Thyroid cancers affected approximately 2% of individuals with FAP with a mean age at diagnosis of 28 years (range: 12-62 years of age) [Cetta et al 2000]. A female preponderance is observed. Papillary histology predominates and may commonly have a cribiform pattern. Familial occurrence has been observed.

Pregnancy/hormone use.  Limited information is available on the impact of pregnancy on females with FAP. In one study of 58 Danish women with FAP, the same frequency of fertility, pregnancy, and delivery was observed as in a control population [Johansen et al 1990]. A larger study of 162 women with FAP compared fertility rates before and after two types of colorectal surgery with a control population. Women with FAP who had not yet undergone surgery had the same fertility as a control population of normal women. Additionally, those women with FAP who had a colectomy with ileorectal anastomosis (IRA) had the same fertility as the control population. Fertility was significantly reduced in women with FAP who had a protocolectomy with ileal pouch-anal anastomosis (IPAA) compared to the control population [Olsen et al 2003].

Women who have undergone colectomy are considered to have the same risk of obstetrical complications as any other woman who has had major abdominal surgery. As anti-estrogen medications have been successfully used in the treatment of desmoid tumors, the development of desmoid tumors is thought to be affected by hormones important in pregnancy. However, one study has shown that women who had a previous pregnancy and developed a desmoid tumor had significantly fewer complications from the desmoid tumor than those who had never had a pregnancy [Church & McGannon 2000].

Some studies have suggested that female hormones protect against colorectal cancer development in the general population. A case report in an individual with FAP has shown reduction in polyps after use of oral contraceptives [Giardiello et al 2005].

Gardner Syndrome

Gardner syndrome (GS) is the association of colonic adenomatous polyposis of classic FAP with osteomas, and soft tissue tumors (epidermoid cysts, fibromas, desmoid tumors) [Gardner & Richards 1953]. These benign extraintestinal growths occur in about 20% of individuals and families with FAP. When these findings are prominent, many clinicians continue to use the term GS. Osteomas are most commonly found on the mandible and skull, although any bone of the body may be involved. Epidermoid cysts occur on any cutaneous surface and are mainly of cosmetic concern, as they do not appear to have malignant potential. Supernumerary teeth, odontomas, and desmoid tumors were originally described as a part of GS; however, like osteomas and epidermoid cysts, they can occur in any individual with FAP, whether or not other extraintestinal findings are present.

Although GS was once thought to be a distinct clinical entity, it is now known that mutations in the APC gene give rise to both classic FAP and GS. Other manifestations of FAP, such as upper gastrointestinal polyposis, are also found in GS. Some correlation exists between extraintestinal growths and mutation location in APC; see Genotype-Phenotype Correlations .

Turcot Syndrome

Turcot syndrome is the association of colonic adenomatous polyposis of classic FAP and CNS tumors, usually medulloblastoma. The risk of CNS tumors is substantially increased in persons with FAP generally, although the absolute risk is only approximately 1%. Families with APC-associated polyposis conditions and multiple individuals with CNS tumors raise the possibility of mutation specificity or modifying genes.

Attenuated FAP

Attenuated FAP (AFAP) is characterized by a significant risk for colon cancer, but fewer colonic polyps (average of 30) than classic FAP. Polyps tend to be found more proximally in the colon than in classic FAP. The average age of colon cancer diagnosis in individuals with AFAP is age 50-55 years — 10-15 years later than in those with classic FAP, but earlier than that seen in individuals with sporadically occurring colon cancer [Spirio et al 1993 , Giardiello et al 1997]. Upper gastrointestinal polyps and cancers may be seen in individuals with AFAP [Burt 2003] and, although the extraintestinal manifestations of FAP may be present, CHRPE lesions and desmoid tumors are rare. For excellent investigations and review of AFAP, see Knudsen et al 2003 and Burt et al 2004 .

Genotype-Phenotype Correlations

Although variation occurs among and within individuals and among and within families with identical mutations in the APC gene [Giardiello et al 1994 , Friedl et al 2001], much effort has gone into making genotype-phenotype correlations. Some have suggested basing management strategies on these associations [Vasen et al 1996]; others feel that therapeutic decisions should not be based on genotype [Friedl et al 2001]. While not in routine use at present,f these correlations may become more integral in management decisions in the future.

• Attenuated FAP is associated with mutations in the 5' part of the APC gene (5' to codon 158) [Spirio et al 1993], exon 9 [van der Luijt et al 1995 , Soravia et al 1998], and the distal 3' end of the gene [Friedl et al 1996 , Van der Luijt et al 1996 , Walon et al 1997].
• The most frequent mutation in the APC gene is located at codon 1309. Mutations at this codon lead to a high number of colonic adenomas at an early age [Friedl et al 2001 , Bertario et al 2003]. Analysis of individuals with colonic symptoms revealed that individuals with mutations at codon 1309 presented at an average age of 20 years, individuals with mutations between codon 168 and 1580 (excluding 1309) presented with symptoms at an average age of 30 years, and individuals with mutations 5' of codon 168 and 3' of codon 1580 presented at an average age of 52 years [Friedl et al 2001].
• Profuse polyposis (an average of 5000 polyps) has been reported with mutations in codons 1250-1464 [Nagase et al 1992].
• Prominent extracolonic manifestations often correlate, but not completely, with more distal APC gene mutation. A retrospective study of 190 individuals with FAP compared nine extracolonic manifestations (desmoid tumors, osteomas, epidermoid cysts, duodenal adenomas, gastric polyps, hepatoblastoma, dental anomalies, periampullary cancers, and brain tumors) [Wallis et al 1999]. Results showed that individuals with mutations in codons 1395-1493 have significantly higher rates of desmoid tumors, osteomas, and epidermoid cysts than those with mutations in codons 177-452. Additionally, affected individuals with mutations in codons 1395-1493 have significantly higher rates of desmoid tumors and osteomas than those with mutations in codons 457-1309. Of individuals with APC mutations in codons 177-452, none developed osteomas, hepatoblastomas, periampullary region tumors, or brain cancers. Hepatoblastoma and brain cancer were seen only in individuals with mutations in codons 457-1309.
• Mutations between codons 1444 and 1580 are associated with a higher incidence of desmoid tumors [Caspari et al 1995 , Davies et al 1995]. A study of 269 individuals with identifiable APC mutations found desmoid tumors in 20% of individuals with mutations 5' to codon 1444, 49% of individuals with mutations 3' to codon 1444, and 61% of individuals with mutations in codons 1445-1580 [Friedl et al 2001]. Several families with severe desmoid tumors with mutations at the extreme 3' end of the APC gene have been reported [Eccles et al 1996 , Scott et al 1996 , Couture et al 2000]. A study of Italian individuals with FAP found that mutations between codons 1310 and 2011 are associated with a sixfold risk of desmoid tumors compared to mutations between codons 159 and 495 [Bertario et al 2003].
• The presence of CHRPE is associated with mutations between codons 463 and 1387 [Olschwang et al 1993]. Mutations between codons 1444 and 1578 are associated with the absence of CHRPE [Caspari et al 1995 , Davies et al 1995].
• Molecular genetic testing of 24 individuals with thyroid cancer and FAP reveal that the majority of mutations identified were 5' to codon 1220 [Cetta et al 2000]. In another study, nine of 12 individuals with FAP and thyroid cancer had APC mutations identified proximal to the mutation cluster region (codons 1286-1513) [Truta 2003].
• A fourfold increased risk in duodenal adenomas was found in individuals with mutations between codons 976 and 1067 in one study of Italian individuals with FAP [Bertario et al 2003].

Penetrance

The penetrance of FAP in terms of colonic adenomatous polyposis and colon cancer is virtually 100% in untreated individuals.

The penetrance of other intestinal and extraintestinal manifestations is less well understood and may depend in part on the mutation location in the APC gene.

Anticipation

Anticipation is not described in this condition.

Nomenclature

Other terms used historically for FAP include familial polyposis coli and adenomatous polyposis coli; the latter term is now used for the relevant gene.

The term Gardner syndrome is mainly of historical interest as it is now known to arise from mutations of the APC gene like FAP. Furthermore, subtle extraintestinal manifestations can be found in almost all individuals with FAP with sufficient investigation. Nonetheless individuals and families with particularly prominent extracolonic manifestations will undoubtedly continue to be referred to as having Gardner syndrome.

The risk of CNS tumors is substantially increased in individuals with FAP generally, although the absolute risk is only approximately 1%. In some families with FAP, multiple individuals have CNS tumors, making Turcot syndrome an historical term of uncertain significance as it relates to FAP.

Attenuated FAP (AFAP) appears to be the same as the hereditary flat adenoma syndrome [Lynch et al 1992].

Prevalence

The prevalence data reported from national registries include all of the APC-associated polyposis conditions (except possibly some cases of attenuated FAP); reported prevalence is 2.29-3.2 per 100,000 population [Burn et al 1991 , Jarvinen 1992 , Bulow et al 1996]. APC-associated polyposis conditions historically accounted for about 0.5% of all colorectal cancers; this figure is declining as more at-risk family members undergo successful treatment following early polyp detection and prophylactic colectomy.

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

APC-associated polyposis conditions may be distinguished from other inherited colon cancer conditions and other gastrointestinal polyposis syndromes by molecular genetic testing, histopathologic findings, and phenotypic characteristics. Conditions to consider in the differential diagnosis include the following hereditary disorders:

• MYH-associated polyposis.  The phenotype of MYH-associated polyposis is similar to FAP and attenuated FAP but is inherited in an autosomal recessive manner. Germline mutations in MYH predispose persons to multiple adenoma or polyposis coli. If an APC mutation is not identified in an individual with FAP or attenuated FAP, molecular genetic testing of MYH should be considered [Sieber et al 2003]. Biallelic MYH mutations have also been found in a few individuals diagnosed with colorectal cancer at 50 years of age or younger who have had few or no polyps [Wang et al 2004].

• Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant colon cancer syndrome with proximal colonic predominance. Few colonic adenomas are present. Other malignancies include cancer of the endometrium, ovary, stomach, small intestine, and urinary tract. HNPCC is caused by mutations in DNA mismatch repair genes, primarily MLH1 and MSH2, but also MSH6 and PMS2. It may be difficult to distinguish between HNPCC and attenuated FAP in individuals and families who have few adenomatous colonic polyps [Cao et al 2002]. In this situation, family history of extracolonic cancers and manifestations as well as microsatellite instability (MSI) testing on a tumor block from a colon cancer may be helpful in deciding which condition to pursue further.

• Turcot syndrome is the association of colon cancer or colonic polyposis and CNS tumors, usually medulloblastoma. Two-thirds of persons with Turcot syndrome have a mutation in the APC gene, and one-third have mutations in one of the mismatch repair genes that cause hereditary non-polyposis colon cancer (HNPCC) [Hamilton et al 1995 , Paraf et al 1997]. The CNS tumors in individuals with HNPCC are usually glioblastoma multiforme.

• Peutz-Jeghers syndrome (PJS).  Inherited in an autosomal dominant manner, PJS is characterized by the association of gastrointestinal polyposis and mucocutaneous pigmentation. Peutz-Jeghers type hamartomatous polyps are most prevalent in the small intestine (jejenum, ileum, and duodenum, respectively), but can occur elsewhere in the GI tract. Mucocutaneous hyperpigmentation presents in children under the age of five years as dark blue to dark brown mucocutaneous macules around the mouth, eyes, and nostrils, in the perianal area, on the buccal mucosa, and on the fingers. Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries. Males occasionally develop calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia. Individuals with Peutz-Jeghers syndrome are at increased risk for intestinal and extraintestinal malignancies, including colorectal, esophageal, gastric, breast, ovarian, and pancreatic cancers [Giardiello et al 2000]. Molecular genetic testing of the STK11 gene reveals disease-causing mutations in about 70% of familial cases and 30-70% of nonfamilial cases.

• PTEN hamartoma tumor syndrome (PHTS) is a syndrome comprising hamartomas and cancer that is characterized by germline PTEN mutations and inherited in an autosomal dominant manner. PHTS includes Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba (BRR) syndrome. CS is a multiple hamartoma syndrome with a high risk of benign and malignant tumors of the thyroid, breast, and endometrium. BRR syndrome is a congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, and pigmented macules of the glans penis. Approximately 80% of individuals who meet the diagnostic criteria for CS and 60% of individuals with a clinical diagnosis of BRR syndrome have a detectable PTEN gene mutation.

• Juvenile polyposis syndrome (JPS) is characterized by predisposition for hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. JPS is diagnosed if any one of the following is present: more than five juvenile polyps of the colorectum OR multiple juvenile polyps throughout the GI tract OR any number of juvenile polyps and a family history of juvenile polyps [Jass et al 1988]. The term "juvenile" refers to the type of polyp, not the age of onset of polyps. Most individuals with JPS have some polyps by 20 years of age. Some individuals may only have four or five polyps over their lifetimes, whereas others in the same family may have over a hundred. Most juvenile polyps are benign; however, malignant transformation can occur. Estimates of developing GI cancers in families with JPS range from 9% to 50%. Two genes are known to be associated with JPS: MADH4 (previously SMAD4) and BMPR1A. Approximately 15% of individuals affected with JPS have mutations in the MADH4 gene; approximately 25% have mutations in the BMPR1A gene. JPS is inherited in an autosomal dominant manner.

• Hereditary mixed polyposis syndrome.  Mode of inheritance is unknown. The syndrome is characterized by atypical juvenile polyps, polyps containing mixed histology, or multiple polyps of more than one histologic type in an individual.

• Neurofibromatosis type 1 (NF1).  Individuals with NF1 may exhibit multiple intestinal polypoid neurofibromas or ganglioneuromas in the small bowel, stomach, and colon.

Conditions to be considered in the differential diagnosis include the following acquired disorders:

• Cronkite-Canada syndrome is characterized by generalized gastrointestinal hamartomatous polyposis, cutaneous hyperpigmentation, hair loss, and nail atrophy.

• Nodular lymphoid hyperplasia is a lymphoproliferative disorder resulting in hyperplastic lymphoid nodules in small bowel, stomach, and colon; may be associated with common variable immunodeficiency syndrome.

• Lymphomatous polyposis is characterized by occurrence of primary extranodal lymphomas in the gastrointestinal tract; two types include multiple lymphomatous polyposis and Mediterranean-type lymphoma.

• Inflammatory polyposis is charcterized by acquired; non-neoplastic polyps associated with inflammatory bowel disease, most commonly ulcerative colitis.

• Sporadic colorectal tumors.  The majority of colorectal tumors not known to be familial have been shown to have a somatic mutation in the APC gene [Miyoshi et al 1992 , Powell et al 1992 , Smith et al 1993] that is believed to occur early in colorectal tumorigenesis [Fearon & Vogelstein 1990].

• Hyperplastic polyposis (or metaplastic polyposis) comprises multiple non-neoplastic hyperplastic polyps of the gastrointestinal tract; whether it is inherited or acquired is unknown.

Management

Evaluations at Initial Diagnosis to Establish the Extent of Disease

• Personal medical history with particular attention to features of APC-associated polyposis (colon cancer, colon polyps, rectal bleeding, diarrhea, abdominal pain)
• Family history with particular attention to features of FAP
• Physical examination with particular attention to extraintestinal manifestations of APC-associated polyposis
• Ophthalmologic evaluation for presence of congenital hypertrophy of the retinal pigment epithelium (CHRPE) (optional)
• Colonoscopy with review of pathology
• Consideration of upper GI tract evaluation, including endoscopy with a side-viewing scope and small-bowel X-ray (such as small-bowel enteroclysis or abdominal and pelvic CT with orally administered contrast)
• Molecular genetic testing of the APC gene to confirm the diagnosis if clinical diagnostic criteria are not satisfied. If an individual with a suspected clinical diagnosis of APC-associated polyposis has an identifiable disease-causing alteration in the APC gene, the diagnosis is confirmed. If molecular genetic testing of the APC gene does not reveal an identifiable disease-causing alteration, the diagnosis of APC-associated polyposis is still possible because of the less-than-100% detection rate with current molecular genetic testing methods.

Treatment of Manifestations

Colonic polyps.  Practice parameters, including information on surgery, have been outlined by the American Society of Colon and Rectal Surgeons [Church, Simmang et al 2003].

For individuals with classic FAP, colectomy is recommended after adenomas emerge; colectomy may be delayed depending on the size and number of adenomatous polyps. Colectomy is usually advised when more than 20 or 30 adenomas or multiple adenomas with advanced histology have occurred.

For individuals with attenuated FAP, colectomy may be necessary, but in about one third of individuals, the colonic polyps are limited enough in number that surveillance with periodic colonoscopic polypectomy is sufficient (see Surveillance).

The types of colectomy:

• Total colectomy with mucosal proctectomy with ileo-anal pull through
• Subtotal colectomy with ileorectal anastomosis; often used for individuals with attenuated FAP or in instances in which the rectum is spared of polyps

Note: Colectomy with permanent ileostomy is rarely needed.

A study of individuals with FAP and ileal pouches found that 57% had adenomatous polyps in the ileal pouch. No apparent relationship between the development of pouch adenomas and the severity of polyps in the colon or duodenum was found [Groves et al 2005].

The risk of cancer in the surgical transition zone is very low, but has been reported [Ooi et al 2003].

Small bowel polyps.  Endoscopic or surgical removal of duodenal adenomas should be considered if polyps exhibit villous change or severe dysplasia, exceed one centimeter in diameter, or cause symptoms [Wallace & Phillips 1998 , Saurin et al 1999 , Kadmon et al 2001].

Pancreaticoduodenectomy (Whipple procedure) may occasionally be necessary to treat severe duodenal adenomas.

Osteomas.  These may be removed for cosmetic reasons.

Desmoid tumors.  Treatments used on small numbers of individuals include surgical excision (associated with high rates of recurrence), nonsteroidal anti-inflammatory drugs (NSAIDs), anti-estrogens, cytotoxic chemotherapy, and radiation [Griffioen et al 1998 , Clark et al 1999 , Smith et al 2000 , Tonelli et al 2003]. A review of desmoid treatments can be found in Knudsen & Bulow (2001).

Nonsteroidal anti-inflammatory drugs (NSAIDs).  NSAIDs, especially sulindac, celecoxib, and rofecoxib [Steinbach et al 2000 , Higuchi et al 2003 , Keller & Giardiello 2003], have been shown to cause regression of adenomas in FAP and to decrease the number of polyps requiring ablation in the remaining rectum of persons who have had a subtotal colectomy. NSAID use before colectomy remains experimental.

Celecoxib is approved for use in adenoma management in affected individuals with a remaining rectum. Withdrawal of rofecoxib in 2005 from the market because of untoward cardiovascular and cerebrovascular events and the observation that similar events occur with the doses of celecoxib needed for adenoma regression has brought into question the long-term use of these agents for treatment of FAP. Sulindac appears to be the remaining option.

Surveillance

Recommended surveillance for individuals who have undergone colectomy:

• If total colectomy with ileo-anal pull-through was performed, routine endoscopic surveillance of the ileal pouch every two years is recommended.
• If subtotal colectomy was performed, surveillance of the remaining rectum is recommended every six to 12 months, depending on the number of polyps that develop. Cancer may still occur in the remaining rectum, but the risk is small with the current management [Church, Burke et al 2003].

Recommended surveillance of individuals who are known to have FAP or an APC disease-causing mutation and individuals who are at risk for FAP who have not undergone molecular genetic testing or who are members of families in which molecular genetic testing did not identify a disease-causing mutation [Giardiello et al 2001]:

• Annual screening for hepatoblastoma from birth to age five years by physical examination and/or abdominal ultrasound examination and measurement of serum concentration of alpha-fetoprotein
• Sigmoidoscopy every one to two years beginning at age ten to 12 years
• Colonoscopy once polyps are detected
• Annual colonoscopy if colectomy is delayed more than a year after polyps emerge. If individuals are 10-20 years old and adenomas are smaller than 6.0 mm without villous component, delay in colectomy may be considered.
• Esophagogastroduodenoscopy (EGD) beginning when colonic polyposis is detected or by age 25 years and repeated every one to three years. The frequency of EGD is dependent on the severity of duodenal adenomas. A side-viewing instrument should be used to visualize the duodenal papilla. As adenomatous tissue is commonly found at the papilla, biopsy may be justified if no polyps are visualized but the papilla seems enlarged. In some cases, endoscopic retrograde cholangiopancreatography (ERCP) may be necessary to evaluate for adenomas of the common bile duct.
• Small-bowel X-ray (small-bowel enteroclysis or abdominal and pelvic CT with orally administered contrast) when duodenal adenomas are detected or prior to colectomy, repeated every one to three years depending on findings and presence of symptoms
• Attention to extraintestinal manifestations, usually for cosmetic concerns
• Annual physical examination including palpation of the thyroid

Recommended surveillance of persons at risk for attenuated FAP:

• Colonoscopy every two to three years beginning at 18-20 years of age, depending on the number of polyps
• If polyps are detected or if molecular genetic testing is positive, recommendations for individuals known to have FAP or attenuated FAP and colonic polyps are instituted (see above)

Recommended surveillance of at-risk family members who on molecular genetic testing have not inherited the disease-causing APC mutation previously identified in an affected family member:

• Colon cancer screening for individuals at average risk beginning at age 50 years
• Recommended by some centers: baseline sigmoidoscopy at ages 16, 25, and 35 years to verify molecular genetic test results

Testing of Relatives at Risk

Recommended genetic testing for at-risk family members.   Early recognition of APC-associated polyposis conditions may allow for timely intervention and improved final outcome; thus, surveillance of asymptomatic at-risk children for early manifestations of APC-associated polyposis conditions is appropriate. (See American Gastroenterological Association Medical Position Statement , American College of Medical Genetics/American Society of Human Genetics Joint Statement .) Use of molecular genetic testing for early identification of at-risk family members (see Genetic Counseling) improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited the disease-causing mutation. A cost analysis comparing molecular genetic testing and sigmoidoscopy screening for individuals at risk for APC-associated polyposis conditions shows that genetic testing is more cost effective than sigmoidoscopy in determining who in the family has APC-associated polyposis conditions [Cromwell et al 1998]. Additionally, individuals diagnosed with APC-associated polyposis conditions as a result of having an affected relative have a significantly greater life expectancy than those individuals diagnosed with APC-associated polyposis conditions on the basis of symptoms [Heiskanen et al 2000].

As colon screening for those at risk for classic FAP begins as early as age eight to ten years, molecular genetic testing is generally offered to children at risk for classic FAP at age eight years and older. Colon screening for those at risk for attenuated FAP begins at age 18 years; thus, molecular genetic testing should be offered to those at risk for attenuated FAP at approximately 18 years of age.

Note: No evidence points to an optimal age at which to begin screening; thus, the ages at which testing is performed and screening initiated may vary by center, family history, hepatoblastoma screening, and/or parents'/child's needs.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

NSAIDs have been unsuccessfully used in an attempt to prevent the emergence of colonic adenomatous polyposis [Giardiello & Yang 2002].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

APC-associated polyposis conditions are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 75-80% of individuals with an APC-associated polyposis condition have an affected parent.
• Approximately 20-25% of individuals with an APC-associated polyposis condition have the altered gene as the result of a de novo gene mutation [Bisgaard et al 1994].
• Investigations to determine the parental origin of a de novo APC gene mutation suggest a slight preponderance of mutations of paternal origin (12/16 families;f not statistically significant) [Aretz et al 2004] while another report shows equal maternal and paternal origin [Ripa et al 2002]. Thus, de novo APC mutations do not appear to demonstrate an advanced paternal age effect [Ripa et al 2002 , Aretz et al 2004].
• It is appropriate to evaluate the parents of an affected individual with molecular genetic testing of the APC gene if the disease-causing mutation is known in the proband or for clinical manifestations of APC-associated polyposis conditions.

Sibs of a proband

• The risk to the sibs depends on the genetic status of the parents.
• If a parent is affected, the risk is 50%.
• If neither parent of an individual with an APC-associated polyposis condition meets the clinical diagnostic criteria for an APC-associated polyposis condition, the risk to the sibs of an affected individual of having an APC-associated polyposis condition is that of the general population.
• If neither parent of an individual with an APC-associated polyposis condition is found to have the mutation identified in the proband, the risk to the sibs of having an APC-associated polyposis condition is that of the general population.

Offspring of a proband.  Every child of an individual with an APC-associated polyposis condition has a 50% chance of inheriting the mutation.

Other family members of a proband.  The risk to other family members depends upon the genetic status of the proband's parents. If a parent is found to be affected or to have an APC disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic individuals during adulthood and childhood.  Consideration of molecular genetic testing of young at-risk family members is appropriate for guiding medical management (see Management).

Molecular genetic testing can be used with certainty to clarify the genetic status of at-risk family members when a clinically diagnosed relative has undergone molecular genetic testing and is found to have a mutation in the APC gene or is found to have a truncated APC protein.

The use of molecular genetic testing for determining the genetic status of at-risk relatives when a clinically diagnosed relative is not available for testing is problematic, and test results need to be interpreted with caution. A positive test result in the at-risk family member indicates the presence of an APC disease-causing mutation in the at-risk family member and indicates that the same molecular genetic testing method can be used to assess the genetic status of other at-risk family members. In contrast, when genetic testing is offered to an at-risk family member prior to testing a family member known to be affected, the failure to identify a disease-causing mutation in the at-risk family member does not eliminate the possibility that an APC disease-causing mutation is present. The genetic status of such individuals cannot be determined through molecular genetic testing, and they need to follow the recommendations for clinical surveillance of at-risk family members.

As colon screening for those at risk for classic FAP begins as early as age ten years, molecular genetic testing is generally offered to individuals age eight years and older. Colon screening for those at risk for attenuated FAP (AFAP) begins at age 18 years; thus, molecular genetic testing should be offered at about 18 years of age. Molecular genetic testing may be performed earlier if it alters medical management of the child. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures in a child who has not inherited the altered gene. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and their children. Although most children do not show evidence of clinically significant psychological problems after presymptomatic testing, Codori et al (2003) recommend that long-term psychological support be available to these families.

Other issues to consider.  It is recommended that physicians ordering APC molecular genetic testing and individuals considering undergoing testing understand the risks, benefits, and limitations of the testing prior to sending a sample to a laboratory. A study demonstrated that for almost one-third of individuals assessed for FAP, the physician misinterpreted the test results [Giardiello et al 1997]. In addition, Michie et al (2002) found that at-risk relatives who were found to be mutation negative were more likely to request continued bowel surveillance when results were relayed to them by non-geneticist physicians than by genetics professionals. In a follow-up study evaluating why some at-risk individuals are not reassured by negative molecular genetic test results and request continued surveillance, Michie et al (2003) conclude that effective communication is key to facilitating adaptive behavior. Referral to a genetic counselor and/or a center in which testing is routinely offered is recommended.

Genetic cancer risk assessment and counseling. For comprehensive descriptions of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see:

• Genetic Cancer Risk Assessment and Counseling: Recommendations of the National Society of Genetic Counselors

• Elements of Cancer Genetics Risk Assessment and Counseling (part of PDQ^®, National Cancer Institute)

Considerations in families with an apparent de novo mutation.   When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.

DNA banking.  DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal diagnosis for pregnancies at 50% risk for APC-associated polyposis conditions is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed. The criteria for use of molecular genetic testing discussed in Testing of at-risk asymptomatic individuals during adulthood and childhood apply to prenatal testing as well. It should be noted that detection of an APC mutation in a fetus at risk does not predict the time of onset or severity of the disease.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as the APC-associated polyposis that do not affect intellect and have treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

Preimplantation diagnosis (PGD).   Successful preimplantation diagnosis has been reported for several inherited cancer predisposition syndromes and is an option for couples at risk of having offspring with an APC-associated condition [Rechitsky et al 2002]. The parent's disease-causing allele must be identified before preimplantation diagnosis can be performed. Pregnancy is achieved through assisted reproductive technology (ART) and requires coordination with specialists in fertility and endocrinology. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.

Normal allelic variants: The gene is alternatively spliced in multiple coding and noncoding regions; the main transcript has 15 exons with 8532 base pairs that code for 2844 amino acids and result in a 311.8-kd protein. Exon 15 is large and comprises over three-quarters of the coding region of the gene.

Pathologic allelic variants: Over 826 germline mutations have been found in families with an APC-associated polyposis condition [Beroud et al 2000]. Mutations almost always cause a premature truncation of the APC protein, usually through single amino-acid substitutions or frameshifts. While mutations have been found scattered throughout the gene, they are predominantly located in the 5' end of the gene. The most common germline APC mutation is a 5-bp deletion that results in a frameshift mutation at codon 1309. (For more information, see Genomic Databases table above.)

Normal gene product: The APC protein has been localized to the nucleus and membrane/cytoskeleton in human epithelial cells [Neufeld & White 1997]. It has also been shown to homodimerize [Joslyn et al 1993] and bind to other proteins including GSK3b [Rubinfeld et al 1996], b-catenin [Rubinfeld et al 1993 , Su et al 1993], g-catenin [Hulsken et al 1994 , Rubinfeld et al 1995], tubulin [Munemitsu et al 1994 , Smith et al 1994], EB1 [Su et al 1995], and hDLG, a homolog of the Drosophila discs large tumor-suppressor protein [Matsumine et al 1996]. The APC protein product is a tumor suppressor. APC protein forms a complex with glycogen synthase kinase 3b (GSK-3b) [Rubinfeld et al 1996], which targets b-catenin, a protein involved in both cell adhesion and intracellular signal transduction [Korinek et al 1997 , Morin et al 1997 , Nakamura 1997 , Peifer 1997 , Rubinfeld et al 1997]. The presence of normal APC protein appears to maintain normal apoptosis and may also decrease cell proliferation, probably through its regulation of b-catenin. This pathway is normally involved with Wingless-Wnt signaling, which participates in several known cell growth functions. The APC protein has been shown to accumulate at the kinetochore during mitosis, contribute to kinetochore-microtubule attachment, and play a role in chromosome segregation in mouse embryonic stem cells [Fodde et al 2001 , Kaplan et al 2001]. The APC protein may play a role in chromosomal instability, the presence of which is often observed when APC function is lost. Other possible roles for the APC protein include regulation of cell migration up the colonic crypt and cell adhesion through association with E-cadherin, regulation of cell polarity through association with GSK3b and other functions related to association with microtubule bundles [Nathke et al 1996 , Barth et al 1997 , Etienne-Manneville & Hall 2003]. Goss & Groden (2000) provide an excellent review of the function of the APC protein.

Abnormal gene product: Disease-causing mutations in the APC gene most often result in truncated protein products. Experiments have localized normal full-length APC protein to the membrane/cytoskeleton and nuclear fractions of human epithelial cells, but demonstrated that colon cancer cells containing only mutant APC genes revealed no truncated APC protein in nuclear fractions [Neufeld & White 1997].

When the APC gene is mutated and abnormal protein is present, high levels of free cytosolic b-catenin result. Free b-catenin migrates to the nucleus, binds to a transcription factor Tcf-4 or Lef-1 (T cell factor-lymphoid enhancer factor), and may activate expression of genes such as the oncogenes c-Myc and cyclin D1 [Chung 2000]. The specific genes targeted are not yet known, but may include those increasing proliferation or decreasing apoptosis. As APC may be important in cell migration, abnormal APC protein may disrupt normal cellular positioning in the colonic crypt. Additionally, mutations in the APC gene are thought to contribute to chromosomal instability in colorectal cancers [Fodde et al 2001].

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

• American Society of Clinical Oncology (2003) Policy statement (updated): genetic testing for cancer susceptibility
  
  
• American Society of Colon and Rectal Surgeons (2003) Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (FAP and HNPCC)
  
  
• American Society of Human Genetics/American College of Medical Genetics (1995) Points to consider : ethical, legal, and psychosocial implications of genetic testing in children and adolescents
  
  
• American Gastroenterological Association (2001) Medical position statement : hereditary colorectal cancer and genetic testing
  
  
• Giardiello FM, Brensinger JD, Petersen GM (2001) American Gastroenterological Association technical review on hereditary colorectal cancer and genetic testing
  
  
• American College of Medical Genetics/American Society of Human Genetics (2000) Joint statement on genetic testing for colon cancer (Adobe^®Acrobat Reader required)
  
  
• Winawer S, Fletcher R, Rex D, Bond J, Burt R, Ferrucii J, Ganiats T, Levin T, Woolf S, Johnson D, Kirk L, Litin S, Simmang C for the U.S. Multisociety Task Force on Colorectal Cancer (2003) Colorectal cancer screening and surveillance: clinical guidelines and rationale - Update based on new evidence

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