Final Diagnosis -- Familial adenomatous polyposis



Hereditary Colorectal Cancer Syndromes are subdivided into familial adenomatous polyposis (FAP; about 1% of the total cases) and hereditary nonpolyposis colorectal cancer (HNPCC; about 2% of the total cases).

Familial Adenomatous Polyposis (FAP), also known as adenomatous polyposis coli (APC), is an autosomal dominant (AD) disorder affecting roughly 1 in 8,000 individuals in the US. The hallmark of this disease is the development of hundreds of adenomatous polyps in the colon and rectum that usually emerge during the second and third decade of life and harbor a high risk of malignant transformation (100% by age 60). Hundreds to thousands of precancerous colonic polyps develop in the patients with FAP as early as 7 years of age (mean age of 16 years). By the age of 35 years the majority of these patients have polyps (95%) and the progression to colon cancer is inevitable without colectomy. The mean age of colon cancer in untreated individuals is 39 years (39-43 years) and the penetrance is nearly 100%. Patients with FAP are at risk of developing other extracolonic lesions, which tend to run true in families.

Patients with FAP are also at risk of developing other types of cancer (see table 1) and their risk is higher than in the general population. The identification of severe dysplasia in an adenomatous polyp is generally an indication for resection of the affected organ. Adenomas of the ileum have been observed in 83% of FAP patients after colectomy and ileoproctostomy. The incidence of ileal adenomas increases with time following colon resection.

It is now recognized that FAP has a broad spectrum of clinical manifestations and, in addition to classic FAP, includes three phenotypes that previously were thought to be discrete clinical entities distinct from FAP: attenuated FAP, Gardner syndrome, and Turcot syndrome.

Patients with classic FAP present with over 100 colorectal adenomatous polyps or less then 100 adenomatous polyps AND a relative diagnosed with FAP. Patients with attenuated FAP (AFAP) present with colonic adenomatous polyps less than 100 in number and more proximally found in the colon than in classic FAP. In patients with a fewer number of polyps (average of 30), a family history of colon cancer in persons less than age 60 years with multiple adenomatous polyps is necessary for diagnosis. The average age of colon cancer diagnosis in individuals with attenuated FAP is age 50 to 55 years, which is 10-15 years later than that observed in classic FAP. A predominance of right-sided colorectal adenomas and rectal polyp sparing was observed in these patients. AFAP also has been described as "hereditary flat adenoma syndrome" .Colonic adenomas may present with a flat (rather than polypoid) morphology. Gastric fundic polyps and duodenal adenomas are also seen, and, in contrast to what is seen in FAP, CHRPE lesions and desmoid tumors rarely have been described in AFAP.

Gardner syndrome (GS) is the association of colonic adenomatous polyposis, osteomas, and soft tissue tumors (epidermoid cysts, fibromas, desmoid tumors) and was described by Gardner and Richards in 1953. 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.

Turcot syndrome is the association of colon cancer and CNS tumors, usually medulloblastoma. Two-thirds of persons with Turcot syndrome have a mutation in the APC gene and one-third has mutations in one of the mismatch repair genes that cause hereditary non-polyposis colon cancer (HNPCC). The CNS tumors seen in patients with HNPCC are usually glioblastoma multiforme.


The initial observation leading to the localization of the APC gene was the demonstration by Herrera and Sandberg in 1986 of an interstitial deletion affecting chromosome 5q in a patient who manifested features of FAP, but who lacked any prior family history of the syndrome. Subsequent DNA linkage analysis studies confirmed that the polyposis phenotype segregated with DNA markers near 5q21. The identification of the APC gene as the cause of FAP was achieved in 1991 by Groden et al (Cell 66:589, 1991).

FAP is caused by germline mutations in the APC gene. Since the manifestations of FAP can be of endodermal, mesodermal and ectodermal origin, it is likely that APC plays an important role in development, differentiation, and tumor genesis. The APC gene spans approximately 150 kb of genomic DNA and is fragmented into 15 exons which are spliced into an mRNA transcript of about 8 kb. The exon structure of APC is remarkable in that the first 14 exons are relatively small while exon 15 codes for an open reading frame of about 6.5 kb. The gene encodes for a protein of 2,843 amino acids that is expressed in many adult tissues. Almost all APC mutations so far identified are nonsense or frameshift mutations leading to the synthesis of truncated proteins. Mutations are located within the first 2000 codons of the APC gene, and several mutational hot spots have been identified at codons 1061 and 1309. Somatic mutations in colorectal cancer appear to cluster in a region termed the "mutation cluster region," and mutations at codons 1309 and 1450 are most common.

Preliminary findings suggest the relative location of the germline mutation in the APC gene in those with polyposis may be associated with the number of polyps that arise. The location of the APC mutation may partially predict specific phenotypic expression and should help in the design of tailored clinical-management protocols in this subset of FAP patients. A "sparse" phenotype (1,000-2,000 polyps) has been correlated with germ-line APC mutations in the region spanning codons 513-1597 and a "profuse" phenotype (>5,000 polyps) has been demonstrated to segregate with APC mutations in the region spanning codons 1250-1464

Mutations in the 5' region are correlated with an attenuated phenotype. Mutations in last third (3') of the gene are also associated with a milder polyposis phenotype than mutations in the central third of the gene. Extracolonic features, such as desmoid tumors, may be more common in those with 3 mutations. Four distinct mutations in the APC gene have been identified in seven families with the attenuated form of FAP. These mutations that predict truncation products are similar to mutations identified in families with classical FAP and occur either by single base pair changes or frameshifts. These four mutated sites are located very close to one another and nearer the 5' end of the APC gene than any base substitutions or small deletions yet discovered in patients with classical FAP. Further studies have shown that AFAP is caused by mutations in three distinct regions of the APC gene: in the 5' end, in region spanning exons 4 and 5; in exon 9; and at the extreme 3' end. Phenotypic expression in these three groups is variable but milder than that in classical FAP. AFAP families carrying 5' germ-line APC mutations exhibit greater variability with regard to the frequency and age at onset of polyposis, such that the phenotypes of some affected patients are quite similar to that of classical FAP. Furthermore, duodenal adenomas occur with an increased severity in these families.

Clinical review of AFAP families with 5'-end APC mutations demonstrates that, although the number of colorectal adenomas usually is <100, in some cases variability is observed with regard to the number of colonic polyps (i.e., there are >100), with a predominance of polyps located on the right side. In these cases the average age at colorectal cancer diagnosis was 58 years, whereas the average age at polyposis diagnosis was 42 years. Rectal-polyp sparing in patients who underwent total colectomy and ileo-rectal anastomosis, after a mean follow-up period of 11.7 years (range 126 years); and an increased trend toward development of gastric and duodenal adenomas, with the occurrence of duodenal cancer in one case was also observed.

The use of molecular-genetic testing has been suggested as an aid in decision making with respect to the type of surgical procedure (total colectomy vs. restorative proctocolectomy) based on the risk of rectal cancer in FAP. Clinical decision making with respect to the type of surgical procedure should rely on a combination of factors, including age at AFAP diagnosis, number of adenomatous polyps (>20), location of polyps (right-side colon), frequency of polyp recurrence, and polyp morphology (confluent vs. scattered polyps). A patient's compliance with the clinical-surveillance regimen should also be taken into account. Finally, this information needs to be correlated with the molecular diagnosis of AFAP in affected and/or presymptomatic individuals.

Up to 40% of FAP cases have de novo mutations and nearly every family with FAP has its unique mutation. Evaluation of at-risk persons begins by first testing an affected member of the family to establish a detectable mutation in the pedigree. If a mutation is found in an affected family member, then genetic testing in at-risk relatives will provide true positive or negative results. If a mutation is not identified, testing at-risk relatives is not useful because the gene test will be inconclusive: a negative result could be a false negative because the technique used might not be capable of detecting a mutation, even if present. Accurate mutation detection is very important in FAP, and pre-symptomatic detection of mutation carriers represents a life-saving tool. Once the carrier status has been established, colonoscopic surveillance at regular intervals is recommended to allow early polyp detection and prevention of malignancies. Non-carriers within affected kindreds have the same colorectal cancer risk as the general population and can be spared the frequent surveillance program by colonoscopy.


Differences in the APC mutation sites alone cannot completely account for intra and interfamilial variation in the polyposis phenotypes in these families. Another likely explanation for phenotypic variability is the presence of a modifier gene(s) that may influence the phenotypic expression of the APC gene. It is also likely that environmental factors, such as diet, play an important role in AFAP, as has been demonstrated in the mouse models of FAP.

In our case, the patient presented with the clinical picture of an attenuated form of FAP (negative family history, late presentation (older then 40 years old), no evidence of cancer, sparing of the rectum by polyps), but the colectomy showed over 100 small, sessile, adenomatous colonic polyps. By definition, the later findings classified this patient as a classic FAP, in contradiction with the strong clinical evidence of this being an attenuated FAP. However, the Q161X mutation identified in this patient is situated in the close proximity to the codons usually mutated in the attenuated form of the disease (5' to codon 158). Furthermore, this mutation was described in the literature in only one other patient, which presented with an attenuated phenotype of FAP (12). These somehow contradictory findings raise the possibility that this patient and her relatives carrying the same mutation, are more likely to have a clinical phenotype most similar to the attenuated form of FAP. The fact that two different patients identified as carriers of the same mutation (Q161X) have similar phenotypes, possibly representing variations in the attenuated form of FAP would suggest that the cut-off point between mutations characteristic of classical or attenuated forms of FAP should be extended from codon 158 to codon 161. Follow up studies of these two families, carriers of the Q161X mutation as well as new identified mutations in the area of codons 158-161 would bring new information and would clarify this hypothesis.

Based on all the above information, the importance of customized clinical management should be considered in AFAP patients and all their relatives in the following forms:

  1. Predictive genetic testing for presymptomatic relatives (siblings and children)
  2. Colonoscopy, as opposed to sigmoidoscopy, should be advised for endoscopic surveillance of the relatives carrying the mutation, because of the right-side location of colorectal adenomas in AFAP;
  3. Upper gastro intestinal endoscopic surveillance in an attempt to detect premalignant gastric or duodenal tumors (for both the patients and her relatives carrying the mutation)
  4. There is rare occurrence of rectal polyps in AFAP; however, further clinical studies with longer follow-up are needed in order to prove that the risk of rectal cancer is lower in AFAP than in classical FAP and colonoscopy is suggested for surveillance of the rectum.

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  1. A role for the Adenomatous Polyposis Coli protein in chromosome segregation Kaplan, et al. (2001), Nature Cell Biol 3:429-432
  2. Genotype-phenotype correlations at the adenomatous polyposis coli (APC) gene. Fodde, R and Khan, P. Crit Rev Oncog 6 (1995) 291-303.
  3. Mutations in the APC tumour suppressor gene cause chromosomal instability Fodde, et al. (2001),. Nat Cell Biol 3:433 - 438)
  4. Rapid detection of translation-terminating mutations at the adenomatous polyposis coli (APC) gene by direct protein truncation test, Van der Luijt R, Khan PM, Vasen H, van Leeuwen C, Tops C, Roest P, den Dunnen J, Fodde R (1994) Genomics 20:1-4.
  5. Mutation detection by denaturing gradient gel electrophoresis (DGGE), Fodde, R and Losekoot, M.. Hum Mutat 3 (1994) 83-94.
  6. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66(1991)589-600. Groden, J., Thliveris, A., Samowitz, W., Carlson, M., Gelbert, L., Albertsen, H., Joslyn, G., Stevens, J., Spirio, L., Robertson, M., Sargeant, L., Krapcho, K., Cell 66(1991)589-600.
  7. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Nishisho, I., Nakamura, Y., Miyoshi, Y., Miki, Y., Ando, H., Horii, A., Koyama, K., Utsunomiya, J., Baba, S., Hedge, P., Markham, A., Krush, A.J., Petersen, G., Hamilton, S.R., Nilbert, M.C., Levy, D.B., Bryan, T.M., Preisinger, A.C., Smith, K.J., Su, L.K., Kinzler, K.W. and Vogelstein, B., Science 253(1991)665-669
  8. APC mutations occur early during colorectal tumorigenesis. Powell, S.M., Zilz, N., Beazer-Barclay, Y., Bryan, T.M., Hamilton, S.R., Thibodeau, S.N., Vogelstein, B. and Kinzler, K.W., Nature 359(1992)235-237
  9. Alleles of the APC Gene: an Attenuated Form of Familial Polyposis L. Spirio, S. Olschwang, J. Groden, M. Robertson, W. Samowitz, G. Joslyn, L. Gelbert, A. Thliveris, M. Carlson, and B. Otterud ,Cell 1993 75: 951
  10. Genotype-phenotype correlations in attenuated adenomatous polyposis coli, Soravia C, et al, Am J Hum Genet 1998; 62(6):1290-301
  11. Germline mutations in the 3' part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli, Van der Luijt RB, et al. Hum Genet. 1996; 98(6):727-34
  12. Serrated adenoma in familial adenomatous polyposis: relation to germline APC gene mutation, Matsumoto T, et al. Gut. 2002; 50:402-404.

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Contributed by Diana Ionescu, MD, Federico Monzon, MD, Georgios Papachristou MD, Robert Schoen MD, Karen Weck, MD and Sydney Finkelstein, MD, PhD

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