Familial Adenomatous Polyposis Gene Research Articles

Familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominant condition resulting in the development of more than 100 adenomatous polyps in the large bowel. In addition, a number of extracolonic manifestations of the condition may occur. Recently, increasing knowledge relating to the extracolonic abnormalities, and localization and sequencing of the gene for FAP, have had important implications for screening and long-term follow-up of those affected. In this review the natural history of the disease and the extracolonic manifestations associated with it are considered. Surgical management and advances in understanding at a molecular level are discussed, as well as the problems relating to screening for FAP and the implications of the new knowledge.

Can resistant starch and/or aspirin prevent the development of colonic neoplasia? The Concerted Action Polyp Prevention (CAPP) 1 Study.

Loss of function of the adenomatous polyposis coli (APC) tumour suppressor gene through truncating mutations or other means is an early event in most colo-rectal cancer (CRC). The APC gene encodes a large multifunctional protein that plays key roles in several cellular processes, including the wnt signalling pathway where an intact APC protein is essential for down regulation of beta-catenin. The APC protein also plays a role in regulation of cell proliferation, differentiation, apoptosis, cell-cell adhesion, cell migration and chromosomal stability during mitosis. Acquisition of a non-functional APC gene can occur by inheritance (in the disease familial adenomatous polyposis (FAP)) or by a sporadic event in a somatic cell. Whilst there is strong epidemiological evidence that variation in diet is a major determinant of variation in CRC incidence, conventional adenoma recurrence trials in sporadic cases of the disease have been relatively unsuccessful in identifying potentially protective food components. Since the genetic basis of CRC in FAP and in sporadic CRC is similar, intervention trials in FAP gene carriers provide an attractive strategy for investigation of potential chemo-preventive agents, since smaller numbers of subjects and shorter time frames are needed. The Concerted Action Polyp Prevention (CAPP) 1 Study is using a 2 x 2 factorial design to test the efficacy of resistant starch (30 g raw potato starch-Hylon VII (1:1, w/w)/d) and aspirin (600 mg/d) in suppressing colo-rectal adenoma formation in young subjects with FAP. Biopsies of macroscopically-normal rectal mucosa are also being collected for assay of putative biomarkers of CRC risk.

SomaticApc mutations are selected upon their capacity to inactivate the ?-catenin downregulating activity

The APC gene, originally identified as the gene for familial adenomatous polyposis (FAP), is now considered as the true "gatekeeper" of colonic epithelial proliferation. Its main tumor suppressing activity seems to reside in the capacity to properly regulate intracellular beta-catenin signaling. Most somatic APC mutations are detected between codons 1286 and 1513, the mutation cluster region (MCR). This clustering can be explained either by the presence of mutation-prone sequences within the MCR, or by the selective advantage provided by the resulting truncated polypeptides. Here, a Msh2-deficient mouse model (Msh2(delta 7N) ) was generated and bred with Apc(1638N) and Apc(Min) that allowed the comparison of the somatic mutation spectra along the Apc gene in the different allelic combinations. Mutations identified in Msh2(delta 7N/delta 7N) tumors are predominantly dinucleotide deletions at simple sequence repeats leading to truncated Apc polypeptides that partially retain the 20 a.a. beta-catenin downregulating motifs. In contrast, the somatic mutations identified in the wild type Apc allele of Msh2(delta 7N/delta 7N) /Apc(+/1638N) and Msh2(delta 7N/delta 7N) /Apc(+/Min) tumors are clustered more to the 5' end, thereby completely inactivating the beta-catenin downregulating activity of APC. These results indicate that somatic Apc mutations are selected during intestinal tumorigenesis and that inactivation of the beta-catenin downregulating function of APC is likely to represent the main selective factor.

Inherited predisposition to colon cancer.

Colorectal cancer is one of the most common malignancies in the United States. Although both genetic and environmental factors play a role in colorectal tumorigenesis, recent advances in genetics have more clearly defined the impact of inheritance in the multistep process of the disease. Researchers have identified single genes that confer a susceptibility to familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). Because these genes are inherited in an autosomal dominant fashion, offspring of carriers have a 50% chance of inheriting the gene mutation and its associated risk. The FAP gene, when mutated, initiates the neoplastic process. HNPCC gene mutations disrupt mismatch repair, thus inducing progression of tumor formation. Discovery of these genes has helped our understanding of sporadic colon cancer as well. Genetic testing for the FAP and HNPCC genes is now available, and results of this testing have implications for surveillance and management. In addition, testing raises complex psychosocial and ethical issues. At present, genetic testing is primarily conducted in the research setting, but it will soon be available in the clinical arena. To prepare for the challenges that these new advances will present, nurses must begin now to enhance their knowledge of genetics and its application to oncology.

Parents' responses to predictive genetic testing in their children: report of a single case study.

There is a widely held view among health professionals that predictive genetic testing of children for late onset diseases is not desirable clinical practice. Yet, little is known about the views of parents, or their responses, to predictive genetic testing in their children. Since such testing is being carried out in some genetic centres, the opportunity was taken to conduct a single case study of the parents of 2 and 4 year old sisters who were tested for the gene for familial adenomatous polyposis. Interviews before testing, after, and 15 months later showed a stable attitude, that parental responsibility included making decisions about such testing, and that the role of health professionals should be one of information giving rather than decision making. These parents had no regrets about having their children tested and reported no changes in their behaviour towards either the child who tested positively or the child who tested negatively. Using standardised scales, mood was found to be within the normal range both before and after testing in the mother and father. This case study is a first step towards systematic empirical studies determining the consequences of acquiescing to parents' requests for genetic testing in their children.

Deletion (5q) in a desmoid tumor of a patient with Gardner's syndrome

Desmoid tumors are associated with as many as 20% of cases of familial adenomatous polyposis (FAP) and Gardner's syndrome. In the present study, four specimens from different regions of a massive intraabdominal desmoid tumor from a 23-year-old white male with Gardner's syndrome were analyzed cytogenetically. Two different clonal abnormalities were observed. Two of the four specimens analyzed showed a del(5)(q14q31), which involves the region q21→22 where the familial adenomatous polyposis gene is localized. In the two other specimens, a balanced translocation involving chromosomes 3 and 4 and an inv(4) was detected. Our findings confirm previous reports about the importance of chromosome defects on 5q in development of desmoid tumors, particularly in patients with Gardner's syndrome.

Aspirin, NSAIDs, and Risk Reduction of Colorectal Cancer

CANCERS OF the colon and rectum cumulatively account for approximately 15% of all visceral tumors, affecting about one person in 20 in the United States and most other Western countries. Rapid advances in molecular biology may soon allow for genetic screening of individuals at risk for the development of colorectal cancer. The gene for familial adenomatous polyposis has been cloned and sequenced, and recently the gene coding for hereditary nonpolyposis colorectal cancer has been mapped to a locus on chromosome 2.¹Familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer may account for as much as 5% to 14% of all colorectal cancer in industrialized nations, but men and women over the age of 40 years still constitute the the largest population at risk. During the last several decades, the incidence of these cancers has remained relatively constant, although there has been a progressive trend toward disease of the more

Exon eight APC mutations account for a disproportionate number of familial adenomatous polyposis families.

The familial adenomatous polyposis gene, APC, has recently been identified. Detection of APC mutations will facilitate genetic screening in family members at risk for this disease. The length of APC makes it impractical to examine the entire coding sequence in each new family encountered. Identification of mutation cluster regions within the gene has therefore become a priority. Initial reports suggested that exon eight might contain a disproportionate number of mutations. This study describes direct sequencing of exon eight in 21 unrelated Australians with familial adenomatous polyposis. Mutations were detected in three of the 21 subjects (14%). Two were previously described point mutations changing an arginine to a stop codon. The third was a novel two base-pair deletion producing a frameshift and downstream stop codon. All three mutations segregated with the disease gene in their respective families. Three at risk children from two of these families were studied and shown not to have inherited the disease producing mutation. These results confirm that exon eight is a frequent site of mutation in familial adenomatous polyposis and should be examined routinely in families requesting genetic screening.

Genetic heterogeneity of congenital hypertrophy of the retinal pigment epithelium (CHRPE) in families with familial adenomatous polyposis.

One hundred and eighteen subjects with familial adenomatous polyposis (FAP) and 80 of their relatives who were at low risk (< 0.01) of carrying the FAP gene were scored by one of us (BJ) or by colleagues to assess the frequency of congenital hypertrophy of the retinal pigment epithelium (CHRPE). A CHRPE is defined as an "oval pigmented lesion surrounded by depigmented halo". Seventy five (63.6%) of the FAP cases and one (1.2%) of their relatives had at least one CHRPE. There was no systematic difference in the number of CHRPEs in the left and right eyes so all analyses are based on total number of CHRPEs and the findings were highly correlated (p = 0.001 for a test of no correlation). There was also no evidence of any age effect in total number of CHRPEs in affected subjects. In 26 families there was more than one subject affected with FAP. There was a significant common family effect with respect to CHRPE expression for total number of CHRPEs with an F statistic of 1.73 (p = 0.02 for a test of no family aggregation) indicating that family members are more similar to each other than to affected subjects from other families. This may indicate that specific mutations play a role in determining the number of CHRPEs. Nine affected subjects had intra-abdominal desmoids, and in these the frequency of each of the types of CHRPE was no higher (in fact, slightly lower) than the average for affected subjects without desmoids, but this difference was not significant (p > 0.3).

CONGENITAL HYPERTROPHY OF THE RETINAL PIGMENT EPITHELIUM ASSOCIATED WITH FAMILIAL ADENOMATOUS POLYPOSIS

Multiple, bilateral areas of congenital hypertrophy of the retinal pigment epithelium (CHRPE) have been described in association with familial adenomatous polyposis (FAP). Histopathologic findings have suggested a generalized effect of the FAP gene on the RPE, which could impair the functional integrity of the RPE. The clinical, psychophysical, electrophysiologic, and fluorescein angiographic findings in CHRPE in subjects with FAP were assessed. RPE function was assessed in 7 subjects with CHRPE and a family history of FAP. Four had documented FAP (mean age = 22.25 years) and the other three were siblings of affected subjects, with a 50% risk of developing FAP (mean age = 6.33 years). All subjects underwent comprehensive ophthalmologic examination. All subjects showed mild hyperopia (mean, +1.13 D; best corrected visual acuity, 20/20 or better). On perimetry, there were scotomas corresponding to some lesions. ERG showed normal rod, maximal, single-flash cone, and flicker responses. Light-dark ratio was within the normal range on EOG. Fluorescein angiography demonstrated normal retinal vasculature overlying the CHRPE lesions, which blocked background choroidal fluorescence. A normal choriocapillaris was observed through some hypopigmented lacuna. CHRPE has been related to generalized expression of an abnormal gene in RPE, but its functional abnormalities tend to be localized.

Evolution of hereditary bowel cancer

Familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) are both inherited as autosomal dominant conditions in which the mutation gives rise to a tendency to produce precancerous adenomas. However these two forms of hereditary bowel cancer show important differences at the clinical, pathological and molecular genetic levels. It is argued that the first tissue manifestation of FAP is the unicryptal adenoma. The existence of a preceding field change characterised by diffuse hyperproliferation and various altered phenotypes does not stand up to critical scrutiny. The processes of neoplastic evolution in FAP and HNPCC are compared in detail. It is suggested that an understanding of the function of the FAP and HNPCC genes will lead to the development of cancer prevention strategies aimed at blocking the earliest stages of neoplastic development.

Screening, Management, and Surveillance for Families with Familial Adenomatous Polyposis

The natural history of familial adenomatous polyposis (FAP) has been greatly improved with the advent of registries whose mandate is to improve the detection and management of affected individuals and their families, and to develop new knowledge concerning the disease. The most impressive results of these registries have been to greatly reduce the incidence of colorectal cancer and to facilitate cloning of the FAP gene.

Colonic fermentation of complex carbohydrates in patients with familial adenomatous polyposis.

Decreased production of butyric acid by colonic carbohydrate fermentation may predispose to colonic carcinogenesis, with the implicit assumption that the decrease in faecal butyrate found predates the development of the tumour. The influence of the genetic predisposition to colonic tumours and the presence of colonic polyps on in vitro fermentation of carbohydrates was examined. Stool samples from 11 normal controls and 20 patients with familial adenomatous polyposis (FAP) were incubated anaerobically with a range of carbohydrates. Fermentation patterns were similar for glucose and raffinose. These sugars produced different short chain fatty acid (SCFA) patterns from the two polysaccharides, starch and arabinogalactan, which differed one from the other. The FAP gene carriers with polyps produced less butyrate than normal controls (p < 0.005) and gene carriers without polyps (p < 0.05). There were corresponding decreases in the molar ratios of butyrate. Gene carriers without polyps produced less absolute amounts of acetate than normal controls (p < 0.05) and slightly less total SCFAs (p < 0.05) but were otherwise not significantly different. The decreased production of butyrate noted by other workers may be secondary to the tumours rather than a contributory cause.

Genetic evidence that Turcot syndrome is not allelic to familial adenomatous polyposis.

Turcot syndrome (TS) is a rare genetic disease in which brain tumors occur in association with colonic polyposis. Since Turcot's original description in 1959, there have been disagreements about the mode of inheritance as well as the clinical expression of this condition. Some investigators maintain that TS is a phenotypic variant of the autosomal dominant familial adenomatous polyposis (FAP), while others observe that there are clinical differences between TS and FAP, and that the pattern of inheritance of TS is autosomal recessive. The distribution of persons with colonic lesions in a family with a patient of colonic polyposis and a brain tumor, described in this report, favored the recessive hypothesis. In this family, the involvement of the FAP gene on chromosome 5q21-q22 could be excluded by a linkage study using a panel of FAP-linked DNA markers. This finding, which indicates the occurrence of another polyposis gene elsewhere in the genome, will have consequences for the presymptomatic diagnosis of FAP by linked DNA markers. We conclude that TS is a distinct clinical-genetical entity with the triad of atypical polyposis coli, CNS tumors, and a recessive mode of inheritance.

Retinal Pigment Epithelium Lesions as a Biomarker of Disease in Patients with Familial Adenomatous Polyposis: A Follow-up Report

The sensitivity of retinal pigment epithelium (RPE) lesions as a predictive congenital marker for the development of familial adenomatous polyposis (FAP) is evaluated. In a prospective study, 34 patients at 50% risk of inheriting FAP were examined. Based on the presence or absence of four or more RPE lesions, patients were categorized as those who had inherited or those who lacked the FAP genes. All patients received dilated fundus examinations with binocular indirect ophthalmoscopy and all RPE lesions were documented with fundus photography. All patients underwent annual sigmoidoscopy to determine the presence or absence of polyps. A 3-year follow-up analysis showed that 8 of 14 patients who were positive for RPE lesions later developed polyps. Of the 20 patients considered negative for FAP based on normal fundus examination, none has developed polyps. The authors urge all patient at risk of inheriting FAP to undergo dilated fundus examination with binocular indirect ophthalmoscopy and wide-angle fundus photography at the earliest age possible. All patients with 4 or more RPE lesions should undergo annual sigmoidoscopic examinations beginning before 10 years of age.

Multistage carcinogenesis: population-based model for colon cancer.

Recent laboratory work and previous models suggest that multiple mutations are associated with the development of colon cancer. To estimate the number of mutations required for colon carcinogenesis, we used likelihood analysis to obtain the best fit between mathematical models postulating different numbers of rate-limiting events and data on incidence rates of colon cancer in two human populations--the general population of Birmingham, England, from 1968 to 1972 and patients with familial adenomatous polyposis (FAP) diagnosed at Saint Mark's Hospital, London, England, between 1925 and 1965. The Armitage-Doll model and two- and three-mutation models that explicitly incorporated cell proliferation kinetics were used. When cell kinetics were considered, models postulating either two or three rate-limiting events described the incidence rates of colon cancer equally well in both human populations. A comparison of the incidence rate of colon cancer in the general population with that in patients with polyposis suggests that a mutation at the FAP gene locus is not one of the rate-limiting events in colon carcinogenesis. Compared with the two-mutation model, the three-mutation model was more consistent with the number of mutations reported to date in colon cancer and with mutation rates measured in the laboratory. A mutation at the FAP locus may not be a rate-limiting step but may act indirectly by stimulating the proliferation of stem cells. Thus, the development of colon cancer in patients with FAP does not appear to fit the retinoblastoma paradigm.

Risk estimation in familial adenomatous polyposis using DNA probes linked to the familial adenomatous polyposis gene.

The familial adenomatous polyposis gene has recently been assigned to the long arm of chromosome five through linkage to several 5q DNA probes. These probes can now be used to trace inheritance of the disease gene in affected families. In this study, DNA samples from 152 members of 10 Australian familial adenomatous polyposis families have been examined for restriction fragment length polymorphisms detected by DNA probes C11P11, ECB27, and YN5.48. Linkage analysis confirmed linkage between the familial adenomatous polyposis gene and each probe with a maximum combined LOD score of 2.82 for C11P11, 2.90 for ECB27 and 5.49 for YN5.48 all at a recombination fraction of zero. Risk estimates were determined for the 51 at risk individuals in these families based on their restriction fragment length polymorphism data alone or in addition by including the effect of age dependent penetrance. Thirty two of those at risk (63%) could be assigned specific high (greater than or equal to 95%) or low (less than or equal to 5%) risks of developing familial adenomatous polyposis on the basis of their probe results. When the effect of age dependent penetrance was included, 26 (51%) fell at the extremes of risk (greater than or equal to 99% or less than or equal to 1%). Such estimates provide a sound basis for planning sigmoidoscopic screening of at risk family members and will thus facilitate surveillance in familial adenomatous polyposis families.

Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage

Restriction fragment-length polymorphisms in the chromosome 5q21–22 region can now be used clinically for premorbid diagnosis and counseling in familial adenomatous polyposis. Two families are presented in which DNA diagnosis for familial adenomatous polyposis was performed using linked restriction fragment-length polymorphisms. Screening guidelines are improved using data from the polyposis registers at St. Mark's Hospital (London) and Western Australia (Perth) on at-risk family members who subsequently developed familial adenomatous polyposis. In these registers, 103 of 137 relatives tested positive on initial screening; of the remaining 34, the average interval between initial negative screening and development of familial adenomatous polyposis was 7.5 years. All those who had inherited the familial adenomatous polyposis gene manifested the polyps by age 34 years. Combined with linkage marker data, the a priori 50% risk for relatives can now be reduced to < 0.5% by age 30 years if there is an initial negative result on sigmoidoscopy and a negative diagnosis by linkage analysis. The screening management for those found by linkage to have inherited familial adenomatous polyposis remains unchanged from established recommendations; however, for individuals who most likely have not inherited familial adenomatous polyposis, the clinician can emphasize the positive aspects of screening management, including longer screening intervals.

Probe KK5.33 (D5S85) improves indirect genotype analysis in familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by the appearance of hundreds to thousands of adenomatous polyps in the entire colon. If untreated, all patients develop colonic adenocarcinoma. Since the gene leading to FAP was mapped to chromosome 5@1-@2 by use of probe c11pll (Bodmer et al. 1987; Leppert et al. 1987), several additional polymorphic DNA markers from this chromosomal region have been developed and used for linkage analysis (Nakamura et al. 1988; Murday et al. 1989; Meera Khan et al. 1988). Tops et al. (1989) proposed the use of probes pi227 (D5S37) and YN5.48 (D5S81) as flanking markers. Pi227 is located 5 cM proximal to the FAP gene,

Normal human chromosome 5, on which a familial adenomatous polyposis gene is located, has tumor suppressive activity

The suppressive activity of normal human chromosome 5 was detected by means of the chromosomal transfer technique using DT cells as recipients. A hybrid clone, which exhibited reduced tumorigenicity, contained chromosomal regions such as 5pter-p15, q21 and q33-qter. Since a familial adenomatous polyposis gene has been reported to be located at 5q21-q22, the suppressive activity of chromosome 5 might be due to this gene.