AGA technical review on hereditary colorectal cancer and genetic testing.

This literature review and the recommendations therein were prepared for the American Gastroenterological Association (AGA) Clinical Practice and Practice Economics Committee. The paper was approved by the Committee on March 20, 2001, and by the AGA Governing Board on April 18, 2001.

Very high risk of cancer in familial Peutz-Jeghers syndrome.

BACKGROUND & AIMS: The Peutz-Jeghers syndrome (PJS) is an autosomal dominant polyposis disorder with increased risk of multiple cancers, but literature estimates of risk vary. METHODS: We performed an individual patient meta-analysis to determine the relative risk (RR) of cancer in patients with PJS compared with the general population based on 210 individuals described in 6 publications. RESULTS: For patients with PJS, the RR for all cancers was 15.2 (95% confidence limits [CL], 2, 19). A statistically significant increase of RR was noted for esophagus (57; CL, 2.5, 557), stomach (213; CL, 96, 368), small intestine (520; CL, 220, 1306), colon (84; CL, 47, 137), pancreas (132; CL, 44, 261), lung (17.0; CL, 5.4, 39), breast (15.2; CL, 7.6, 27), uterus (16.0; CL, 1.9, 56), ovary (27; CL, 7.3, 68), but not testicular or cervical malignancies. Cumulative risk for all cancer was 93% from age 15 to 64 years old. CONCLUSIONS: Patients with PJS are at very high relative and absolute risk for gastrointestinal and nongastrointestinal cancers.

Genetic counseling and testing: implications for clinical practice.

As the genetic basis of many human illnesses becomes known, the provision of genetic counseling to individuals and family has gained importance. Patients concerned about genetic conditions within their family require comprehensive services that address the medical and emotional aspects of disease. The use of these types of genetic services and testing can raise ethical and social concerns. Key components of the genetic counseling process and the complex issues that surround genetic information are discussed.

Response to genetic counseling and testing for the APC I1307K mutation.

The APC I1307K gene mutation is associated with increased colorectal cancer (CRC) risk in Ashkenazi Jews. Factors predicting acceptance of this and other hereditary colon cancer mutation tests in a clinical setting are unknown. We analyzed sex, age, family history, personal history, and gene test results of patients at increased risk for cancer who sought cancer risk counseling at the Johns Hopkins (JH) CRC Risk Assessment Clinic (n = 91), and those submitting samples to the JH Pathology Molecular Diagnostic Laboratory (n = 256) for APC I1307K testing. Of patients seen at the JH Clinic, 77/91 (84.6%) elected APC I1307K testing after pretest counseling (acceptors). There were no statistically significant differences in demographic characteristics between acceptors and decliners. In comparison, only 8 of 57 (14.0%) patients offered HNPCC testing proceeded with testing (P < 0.001). Of 256 individuals tested at the JH laboratory, most were male (61.3%) and most had a personal or family history of colorectal cancer or polyps. Test positivity correlated with increasing risk of colorectal cancer. Acceptance of testing for the APC I1307K mutation is high, with more men than women pursuing counseling and testing. The reported association between the APC I1307K mutation and colon cancer risk was supported by a correlation in these data between personal or family history of CRC or polyps and a gene mutation.

Attitudes toward colon cancer gene testing: factors predicting test uptake.

OBJECTIVES: Genetic discoveries in hereditary nonpolyposis colorectal cancer (HNPCC) have made possible genetic testing to determine susceptibility to this form of colorectal cancer (CRC). This study measured the uptake of genetic testing for HNPCC among first-degree relatives of CRC patients and conducted a preliminary analysis of the predictors of test uptake. MATERIALS AND METHODS: We compared 77 test acceptors and 181 decliners on demographic, medical history, and psychological characteristics, controlling for distance from the testing center. The psychological factors studied were risk perception for CRC, frequency of cancer thoughts, and perceived ability to cope with unfavorable genetic information. RESULTS: In the final regression model, after accounting for all variables, the significant predictors of test uptake were increased risk perception, greater perceived confidence in ability to cope with unfavorable genetic information, more frequent cancer thoughts, and having had at least one colonoscopy. The association between risk perception and uptake was dependent on frequency of cancer thoughts. Among those who thought about getting CRC more often, the probability of testing increased as perceived risk increased to approximately 50% likelihood of getting CRC and then leveled off. In contrast, among those who never or rarely thought about getting CRC, risk perception was unrelated to testing decision. CONCLUSIONS: Our findings are consistent with the associations reported between psychological factors and other cancer screening behaviors.

Analysis of masked mutations in familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is an autosomal-dominant disease characterized by the development of hundreds of adenomatous polyps of the colorectum. Approximately 80% of FAP patients can be shown to have truncating mutations of the APC gene. To determine the cause of FAP in the other 20% of patients, MAMA (monoallelic mutation analysis) was used to independently examine the status of each of the two APC alleles. Seven of nine patients analyzed were found to have significantly reduced expression from one of their two alleles whereas two patients were found to have full-length expression from both alleles. We conclude that more than 95% of patients with FAP have inactivating mutations in APC and that a combination of MAMA and standard genetic tests will identify APC abnormalities in the vast majority of such patients. That no APC expression from the mutant allele is found in some FAP patients argues strongly against the requirement for dominant negative effects of APC mutations. The results also suggest that there may be at least one additional gene, besides APC, that can give rise to FAP.

Genetic testing and counseling for hereditary forms of colorectal cancer.

The discovery of genes responsible for inherited forms of colorectal cancer have the potential to improve cancer risk assessment and counseling. Germline mutations (nonsense, frameshift) of APC are associated with familial adenomatous polyposis, an autosomal dominant syndrome, clinically characterized by young onset, hundreds of adenomatous polyps in the colon, and increased risk for extracolonic tumors. Mutations in APC are also associated with forms of attenuated familial adenomatous polyposis. Germline mutations in five mismatch repair related genes (hMSH2, hMLH1, hMSH6, hPMS1, and hPMS2) cause hereditary nonpolyposis colorectal cancer and are associated with increased risk of somatic genetic alterations and high DNA microsatellite instability. Hereditary nonpolyposis colorectal cancer is characterized by young onset colorectal cancer, proximal colon location, and increased risk of extracolonic cancers. A missense mutation in APC (I1307K) is associated with some familial colorectal cancer in Ashkenazic Jews. For persons at risk for hereditary forms of colorectal cancer, testing algorithms and gene test interpretations depend on identification of the pedigree germline gene mutation. Careful evaluation of the kindred for characteristic aggregation of tumor types among affected individuals and the availability of affected persons for testing are important issues in implementing genetic testing and follow-up management. Case reports illustrate the importance of genetic counseling as a component of cancer genetic risk assessment. The genetic counseling process includes exploration of patient risk perception, sources of anxiety related to cancer risk, patient education (specific cancer-related issues, prevention/intervention options), discussion of possible gene test options, test limitations, and consequences of various gene test outcomes.

Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene.

BACKGROUND: Germline mutation in the adenomatous polyposis coli (APC) gene on chromosome 5 causes familial adenomatous polyposis. "Attenuated" phenotype has been reported with mutation in the 5' end of the gene (5' to codon 158), but genotype-phenotype relations at the 3' end (3' to codon 1596) have not been described fully. AIMS: To describe and compare colorectal and extracolonic phenotypes in a case series of families with mutation in the 3' end of the APC gene. METHODS: Thirty one at risk or affected members from four families with a mutation in the APC gene located at codon 1979 or 2644 were evaluated. RESULTS: Variable intrapedigree colorectal phenotype was observed: some members at older age had oligopolyposis (fewer than one hundred colorectal adenomas) whereas other members had classic polyposis at young age. Colorectal cancer was diagnosed at older mean age (50 (7) years) in the four families than in classic FAP pedigrees (39 (14) years). Extracolonic lesions characteristic of FAP occurred with 3' APC mutations, but variability in intrapedigree and interpedigree extracolonic phenotype and dissociation of severity of extracolonic manifestations from number of colorectal polyps was noted. CONCLUSIONS: Families with 3' mutations of the APC gene exhibit variable intrapedigree phenotype similar to the heterogeneity noted in families with proximal 5' mutations. Genotyping of FAP and oligopolyposis pedigrees can guide appropriate surveillance of the upper and lower gastrointestinal tract in affected members.

Cost analysis of alternative approaches to colorectal screening in familial adenomatous polyposis.

BACKGROUND & AIMS: The commercial availability of gene testing for familial adenomatous polyposis (FAP) represents an important advance in screening for inherited colon cancer. We investigated the financial impact of this diagnostic tool on colorectal screening for FAP. METHODS: Decision analysis was used to compare per-person costs with third-party payers of three colorectal screening strategies used to diagnose FAP in at-risk persons. The strategies included conventional serial flexible sigmoidoscopy and two different APC gene testing approaches. RESULTS: For 1 at-risk relative who begins screening at age 12 years, average screening costs are $2625 when genotyping the proband first, $2674 when genotyping the at-risk relative first, and $3208 for conventional sigmoidoscopy. The cost advantage of genotyping increases as the pedigree size increases. For a pedigree of 5 at-risk relatives, sigmoidoscopy would have to cost less than $85.60 (professional plus facility fee) for conventional screening to compete with genotyping. The cost advantage of genotyping is diminished for at-risk relatives who begin FAP screening at older ages. CONCLUSIONS: The choice of least expensive FAP screening strategy depends on the cost of flexible sigmoidoscopy, patient age when screening starts, and pedigree size. Genotyping can substantially reduce the cost of FAP screening and, when possible, should start with the proband.

Phenotypic expression of disease in families that have mutations in the 5' region of the adenomatous polyposis coli gene.

BACKGROUND: Germline mutation in a gene on chromosome 5 (the adenomatous polyposis coli gene) causes familial adenomatous polyposis of the colorectum. Phenotypic manifestations of this condition vary, but the exact relation of the phenotype to the mutation site along the gene has not been fully described. OBJECTIVE: To determine how the location of mutations along a gene that is associated with multiple colorectal polyps (the adenomatous polyposis coli gene) is related to the phenotypic expression of the syndrome in families. DESIGN: Prospective cohort study. SETTING: Polyposis registry. PATIENTS: 20 patients from 7 families that had mutations in the adenomatous polyposis coli gene that were located toward the 5' end of codon 158 (proximal 5' families), were compared with 52 patients from 7 families that had mutations downstream from codon 158, in codons 179 to 625 (distal 5' families). MEASUREMENTS: Sex, age at diagnosis of familial adenomatous polyposis, number of polyps at first examination of the colon, distribution of polyps, age at diagnosis of colorectal cancer, and location of colorectal cancer. RESULTS: Mutations that were proximal to codon 158 were found in 7 of 112 families (6%). At the first examination of the colon, 8 of 17 (47%) patients in proximal 5' families and 9 of 48 (19%) patients of similar ages in distal 5' families were found to have fewer than 100 adenomas (P = 0.029). The distribution of polyps was frequently right-sided in patients in proximal 5' families (P = 0.001). The cumulative probability of survival without colorectal cancer was greater for patients in proximal 5' families (P = 0.041). CONCLUSIONS: Families with adenomatous polyposis that have proximal 5' mutations of the adenomatous polyposis coli gene are more likely to have a heterogeneous phenotype with delayed development of colonic polyposis and colorectal cancer than are families with distal 5' mutations of the gene. Management should include genotyping of patients who are at risk, colonoscopic surveillance of genotypically positive persons, and prophylactic colectomy if several adenomas are found.

The use and interpretation of commercial APC gene testing for familial adenomatous polyposis.

BACKGROUND: The use of commercially available tests for genes linked to familial cancer has aroused concern about the impact of these tests on patients. Familial adenomatous polyposis is an autosomal dominant disease caused by a germ-line mutation of the adenomatous polyposis coli (APC) gene that causes colorectal cancer if prophylactic colectomy is not performed. We evaluated the clinical use of commercial APC gene testing. METHODS: We assessed indications for APC gene testing, whether informed consent was obtained and genetic counseling was offered before testing, and the interpretation of the results through telephone interviews with physicians and genetic counselors in a nationwide sample of 177 patients from 125 families who underwent testing during 1995. RESULTS: Of the 177 patients tested, 83.0 percent had clinical features of familial adenomatous polyposis or were at risk for the disease-both valid indications for being tested. The appropriate strategy for presymptomatic testing was used in 79.4 percent (50 of 63 patients). Only 18.6 percent (33 of 177) received genetic counseling before the test, and only 16.9 percent (28 of 166) provided written informed consent. In 31.6 percent of the cases the physicians misinterpreted the test results. Among the patients with unconventional indications for testing, the rate of positive results was only 2.3 percent (1 of 44). CONCLUSIONS: Patients who underwent genetic tests for familial adenomatous polyposis often received inadequate counseling and would have been given incorrectly interpreted results. Physicians should be prepared to offer genetic counseling if they order genetic tests.

Hepatoblastoma and APC gene mutation in familial adenomatous polyposis.

BACKGROUND: Hepatoblastoma is a rare, rapidly progressive, usually fatal childhood malignancy, which if confined to the liver can be cured by radical surgical resection. An association between hepatoblastoma and familial adenomatous polyposis (FAP), which is due to germline mutation of the APC (adenomatous polyposis coli) gene, has been confirmed, but correlation with site of APC mutation has not been studied. AIM: To analyse the APC mutational spectrum in FAP families with hepatoblastoma as a possible basis to select kindreds for surveillance. PATIENTS: Eight patients with hepatoblastoma in seven FAP kindreds were compared with 97 families with identified APC gene mutation in a large Registry. METHODS: APC gene mutation was evaluated by RNase protection assay or in vitro synthesis protein assay. The chi 2 test and correlation were used for data analysis. RESULTS: APC gene mutation was identified in all seven FAP kindreds in which an at risk member developed hepatoblastoma. A male predominance was noted (six of eight), similar to literature cases (18 of 25, p < 0.01. Mutations were restricted to codons 141 to 1230, but no significant difference in site of mutation between pedigrees with and without hepatoblastoma was identified. CONCLUSIONS: Hepatoblastoma occurs primarily in boys in FAP kindreds and is associated with germline APC mutation in the 5' end of the gene. However, the site of APC mutation cannot be used to predict occurrence of this extracolonic cancer in FAP pedigrees.

Sulindac induced regression of colorectal adenomas in familial adenomatous polyposis: evaluation of predictive factors.

BACKGROUND: Sulindac, a non-steroidal anti-inflammatory drug, causes regression of colorectal adenomas in patients with familial adenomatous polyposis (FAP) but the response is variable. Specific clinical factors predictive of sulindac induced regression have not been studied. METHODS: 22 patients with FAP were given sulindac 150 mg orally twice a day. Polyp number and size were determined before treatment and at three months. The relation of nine clinical factors to polyp regression (per cent of baseline polyp number after treatment) was evaluated by univariate and multivariate analysis. RESULTS: After three months of sulindac, polyp number had decreased to 45 per cent of baseline and polyp size to 50 per cent of baseline (p < 0.001 and p < 0.01, respectively). Univariate analysis showed greater polyp regression in older patients (p = 0.004), those with previous colectomy and ileorectal anastomosis (p = 0.001), and patients without identifiable mutation of the APC gene responsible for FAP (p = 0.05). With multivariate regression analysis, response to sulindac treatment was associated with previous subtotal colectomy. CONCLUSIONS: Sulindac treatment seems effective in producing regression of colorectal adenomas of FAP patients with previous subtotal colectomy regardless of baseline polyp number and size. Changed sulindac metabolism, reduced area of the target mucosa, or changed epithelial characteristics after ileorectal anastomosis may explain these findings.

The Amish: Perceptions of genetic disorders and services.

Previous studies of the closed Amish population have proven to be valuable in the field of genetics, however they have not explored the Amish parents' opinions and attitudes concerning genetic conditions and services. This exploration is necessary in order to provide culturally sensitive health care to a population at an increased risk for certain genetic conditions. The purpose of the present study was to examine the Amish population's general knowledge of genetic disorders, services, and the terminology used in describing inherited conditions, as well as their attitudes toward medical care and ethical and reproductive issues. Information was obtained from 17 Amish families, 12 who had an incidence of a genetic condition and five who had one or more children with other special health care needs, during personal interviews conducted in their homes in Lancaster, Pennsylvania. Results of the interviews showed that the birth of an affected child did not deter subsequent reproduction, that the majority of the parents were never offered genetic counseling or prenatal testing, and that the parents are interested in understanding the cause of their children's problems and recurrence risks.