Genetic Testing For Hereditary Nonpolyposis Colorectal Cancer Research Articles

Awareness and uptake of genetic testing among individuals at-risk for hereditary colon cancer

Background Referral for genetic counseling and testing is appropriate for individuals whose families meet clinical criteria for Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and for some families with members that meet the Bethesda criteria. The FHPP is a prospective randomized trial to evaluate an intervention to promote colonoscopy in members of high risk CRC families. FHPP participants were surveyed to assess their knowledge about and utilization of genetic testing for HNPCC.

Randomized trial of a decision aid for individuals considering genetic testing for hereditary nonpolyposis colorectal cancer risk

Despite the potential benefits of genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC) risk, individuals can find the genetic testing decision-making process complicated and challenging. The goal of the current study was to measure the effectiveness of a tailored decision aid designed specifically to assist individuals to make informed decisions regarding genetic testing for HNPCC risk. In all, 153 individuals were randomized to receive the decision aid or a control pamphlet at the end of their first genetic counseling consultation. Of these, 109 (71.2%) completed the first questionnaire 1 week after consultation, whereas 95 (62.1%) completed the 6-month follow-up questionnaire. Although the decision aid had no significant effect on postdecisional regret or actual genetic testing decision, the trial results demonstrated that participants who received the decision aid had significantly lower levels of decisional conflict (ie, uncertainty) regarding genetic testing (chi-square(1) = 8.97; P = .003) and were more likely to be classified as having made an informed choice concerning genetic testing (chi-square(1) = 4.37; P = .037) than participants who received a control pamphlet. Also, men who received the decision aid had significantly higher knowledge levels regarding genetic testing compared with men who received the control pamphlet, whereas no such differences were found for women (chi-square(2) = 6.76; P = .034). A decision aid for individuals considering genetic testing for HNPCC is an effective intervention to reduce uncertainty and assist individuals to make an informed choice regarding genetic testing for HNPCC after genetic counseling.

A Prospective, Multicenter, Population-Based Study of BRAF Mutational Analysis for Lynch Syndrome Screening

Mismatch repair (MMR) deficiencies are the hallmark of tumors arising in Lynch syndrome, however, in approximately 15% of sporadic colorectal cancers (CRC) these deficiencies most often are associated with somatic methylation of the MMR gene MLH1. Recently, an oncogenic mutation in the BRAF gene has been involved in sporadic CRC showing MMR deficiencies as a result of MLH1 promoter methylation. The aim of this study was to evaluate the contribution of BRAF V600E mutation analysis in the identification of MSH2/MLH1 gene mutation carriers in newly diagnosed CRC patients. BRAF V600E mutation was analyzed in CRC patients with MMR deficiencies (microsatellite instability and/or lack of MLH1/MSH2 protein expression) in the EPICOLON population-based study. The effectiveness and efficiency of different strategies were evaluated with respect to the presence of MSH2/MLH1 germline mutations. MMR deficiencies were detected in 119 of the 1222 CRC patients with tumors showing either microsatellite instability (n = 111) or loss of protein expression (n = 81). BRAF mutation was detected in 22 (18.5%) of the patients. None of the patients with unambiguous germline mutation had BRAF mutation. Regardless of the strategy used to identify MSH2/MLH1 gene carriers, the introduction of BRAF analysis in these patients slightly improves their effectiveness. The introduction of BRAF mutation analysis as a step before germline genetic testing in patients with MMR deficiencies achieved a significant reduction in costs per mutation detected. Detection of BRAF V600E mutation could simplify and improve the cost effectiveness of genetic testing for hereditary nonpolyposis colorectal cancer, especially in patients whose family history is incomplete or unknown.

Germline missense mutations in mismatch-repair genes and genetic testing for HNPCC

The clinical management of individuals in families with germline mutations in mismatch repair (MMR) genes relies not only on the accurate identification of genetic alterations but also on the interpretation of their pathogenicity. The spectrum of genetic alterations in MMR genes that predispose to hereditary nonpolyposis colorectal cancer (HNPCC) is very diverse. Of all mutations, it is the most difficult to predict the effect of missense mutations on the function of the protein. Therefore it is not always clear whether a missense mutation is pathogenic or just a harmless polymorphism. A number of computational and experimental assays (in vivo and in vitro) have been developed to assess the functional significance of missense mutations in MMR genes. Despite the profusion of such assays, it is not clear that they are sufficiently sensitive and specific to serve as clinically applicable diagnostic tests for HNPCC.

Living with Hereditary Non‐polyposis Colorectal Cancer; Experiences from and Impact of Genetic Testing

Hereditary non-polyposis colorectal cancer (HNPCC) is one of our most common cancer syndromes and an increasing number of individuals live in families with verified hereditary cancer. We conducted an interview study to explore experiences from and perceived impact on life after genetic testing for HNPCC. Three major themes emerged: reactions and emotions, family relations and implications for life. Among the reactions described were suspecting heredity, feelings of guilt, the importance of experiential knowledge, and coping strategies. The impact on family relations was related to perceived responsibility for conveying information, encountering different reactions among family members, and difficulties in communication and relations. The implications described included uncertainty, adaptation, new choices and changes in life, family planning issues, and experiences of surveillance programs. We suggest that the themes and sub-themes identified should be taken into account during genetic counselling in order to facilitate the spread of information and to prepare family members for the impact on life that knowledge about hereditary cancer may have.

Long Term Follow-up of HNPCC Gene Mutation Carriers: Compliance with Screening and Satisfaction with Counseling and Screening Procedures

Hereditary non polyposis colorectal cancer (HNPCC) is a hereditary predisposition to colorectal and endometrial cancer, caused by mutations of the mismatch repair (MMR) genes MSH2, MLH1 and MSH6. Regular colonoscopy reduces the incidence of colorectal cancer in mutation carriers dramatically. The aim of this study was to evaluate the use of colonoscopy by proven HNPCC mutation carriers. We also evaluated the satisfaction with the counseling and screening procedures at the long term. A questionnaire survey was performed among 94 proven MMR gene mutation carriers. Data were analyzed using univariate and multivariate analysis. The average time of follow-up was 3,5 years (range 0.5-8.5 years). The response rate was 74%. The proportion of unaffected mutation carriers under colonoscopic screening increased from 31 to 88% upon genetic testing, and for gynecological screening from 17 to 69%. However, more than half of the responders experienced colonoscopy as unpleasant or painful. About 97% felt well informed during counseling, and 88% felt sufficiently supported. Ten percent of the responders reported a high cancer worry that was significantly (P = 0.007) associated with a high perceived cancer risk. Six responders (9%) regretted being tested. Remarkably, of 4 of these 6 a close relative died recently of cancer. Problems with obtaining a disability or life insurance or mortgage were experienced by 4 out 10 healthy carriers opting for these services. In conclusion, genetic testing for HNPCC considerably improves compliance for screening, which will result in a reduction of HNPCC-related cancer morbidity and mortality in mutation carriers. Most HNPCC gene mutation carriers cope well with their cancer susceptibility on the long term.

Genetic Testing for Inherited Colon Cancer

The genes associated with each of the inherited syndromes of colon cancer have now been identified, and genetic testing is available for diagnosis. These syndromes include familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and, possibly, Cowden's syndrome. Clinical genetic testing approaches have been developed for each of these syndromes and are now a part of accepted clinical care. Disease-causing mutations can be found in the majority of families affected with one of the inherited syndromes, and, most importantly, once a mutation is found in an index case of the family, relatives can be tested for the presence or absence of that mutation with near 100% accuracy. Cancer screening and management in syndrome families is then based on the results of genetic testing. For the physician to order and properly interpret genetic tests, a basic understanding of the types of mutations that lead to inherited disease and the methods for detecting them is vital. These issues will be presented. Additional clinical issues somewhat unique to genetic testing include genetic counseling and informed consent for genetic testing, both of which will also be reviewed. Often the most difficult aspect of genetic testing is deciding which patients and families should undergo the testing. Furthermore, this issue is quite specific for each of the syndromes. Thus, following presentation of general principles of selection for genetic testing, a detailed approach for identifying persons who should undergo testing for each of the individual syndromes will be given, together with relevant descriptions of the syndromes. Finally, the ongoing work to discover new and possibly more common but less penetrant colon cancer susceptibility genes that cause common familial colon cancer will be presented.

Colorectal cancer at a young age

Colorectal cancer at a young age

Genetic Testing for Hereditary Nonpolyposis Colorectal Cancer

Approximately 80 per cent of patients with colorectal cancer have sporadic disease whereas the remaining 20 per cent seem to have a genetic component. Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common autosomal dominant hereditary syndrome predisposing to colorectal cancer. Various methods have been described to screen for HNPCC and to directly test for mismatch repair gene mutations. This study evaluates the initial results of 1) microsatellite instability (MSI) and immunohistochemistry (IHC) staining of tumors and 2) genetic sequencing for mismatch repair gene mutations in patients suspected to have HNPCC. Appropriate patients for HNPCC testing were identified through a high-risk colorectal cancer clinic. Of those patients screened only those who met Amsterdam criteria (AC) for HNPCC or were young age onset (YAO) (<40 years of age) were eligible for testing. The tumors underwent testing for MSI and had IHC performed in those patients with available tumor specimens. MSI was performed on the five markers approved by the NIH consensus conference. MSI-High (MSI-H) was defined as two or more markers being unstable. IHC was done with commercially available stains for MLH1 and MSH2. All patients had sequencing of the MLH1 and MSH2 genes performed to search for mutations by a commercial laboratory. Genetic counseling was provided and written informed consent was obtained. Fourteen patients were part of kindreds that met the AC. An additional 10 patients were <40 years of age at diagnosis of colorectal cancer but lacked any family history. Testing for MSI and IHC was performed on those available tissue blocks. Of the AC patients five had MSH2 mutations and two had MLH1 variants. Of the five with MSH2 mutations three of four had MSI-H tumors and all four had loss of expression of MSH2 on IHC. Of the MLH1 variants only one had MSI-H tumor and lacked expression of MLH-1 on IHC. Of those patients with no mutation identified three of six had MSI-H tumors. For those patients YAO no genetic mutations were identified. Two of the seven had MSI-H tumors. Genetic testing for HNPCC even in those patients fulfilling the rigid AC yielded mutations in only five of 14 patients with variants of unknown significance being found in an additional two patients. Only one MSH2 variant of unknown significance was identified in the 10 YAO patients, which would suggest that screening in this group of patients with MSI and/or IHC would be appropriate.

Genetic testing for hereditary nonpolyposis colorectal cancer

Colorectal cancer remains a major cause of morbidity and mortality in United States. While most newly diagnosed cases are sporadic, a small percent of colorectal cancers are due to hereditary cancer syndromes, of which hereditary nonpolyposis colorectal cancer (HNPCC) is the most common. HNPCC is caused by mutations resulting in defective DNA mismatch repair gene function. Advances in molecular technology have enabled us to use genetic testing for HNPCC genes to identify high-risk families. Over the past several years, genetic testing for HNPCC has evolved from a research endeavor to a clinical test that often is an integral part of providing care for high-risk families. This article reviews the available genetic tests, genetic testing recommendations, interpretation of test results, and the clinical impact of genetic testing for HNPCC.