Awareness of endometrial cancer risk and compliance with screening in hereditary nonpolyposis colorectal cancer.

OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer (HNPCC) have a 40-60% lifetime risk for endometrial cancer. Guidelines in Denmark recommend gynecologic screening for female members of families with HNPCC. We estimated the knowledge of endometrial cancer risk and identified possible predictors of compliance with the screening among women from families with HNPCC. METHODS: A questionnaire exploring the knowledge of endometrial cancer risk and compliance with screening was sent to 707 women from families with HNPCC who had been recommended endometrial cancer surveillance. The response rate after one reminder was 86% (606 of 707). Data were analyzed by simple and multivariable logistic regression models. RESULTS: Four hundred seventy-one women were included in the final analyses; 65% reported being aware of the increased risk of endometrial cancer. The awareness was significantly greater among women with high educational level (81%; P<.001), women who had received genetic counseling (75%; P<.001), women with family history of gynecologic cancer (76%; P<.001), and those with high perceived endometrial cancer risk (77%; P<.001). Overall, 67% had participated in gynecologic screening. No significant differences were found in compliance regarding women's educational level or their family risk classification. Analyses of data in a multivariable logistic regression model showed that knowledge of endometrial cancer risk was the most important predictor for positive compliance with the gynecologic screening (odds ratio 4.86, 95% confidence interval 3.05-7.74). CONCLUSION: Women's awareness of endometrial cancer risk is the most important predictor of their compliance with gynecologic screening in families with HNPCC. LEVEL OF EVIDENCE: II.

Biomedical informatics as support to individual healthcare in hereditary colon cancer: the Danish HNPCC system.

The Danish HNPCC register is a publically financed national database. The register gathers epidemiological and genomic data in HNPCC families to improve prognosis by screening and identifying family members at risk. Diagnostic data are generated throughout the country and collected over several decades. Until recently, paper-based reports were sent to the register and typed into the database. In the EC cofunded-INFOBIOMED network of excellence, the register was a model for electronic exchange of epidemiological and genomic data between diagnosing/treating departments and the central database. The aim of digitization was to optimize the organization of screening by facilitating combination of genotype-phenotype information, and to generate IT-tools sufficiently usable and generic to be implemented in other countries and for other oncogenetic diseases. The focus was on integration of heterogeneous data, elaboration, and dissemination of classification systems and development of communication standards. At the conclusion of the EU project in 2007 the system was implemented in 12 pilot departments. In the surgical departments this resulted in a 192% increase of reports to the database. Several gaps were identified: lack of standards for data to be exchanged, lack of local databases suitable for direct communication, reporting being time-consuming and dependent on interest and feedback.

Deciphering the colon cancer genes--report of the InSiGHT-Human Variome Project Workshop, UNESCO, Paris 2010.

The Human Variome Project (HVP) has established a pilot program with the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) to compile all inherited variation affecting colon cancer susceptibility genes. An HVP-InSiGHT Workshop was held on May 10, 2010, prior to the HVP Integration and Implementation Meeting at UNESCO in Paris, to review the progress of this pilot program. A wide range of topics were covered, including issues relating to genotype-phenotype data submission to the InSiGHT Colon Cancer Gene Variant Databases (chromium.liacs.nl/LOVD2/colon_cancer/home.php). The meeting also canvassed the recent exciting developments in models to evaluate the pathogenicity of unclassified variants using in silico data, tumor pathology information, and functional assays, and made further plans for the future progress and sustainability of the pilot program.

Planning the human variome project: the Spain report.

The remarkable progress in characterizing the human genome sequence, exemplified by the Human Genome Project and the HapMap Consortium, has led to the perception that knowledge and the tools (e.g., microarrays) are sufficient for many if not most biomedical research efforts. A large amount of data from diverse studies proves this perception inaccurate at best, and at worst, an impediment for further efforts to characterize the variation in the human genome. Because variation in genotype and environment are the fundamental basis to understand phenotypic variability and heritability at the population level, identifying the range of human genetic variation is crucial to the development of personalized nutrition and medicine. The Human Variome Project (HVP; http://www.humanvariomeproject.org/) was proposed initially to systematically collect mutations that cause human disease and create a cyber infrastructure to link locus specific databases (LSDB). We report here the discussions and recommendations from the 2008 HVP planning meeting held in San Feliu de Guixols, Spain, in May 2008.

Cost-effectiveness of surveillance programs for families at high and moderate risk of hereditary non-polyposis colorectal cancer.

OBJECTIVES: Surveillance programs are recommended to both families at high risk (Amsterdam-positive families with known- and unknown mutation) and moderate risk (families not fulfilling all Amsterdam criteria) of colorectal cancer (CRC). Cost-effectiveness has so far only been estimated for the group at high risk. The aim of the present study is to determine cost-effectiveness of surveillance programs where families at both high and moderate risk of HNPCC participate. METHODS: A decision analytic model (Markov model) is developed to assess surveillance programs where families at high and moderate risk of HNPCC are offered surveillance from age 25 and age 45, respectively. The model includes costs for all families referred to genetic counseling, including genetic risk assessment, mutation analysis, and surveillance in relevant families with or without known mutation, plus the costs related to any surgical treatment. The risk of metachronous CRC is also modeled. RESULTS: Incremental costs per life year gained are estimated to be euro 980 when families at both high and moderate risk of HNPCC undergo surveillance (euro 508 for high risk and euro 1600 for moderate risk) and euro 1947 when the moderate risk group is evaluated genetically but not offered surveillance. Sensitivity analysis showed these findings to be robust, although cost-effectiveness can be improved in cases of more conservative referrals to genetic counseling. CONCLUSIONS: The result for high risk families confirms the findings in similar studies. Somewhat surprisingly, cost-effectiveness improves when surveillance of the moderate risk groups are included in the decision model.

[Serrated, hyperplastic and hyperplasia-like colorectal polyps]. / Serrate, hyperplastiske-og hyperplasilignende, kolorektale polypper.

The colorectal hyperplastic polyp has generally been considered a finding of no clinical significance. Recent research has, however, called attention to the existence of some variants of hyperplastic polyp which are potentially malignant. The term "advanced serrated polyp" has been coined for such cases, which comprise mixed hyperplastic/adenomatous tissue, serrated adenoma, and sessile serrated polyp, in contrast to the traditional hyperplastic polyp. Since epithelial dysplasia is an integrated component of mixed hyperplastic/adenomatous polyp and of the serrated adenoma, such a diagnosis would dictate control colonoscopy comparable to the guidelines for subjects with conventional adenomas. The cytology of the sessile serrated polyp is, however, closer to that of the traditional hyperplastic polyp, whereas the architecture mimics that of the serrated adenoma. For this reason, a consensus regarding the optimal management of such patients has not been obtained, but if the polyp is sizeable and located in the right colon, control should be considered. The small, usually left-sided traditional polyp as a rule needs no follow-up, but the context in which such a lesion is found and its morphology may influence the clinical decision. Future large-scale investigations of serrated colorectal polyps, including interobserver studies, will be required to identify histological details of clinical utility which can be adopted in daily routine practice.

[Hyperplastic colorectal polyposis]. / Hyperplastisk kolorektal polypose.

Two cases of hyperplastic polyposis are presented, a 59-year-old female with >50 colorectal serrated polyps in a pancolic distribution and a 69-year-old female with four mucinous colorectal carcinomas and seven serrated polyps, three of which >10 mm. The pathological tissue of the latter patient was confined to the right colon and the neoplastic areas displayed loss of MLH1 expression. Three first degree relatives of this patient had carcinoma of the large bowel, breast and ovary, respectively. A first degree relative of the former patient succumbed to a colorectal carcinoma.

[Familial colorectal cancer]. / Familiaer kolorektal cancer.

The most frequent monogenic predisposition to CRC is hereditary non-polyposis colorectal cancer (HNPCC). Less frequent are syndromes with polyposis. In some families the occurrence of CRC indicates a familial risk of CRC without the diagnostic criteria for the above syndromes being fulfilled. In families where causative mutations are identified, predictive genetic testing is offered. When no mutation is identified in a family, the risk of individual members of the family is evaluated according to the family history. Individuals with a high risk of CRC are offered surveillance.

[Hereditary colorectal cancer]. / Arvelig kolorektal cancer.

HNPCC and FAP are inherited diseases with a lifetime risk of colorectal cancer (CRC) of 80-100% in gene carriers. Disease-causing mutations have been identified in the APC gene at FAP and in MMR genes at HNPCC. In FAP-patients, screening has reduced the prevalence of CRC by 55%, and the survival rate has improved considerably. For HNPCC-patients, 77% of CRCs found by screening were Duke' A or B, and survival after CRC has improved significantly since 1990. Continuous central registration in the HNPCC and Polyposis registers is recommended to ensure identification of high-risk families and evaluate the effect of screening.

[Prevention of colorectal cancer in families with hereditary nonpolyposis colorectal cancer]. / Forebyggelse af kolorektal cancer i hereditaer non-polyposis kolorektal cancer-familier.

INTRODUCTION: Hereditary non-polyposis colorectal cancer (HNPCC) is a dominant inherited colorectal cancer syndrome, with lifetime risk up to 90% of developing colorectal cancer (CRC) for carriers of the genes. Screening with colonoscopy can reduce the CRC-rate by 62% and prevent CRC-deaths. The HNPCC-Register was established with the aim of identification and registration of Danish HNPCC-families and coordination of surveillance. MATERIALS AND METHODS: The results of 703 colonic screenings in 396 asymptomatic individuals from 150 HNPCC-families were analysed and related to the family diagnosis. RESULTS: In 112 asymptomatic individuals, 31, colorectal cancers and 140 adenomas were diagnosed. Neoplasia was found in one fifth of the examinations and almost one third of the individuals developed an asymptomatic neoplasia which was detected by screening. At the time of the diagnosis, 77% of the colorectal cancers were localized (Dukes stage A or B). DISCUSSION: In Finland, screening for colorectal cancers in HNPCC-families prevents 25-45-fold more CRC-deaths compared to general population screening for colorectal cancer. The results of the Danish colonic HNPCC-screening reveal neoplasia in 21% of the examinations and the colorectal cancers found by screening were at a more favourable Dukes stage compared to sporadic CRC, and probably also CRC found by general population screening. The HNPCC-Register initiates surveillance together with the clinical genetic departments, but the results of the recommended colonic examinations are not automatically reported to the HNPCC-Register. To enable an in-depth investigation of the effect of CRC-screening in all Danish HNPCC-families, further financial resources should be allocated to the HNPCC-Register to collect the results.