Inge Bernstein

Guidelines for the clinical management of familial adenomatous polyposis (FAP)

Background: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.

Reduced Frequency of Extracolonic Cancers in Hereditary Nonpolyposis Colorectal Cancer Families with Monoallelic hMLH1 Expression

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease caused by mutations in one of at least four different DNA mismatch repair genes, hMLH1, hMSH2, hPMS1, and hPMS2. Phenotypically, HNPCC is characterized by the early onset of colorectal cancers and various extracolonic cancers. Depending on the presence or absence of extracolonic tumors, HNPCG-has been divided into two syndromes (Lynch syndrome I and Lynch syndrome II), but, so far, no correlation to distinct genotypes has been demonstrated. In this study, we present a frequent hMLH1 intron 14 founder mutation that is associated with a highly reduced frequency of extracolonic tumors. The mutation disrupts the splice donor site and silences the mutated allele. Tumors exhibited microsatellite instability, and loss of the wild-type hMLH1 allele was prevalent. We propose that the mutation results in a milder phenotype, because the mutated hMLH1 protein is prevented from exerting a dominant negative effect on the concerted action of the mismatch repair system.

Hereditary Non-Polyposis Colorectal Cancer: Clinical Features and Survival Results from the Danish HNPCC Register

BACKGROUND Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited syndrome characterized by the development of colorectal cancer (CRC) and other carcinomas. Our aim was to evaluate tumour parameters and survival in HNPCC. METHODS One hundred and eight Danish HNPCC patients were compared with 870 patients with sporadic colorectal cancer. RESULTS The median age at CRC diagnosis was 41 years in the HNPCC group. HNPCC patients had significantly more carcinomas located to the right colon (68% against 49% in controls), more synchromous tumours (7% versus 1%), more metachronous CRC after 10 years (29% versus 5%), more localized carcinomas (62% versus 39%), and significantly higher crude cumulative 5-year survival (56% versus 30%). CONCLUSIONS CRC in HNPCC behaves differently compared to sporadic cases concerning age of onset, frequency of multiple lesions, and location. The metastatic tendency is less than in sporadic CRC and the survival is better.

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.

A parametric model for analyzing anticipation in genetically predisposed families.

Anticipation, i.e. a decreasing age-at-onset in subsequent generations has been observed in a number of genetically triggered diseases. The impact of anticipation is generally studied in affected parent-child pairs. These analyses are restricted to pairs in which both individuals have been affected and are sensitive to right truncation of the data. We propose a normal random effects model that allows for right-censored observations and includes covariates, and draw statistical inference based on the likelihood function. We applied the model to the hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome family cohort from the national Danish HNPCC register. Age-at-onset was analyzed in 824 individuals from 2-4 generations in 125 families with proved disease-predisposing mutations. A significant effect from anticipation was identified with a mean of 3 years earlier age-at-onset per generation. The suggested model corrects for incomplete observations and considers families rather than affected pairs and thereby allows for studies of large sample sets, facilitates subgroup analyses and provides generation effect estimates.

Hepatoblastoma in two cousins in a family with adenomatous polyposis

Two cases of hepatoblastoma in cousins in a family with familial adenomatous polyposis (FAP) are reported. Twenty-five cases of hepatoblastoma with family history of FAP have been documented in the literature, but there has never been a report of two cases of hepatoblastoma in the same polyposis family.

Functional characterization of rare missense mutations in MLH1 and MSH2 identified in Danish colorectal cancer patients

Recently, we have performed a population based study to analyse the frequency of colorectal cancer related MLH1 and MSH2 missense mutations in the Danish population. Half of the analyzed mutations were rare and most likely only present in the families where they were identified originally. Some of the missense mutations were located in conserved regions in the MLH1 and MSH2 proteins indicating a relation to disease development. In the present study, we functionally characterized 10 rare missense mutations in MLH1 and MSH2 identified in 13 Danish CRC families. To elucidate the pathogenicity of the missense mutations, we carried out in vitro functional analyses. The missense mutations were analyzed for their effect on protein expression and repair efficiency. The results of the functional analysis were correlated with clinical data on the families carrying these mutations. Eight missense mutations resulted in proteins with expression and repair efficiency similar to the wild type. One missense mutation (MSH2 p.Met688Val) caused reduced protein expression and one (MSH2 p.Leu187Arg) caused both reduced protein expression and repair deficiency. The MSH2 p.Leu187Arg mutation was found in an Amsterdam II family presenting with high microsatellite instability and loss of MSH2 and MSH6 proteins in tumours. In conclusion, only 1/10 missense mutations displayed repair deficiency and could be classified as pathogenic. No final conclusion can be drawn on the MSH2 p.Met688Val mutation, which caused reduced protein expression. Although, no deficiencies have been identified in the proteins harbouring the other missense mutations, pathogenicity of these variants cannot be unambiguously excluded.

Mandibular Osteomas in Sporadic Colorectal Carcinoma a Genetic Marker

Pantomography of the mandible was performed in 98 patients with sporadic colorectal adenocarcinoma. Twenty-eight patients (29%) had osteomas versus 5% in a control group (P < 0.001). Mandibular osteomas are found in most patients with the premalignant dominant syndrome familial adenomatous polyposis. Sporadic colorectal cancer examinations of married couples have shown that diet has only a moderate influence on the development of colorectal cancer, whereas pedigree studies indicate a genetic component. On this basis we conclude that mandibular osteomas are probably genetic markers of the development of sporadic colorectal carcinoma.

The utility of P16 in identifying Lynch Syndrome (LS)

P1-1 Reproducibility of Human Papillomavirus detection using the Roche cobas HPV Test, QIAGEN Hybrid Capture 2, Gen-Probe APTIMA, and Genomica CLART assays; Implications for molecular cervical screening Ejegod DM, Preisler S, Rebolj M, Untermann A, Lynge E, Rygaard C, Bonde J Department of Pathology, Copenhagen University Hospital, Hvidovre; Clinical Research Centre, Copenhagen University Hospital, Hvidovre; Department of Public Health, University of Copenhagen