Hans F. A. Vasen

Genetic Heterogeneity and Penetrance Analysis of the BRCA1 and BRCA2 Genes in Breast Cancer Families

The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years. The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC ☆

One of the first successful efforts of the International Collaborative Group on HNPCC (ICG-HNPCC) at its meeting in Amsterdam in 1990 was the establishment of a set of selection criteria for families with hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) to provide a basis for uniformity in collaborative studies (Table 1).1 Until 1990, such criteria were lacking and the descriptions of the syndrome in the literature varied widely. In the absence of a common nomenclature it was impossible to compare the results of different studies on HNPCC. The wide acceptance of the ICG criteria is reflected by the fact that almost all investigators currently make use of them. However, the criteria have also been criticized. Some investigators feel that the criteria exclude some classic HNPCC families because they do not take into account the extracolonic cancers that are part of the syndrome. There is also concern that the criteria are being used inappropriately for the diagnosis of HNPCC. As criteria for the selection of families for research, they were originally aimed at specificity more than sensitivity. It is now considered that many true HNPCC families would be missed if the criteria are applied to clinical diagnosis, and that families not meeting the criteria might be falsely reassured and excluded from genetic counseling, DNA testing, or surveillance. To resolve these problems, many investigators have developed additional criteria.2–6 At the ninth meeting of the ICG-HNPCC held in Noordwijk, the Netherlands, in 1997, a definition of HNPCC was proposed that was aimed at helping clinicians to identify families. This provided a detailed description of the specific features of HNPCC rather than the rigid criteria required for collaborative studies. In addition, at the ninth meeting, and also at the tenth held in Coimbra, Portugal, in 1998, new selection criteria for collaborative studies were proposed that included the extracolonic cancers associated with HNPCC. Definition of HNPCC

The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC)

The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) H. Vasen;J. Mecklin;P. Meera Khan;H. Lynch; Diseases of the Colon & Rectum

Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial

Summary Background Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. Methods In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990. Results 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55·7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0·63 (95% CI 0·35–1·13, p=0·12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0·56 (95% CI 0·32–0·99, p=0·05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0·41 (0·19–0·86, p=0·02) and an IRR of 0·37 (0·18–0·78, p=0·008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups. Interpretation 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55·7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. Funding European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma.

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.

Familial endometrial cancer in female carriers of MSH6 germline mutations.

Hereditary non-polyposis colorectal cancer (HNPCC) is a common autosomal dominant condition characterized by early onset colorectal cancer as well as other tumour types at different anatomical sites1. HNPCC tumours often display a high level of genomic instability, characterized by changes in repeat numbers of simple repetitive sequences (microsatellite instability, MSI), which reflects the malfunction of the DNA mismatch repair machinery2, 3. Accordingly, HNPCC was shown to be caused by germline mutations in the DNA mismatch repair genes (MMR) MSH2, MLH1, PMS1, PMS2 and MSH6 (refs 3, 4, 5, 6). So far, more than 220 predisposing mutations have been identified, most in MSH2 and MLH1 and in families complying with the clinical Amsterdam criteria3, 7, 8 (AMS+). Many HNPCC families, however, do not fully comply with these criteria, and in most cases the causative mutations are unknown.

Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer)

Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews 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 in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.

Clinical findings with implications for genetic testing in families with clustering of colorectal cancer.

BACKGROUND Germ-line mutations in DNA mismatch-repair genes (MSH2, MLH1, PMS1, PMS2, and MSH6) cause susceptibility to hereditary nonpolyposis colorectal cancer. We assessed the prevalence of MSH2 and MLH1 mutations in families suspected of having hereditary nonpolyposis colorectal cancer and evaluated whether clinical findings can predict the outcome of genetic testing. METHODS We used denaturing gradient gel electrophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with familial clustering of colorectal cancer or other cancers associated with hereditary nonpolyposis colorectal cancer. Information on the site of cancer, the age at diagnosis, and the number of affected family members was obtained from all families. RESULTS Mutations of MSH2 or MLH1 were found in 47 of the 184 kindreds (26 percent). Clinical factors associated with these mutations were early age at diagnosis of colorectal cancer, the occurrence in the kindred of endometrial cancer or tumors of the small intestine, a higher number of family members with colorectal or endometrial cancer, the presence of multiple colorectal cancers or both colorectal and endometrial cancers in a single family member, and fulfillment of the Amsterdam criteria for the diagnosis of hereditary nonpolyposis colorectal cancer (at least three family members in two or more successive generations must have colorectal cancer, one of whom is a first-degree relative of the other two; cancer must be diagnosed before the age of 50 in at least one family member; and familial adenomatous polyposis must be ruled out). Multivariate analysis showed that a younger age at diagnosis of colorectal cancer, fulfillment of the Amsterdam criteria, and the presence of endometrial cancer in the kindred were independent predictors of germ-line mutations of MSH2 or MLH1. These results were used to devise a logistic model for estimating the likelihood of a mutation in MSH2 and MLH1. CONCLUSIONS Assessment of clinical findings can improve the rate of detection of mutations of DNA mismatch-repair genes in families suspected of having hereditary nonpolyposis colorectal cancer.

The risk of extra‐colonic, extra‐endometrial cancer in the Lynch syndrome

Persons with the Lynch syndrome (LS) are at high risk for cancer, including cancers of the small bowel, stomach, upper urologic tract (renal pelvis and ureter), ovary, biliary tract and brain tumors, in addition to the more commonly observed colorectal and endometrial cancers. Cancer prevention strategies for these less common cancers require accurate, age‐specific risk estimation. We pooled data from 4 LS research centers in a retrospective cohort study, to produce absolute incidence estimates for these cancer types, and to evaluate several potential risk modifiers. After elimination of 135 persons missing crucial information, cohort included 6,041 members of 261 families with LS‐associated MLH1 or MSH2 mutations. All were either mutation carriers by test, probable mutation carriers (endometrial/colorectal cancer‐affected), or first‐degree relatives of these. Among mutation carriers and probable carriers, urologic tract cancer (N = 98) had an overall lifetime risk (to age 70) of 8.4% (95% CI: 6.6–10.8); risks were higher in males (p < 0.02) and members of MSH2 families (p < 0.0001). Ovarian cancer (N = 72) had an lifetime risk of 6.7% (95% CI: 5.3–9.1); risks were higher in women born after the median year of birth (p < 0.008) and in members of MSH2 families (p < 0.006). Brain tumors and cancers of the small bowel, stomach, breast and biliary tract were less common. Urologic tract cancer and ovarian cancer occur frequently enough in some LS subgroups to justify trials to evaluate promising prevention interventions. Other cancer types studied occur too infrequently to justify strenuous cancer control interventions.

Mutations Associated with HNPCC Predisposition — Update of ICG-HNPCC/INSiGHT Mutation Database

In 1994, the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (ICG-HNPCC) established an international database of mutations identified in families with Lynch (HNPCC) syndrome. The data are publicly available at http://www.nfdht.nl. The information stored in the database was systematically analyzed in 1997, and at that time, 126 different predisposing mutations were reported affecting the DNA mismatch repair genes MSH2 and MLH1 and occurring in 202 families. In 2003, the ICG-HNPCC and the Leeds Castle Polyposis Group (LCPG) merged into a new group, INSiGHT (International Society for Gastrointestinal Hereditary Tumors). The present update of the database of DNA mismatch repair gene mutations of INSiGHT includes 448 mutations that primarily involve MLH1 (50%), MSH2 (39%), and MSH6 (7%) and occur in 748 families from different parts of the world.