Laura Renkonen-Sinisalo

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.

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.

Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts

Lynch syndrome (LS) 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. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.

Peutz–Jeghers syndrome: a systematic review and recommendations for management

Peutz–Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype–phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.

Ten Years After Mutation Testing for Lynch Syndrome: Cancer Incidence and Outcome in Mutation-Positive and Mutation-Negative Family Members

PURPOSE Colonoscopies with polypectomies and endometrial biopsies with transvaginal ultrasonography, repeated at 2- to 3-year intervals, are performed for prevention or early detection of cancer in patients with DNA mismatch repair gene mutation causing Lynch syndrome. The long-term effectiveness of surveillance was evaluated in Lynch syndrome family members tested approximately 10 years ago. MATERIALS AND METHODS Cancer incidence and survival were determined after an 11.5-year follow-up in 242 mutation-positive and 367 mutation-negative participants. These participants in 57 Lynch syndrome families with 14 different mutations were at 50% risk. The median age was 36 years (range, 18 to 72 years) in mutation carriers and 42 years (range, 18 to 72 years) in mutation-negative participants, and none had had cancer of the Lynch syndrome type. RESULTS Compliance was 95.9% for the colonic surveillance and 97.1% for the gynecologic surveillance. Colorectal cancer (CRC) occurred in 30 mutation-positive participants, and 74 participants had adenomas removed. Three patients died of CRC. Endometrial cancer (EC) occurred in 19 of 103 women at risk, and 48 women had prophylactic hysterectomy. Six of 112 women at risk had ovarian cancer. The overall cancer risk ratio (RR) in mutation carriers was 5.80 (95% CI, 3.4 to 9.5). Cancer mortality rate (RR = 2.28; 95% CI, 0.82 to 6.31) and overall death rate (RR = 1.26; 95% CI, 0.65 to 2.46) were not significantly increased. CONCLUSION Long-term compliance in surveillance for CRC and EC exceeded 95% in Lynch syndrome. All CRC deaths were not prevented as a result of noncompliance or missed lesions. Still, after 10 years of surveillance, no significant increase in mortality had occurred compared with mutation-negative relatives.

Common variation near CDKN1A , POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10−10), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10−10) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10−10) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.

Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome

The estimated lifetime risk for endometrial carcinoma (EC) in hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is 32–60%, thus supporting surveillance. The survival rate of EC patients is, however, favourable questioning the need for surveillance. Yet, the effectiveness of gynecological surveillance remains to be shown. The 2 previously published studies were based on transvaginal ultrasound (TVUS) alone. Intrauterine biopsy has not been tested in surveillance for EC in HNPCC families. The effect of gynecological surveillance was evaluated among 175 Finnish mutation carriers. During 759 person years at risk, there were 503 surveillance visits including TVUS and intrauterine biopsy of endometrium at 94% and 74% of the visits, respectively. EC occurred in 14 cases, 11 of which were diagnosed by surveillance, 8 by intrauterine biopsies. TVUS indicated only 4 EC patients but missed 6 other cases. Intrauterine sampling detected 14 additional cases of potentially premalignant hyperplasia. The stage distribution and survival tended to be more favorable in the 14 EC cases of the surveilled group (no deaths) than in the group of 83 symptomatic mutation carriers of whom 6 died of EC, but with no statistical significance. Four cases of ovarian cancer occurred but none was detected by surveillance in TVUS examinations. In conclusion, EC surveillance in HNPCC seems more effective with endometrial biopsies than with TVUS alone. A definite improvement in survival remains to be shown. The detection of early cancer stages and premalignant lesions offers the opportunity to avoid extensive adjuvant treatment.

CTCF/cohesin-binding sites are frequently mutated in cancer

Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes with CTCF (CCCTC-binding factor), affecting genomic stability, expression and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/cohesin-binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in A•T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase ɛ (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome.

Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database.

Objective Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance. Design We undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene. Results 1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards in MLH1 and MSH2 mutation carriers, and from about 40 years in MSH6 and PMS2 carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian. Conclusions The four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established at http://LScarisk.org enabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.

Molecular analysis of endometrial tumorigenesis: importance of complex hyperplasia regardless of atypia.

Purpose: Endometrial carcinoma (EC) is common in the population and the most frequent extracolonic malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC)/Lynch syndrome. We characterized precursor lesions of endometrioid EC to identify markers of malignant transformation and tumor progression. Experimental Design: Serial specimens of normal endometrium, simple hyperplasia, complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma obtained during a 10-year surveillance of DNA mismatch repair (MMR) gene mutation carriers (together 110 samples) were molecularly profiled and compared with a sporadic reference series of endometrial specimens taken for nonmalignant reasons (62 samples). Results: Among MMR gene mutation carriers, decreased MMR protein expression was present in 7% in normal endometrium, 40% in simple hyperplasia, 100% in complex hyperplasia without atypia, 92% in complex hyperplasia with atypia, and 100% in endometrial carcinoma. Microsatellite instability frequencies were lower (6%, 17%, 67%, 38%, and 64%, respectively). Among 24 tumor suppressor genes, the number of methylated loci increased from normal endometrium to simple hyperplasia to complex hyperplasia (complex hyperplasia without atypia/complex hyperplasia with atypia) in both Lynch syndrome and reference series. The most frequently methylated genes were CDH13, RASSF1A, and GSTP1. In MMR gene mutation carriers, MMR and methylation defects appeared up to 12 years before endometrial carcinoma. Conclusions: Molecular changes in endometrial tissue are detectable several years before endometrial carcinoma in genetically predisposed individuals. Abnormal MMR and methylation classify normal endometrium and simple hyperplasia into one category and complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma into another, suggesting that, contrary to a traditional view, complex hyperplasia without atypia and complex hyperplasia with atypia are equally important as precursor lesions of endometrial carcinoma. (Clin Cancer Res 2009;15(18):5772–83)