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Hans F A Vasen,
Ignacio Blanco,
Katja Aktan-Collan,
Jessica P Gopie,
Angel Alonso,
Stefan Aretz,
Inge Bernstein,
Lucio Bertario,
John Burn,
Gabriel Capella, [......],
Laura Renkonen-Sinisalo,
Julian R Sampson,
Astrid Stormorken,
Rolf H Sijmons,
Sabine Tejpar,
Huw J W Thomas,
Nils Rahner,
Juul T Wijnen,
Heikki Juhani Järvinen, Gabriela Möslein
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ABSTRACT: 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.
Gut 02/2013; · 10.11 Impact Factor
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ABSTRACT: Fragestellung und Hintergrund
Das Lynch-Syndrom als das am meisten verbreitete erbliche Kolorektalkarzinomsyndrom und häufigste Ursache des erblichen Endometriumkarzinoms ist charakterisiert durch eine autosomal-dominante Vererbung mit einer Penetranz von 85 bis 90%. Der ursächliche molekulargenetische Mechanismus ist eine Mutation in einem der Mismatch-Reparaturgene.
Patienten und Methodik
Zur Identifikation von Patienten mit Lynch-Syndrom sollte eine Familienanamnese der Kernfamilie erhoben und mit den Amsterdam-Kriterien abgeglichen werden. Eine andere Möglichkeit ist die Anwendung der Bethesda-Kriterien und die nachfolgende Untersuchung auf Mikrosatelliteninstabilität. Bei Patienten mit mikrosatelliteninstabilen Tumoren als Indikator für ein defektes Mismatch-Reparaturgen sind eine genetische Beratung und eine Mutationsanalyse erforderlich. Für Familien, die die Amsterdam-Kriterien erfüllen, wird ein intensiviertes Screening empfohlen, auch wenn keine pathogene Mutation gefunden wird.
Ergebnisse
Das Krebsrisiko von Individuen aus Familien mit einer nachgewiesenen pathogenen Mutation, die negativ getestet werden, entspricht dem der Normalbevölkerung. Sie können daher aus der intensivierten Überwachung entlassen werden. Ein prophylaktischer Eingriff bei High-risk-Individuen ohne Neoplasie wird nicht generell empfohlen. Zum Zeitpunkt eines primären Kolonkarzinoms allerdings sollte eine erweiterte Resektion angesichts der hohen Rate metachroner Karzinome diskutiert werden. Die Bedenken hinsichtlich beeinträchtigender funktioneller Ergebnisse wurden inzwischen in einer großen internationalen Kohortenstudie zur Lebensqualität ausgeräumt. Interessanterweise führt eine erweiterte (prophylaktische) Operation bei gleichen perioperativen Risiken nicht zu einer schlechteren Lebensqualität.
Schlussfolgerung
Unter Beachtung der Risikoreduktion sollte daher eine erweiterte Operation zum Zeitpunkt des ersten Koloneingriffs zumindest diskutiert, wenn nicht sogar empfohlen werden. Eine prophylaktische Hysterektomie und bilaterale Oophorektomie zum Zeitpunkt einer kolorektalen Primäroperation sollten ebenfalls empfohlen werden, wenn die Familienplanung abgeschlossen ist.
coloproctology 05/2012; 34(5):329-340.
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XX - Die Zeitschrift für Frauen in der Medizin. 04/2012; 1(4):206-212.
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ABSTRACT: Lynch syndrome as the most common hereditary colorectal cancer syndrome and the most common cause of hereditary endometrial cancer is characterized by an autosomal dominant inheritance with a penetrance of 85-90%. The molecular genetic underlying mechanism is a mutation in one of the mismatch repair genes.
In order to identify patients with Lynch syndrome, a nuclear family history should be ascertained and matched with the Amsterdam criteria. A different approach for identification is the adherence to Bethesda criteria and subsequent testing for microsatellite instability. In patients with unstable tumors as an indicator for mismatch repair deficiency, genetic counseling and mutation analysis are warranted. For families fulfilling the Amsterdam criteria, intensified screening is recommended, even if a pathogenic mutation is not identified.
Individuals from families with a proven pathogenic mutation that are tested negative are at normal population risk for cancers and may be dismissed from intensified surveillance. Prophylactic surgery in high-risk individuals without neoplasia is not generally recommended. At the time of a colon primary, however, extended surgery should be discussed in the light of a high rate of metachronous cancers. The worries of impairing functional results have now been evaluated in the light of quality of life in a large international cohort. Interestingly, extended (prophylactic) surgery does not lead to inferior quality of life with equal perioperative risks.
Therefore, taking the risk reduction into account, extended surgery at the time of the first colon primary should at least be discussed, if not recommended. Also, prophylactic hysterectomy and bilateral oophorectomy at the time of a colorectal primary should be recommended if family planning has been completed.
Langenbeck s Archives of Surgery 02/2012; 397(4):513-25. · 1.81 Impact Factor
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Hereditary Genetics. 11/2011; 1:e101.
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John Burn,
D Timothy Bishop,
Pamela D Chapman,
Faye Elliott,
Lucio Bertario,
Malcolm G Dunlop,
Diana Eccles,
Anthony Ellis,
D Gareth Evans,
Riccardo Fodde,
Eamonn R Maher, Gabriela Möslein,
Hans F A Vasen,
Julie Coaker,
Robin K S Phillips,
Steffen Bülow,
John C Mathers
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ABSTRACT: Evidence supporting aspirin and resistant starch (RS) for colorectal cancer prevention comes from epidemiologic and laboratory studies (aspirin and RS) and randomized controlled clinical trials (aspirin). Familial adenomatous polyposis (FAP) strikes young people and, untreated, confers virtually a 100% risk of colorectal cancer and early death. We conducted an international, multicenter, randomized, placebo-controlled trial of aspirin (600 mg/d) and/or RS (30 g/d) for from 1 to 12 years to prevent disease progression in FAP patients from 10 to 21 years of age. In a 2 × 2 factorial design, patients were randomly assigned to the following four study arms: aspirin plus RS placebo; RS plus aspirin placebo; aspirin plus RS; RS placebo plus aspirin placebo; they were followed with standard annual clinical examinations including endoscopy. The primary endpoint was polyp number in the rectum and sigmoid colon (at the end of intervention), and the major secondary endpoint was size of the largest polyp. A total of 206 randomized FAP patients commenced intervention, of whom 133 had at least one follow-up endoscopy and were therefore included in the primary analysis. Neither intervention significantly reduced polyp count in the rectum and sigmoid colon: aspirin relative risk = 0.77 (95% CI, 0.54-1.10; versus nonaspirin arms); RS relative risk = 1.05 (95% CI, 0.73-1.49; versus non-RS arms). There was a trend toward a smaller size of largest polyp in patients treated with aspirin versus nonaspirin--mean 3.8 mm versus 5.5 mm for patients treated 1 or more years (adjusted P = 0.09) and mean 3.0 mm versus 6.0 mm for patients treated more than 1 year (P = 0.02); there were similar weaker trends with RS versus non-RS. Exploratory translational endpoints included crypt length (which was significantly shorter in normal-appearing mucosa in the RS group over time) and laboratory measures of proliferation (including Ki67). This clinical trial is the largest ever conducted in the setting of FAP and found a trend of reduced polyp load (number and size) with 600 mg of aspirin daily. RS had no clinical effect on adenomas.
Cancer Prevention Research 05/2011; 4(5):655-65. · 4.91 Impact Factor
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Karin Hardt,
Sven Boris Heick,
Beate Betz,
Timm Goecke,
Haniyeh Yazdanparast,
Robin Küppers,
Kati Servan,
Verena Steinke,
Nils Rahner,
Monika Morak,
Elke Holinski-Feder,
Christoph Engel, Gabriela Möslein,
Hans-Konrad Schackert,
Magnus von Knebel Doeberitz,
Christian Pox,
Johannes H Hegemann,
Brigitte Royer-Pokora
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ABSTRACT: Missense mutations of the DNA mismatch repair gene MLH1 are found in a significant fraction of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) and their pathogenicity often remains unclear. We report here all 88 MLH1 missense variants identified in families from the German HNPCC consortium with clinical details of these patients/families. We investigated 23 MLH1 missense variants by two functional in vivo assays in yeast; seven map to the ATPase and 16 to the protein interaction domain. In the yeast-2-hybrid (Y2H) assay three variants in the ATPase and twelve variants in the interaction domain showed no or a reduced interaction with PMS2; seven showed a normal and one a significantly higher interaction. Using the Lys2A (14) reporter system to study the dominant negative mutator effect (DNE), 16 variants showed no or a low mutator effect, suggesting that these are nonfunctional, three were intermediate and four wild type in this assay. The DNE and Y2H results were concordant for all variants in the interaction domain, whereas slightly divergent results were obtained for variants in the ATPase domain. Analysis of the stability of the missense proteins in yeast and human embryonic kidney cells (293T) revealed a very low expression for seven of the variants in yeast and for nine in human cells. In total 15 variants were classified as deleterious, five were classified as variants of unclassified significance (VUS) and three were basically normal in the functional assays, P603R, K618R, Q689R, suggesting that these are neutral.
Familial Cancer 03/2011; 10(2):273-84. · 1.30 Impact Factor
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Maija R J Kohonen-Corish,
Finlay Macrae,
Maurizio Genuardi,
Stefan Aretz,
Bharati Bapat,
Inge T Bernstein,
John Burn,
Richard G H Cotton,
Johan T den Dunnen,
Thierry Frebourg, [......],
Pål Møller,
Hans Morreau, Gabriela Möslein,
Rolf Sijmons,
Amanda B Spurdle,
Sean Tavtigian,
Carli M J Tops,
Thomas K Weber,
Niels de Wind,
Michael O Woods
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ABSTRACT: 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.
Human Mutation 02/2011; 32(4):491-4. · 5.69 Impact Factor
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Maija R J Kohonen-Corish,
Jumana Y Al-Aama,
Arleen D Auerbach,
Myles Axton,
Carol Isaacson Barash,
Inge Bernstein,
Christophe Béroud,
John Burn,
Fiona Cunningham,
Garry R Cutting, [......],
Sue Povey,
Raj Ramesar,
Sue Richards,
Daniela Seminara,
María-Jesús Sobrido,
Sean Tavtigian,
Graham Taylor,
Mauno Vihinen,
Ingrid Winship,
Richard G H Cotton
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ABSTRACT: The third Human Variome Project (HVP) Meeting "Integration and Implementation" was held under UNESCO Patronage in Paris, France, at the UNESCO Headquarters May 10-14, 2010. The major aims of the HVP are the collection, curation, and distribution of all human genetic variation affecting health. The HVP has drawn together disparate groups, by country, gene of interest, and expertise, who are working for the common good with the shared goal of pushing the boundaries of the human variome and collaborating to avoid unnecessary duplication. The meeting addressed the 12 key areas that form the current framework of HVP activities: Ethics; Nomenclature and Standards; Publication, Credit and Incentives; Data Collection from Clinics; Overall Data Integration and Access-Peripheral Systems/Software; Data Collection from Laboratories; Assessment of Pathogenicity; Country Specific Collection; Translation to Healthcare and Personalized Medicine; Data Transfer, Databasing, and Curation; Overall Data Integration and Access-Central Systems; and Funding Mechanisms and Sustainability. In addition, three societies that support the goals and the mission of HVP also held their own Workshops with the view to advance disease-specific variation data collection and utilization: the International Society for Gastrointestinal Hereditary Tumours, the Micronutrient Genomics Project, and the Neurogenetics Consortium.
Human Mutation 10/2010; 31(12):1374-81. · 5.69 Impact Factor
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Christoph Engel,
Nils Rahner,
Karsten Schulmann,
Elke Holinski-Feder,
Timm O Goecke,
Hans K Schackert,
Matthias Kloor,
Verena Steinke,
Holger Vogelsang, Gabriela Möslein,
Heike Görgens,
Stefan Dechant,
Magnus von Knebel Doeberitz,
Josef Rüschoff,
Nicolaus Friedrichs,
Reinhard Büttner,
Markus Loeffler,
Peter Propping,
Wolff Schmiegel
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ABSTRACT: Individuals with hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome) have a high risk for developing colorectal cancer (CRC). We evaluated the efficacy of annual surveillance colonoscopies to detect adenomas and CRCs.
In a prospective, multicenter cohort study, 1126 individuals underwent 3474 colonoscopies. We considered individuals from 3 groups of HNPCC families: those with a pathogenic germline mutation in a mismatch repair gene (MUT group), those without a mutation but with microsatellite instability (MSI group), and those who fulfilled the Amsterdam criteria without microsatellite instability (MSS group).
Compliance to annual intervals was good, with 81% of colonoscopies completed within 15 months. Ninety-nine CRC events were observed in 90 patients. Seventeen CRCs (17%) were detected through symptoms (8 before baseline colonoscopy, 8 at intervals >15 months to the preceding colonoscopy, and 1 interval cancer). Only 2 of 43 CRCs detected by follow-up colonoscopy were regionally advanced. Tumor stages were significantly lower among CRCs detected by follow-up colonoscopies compared with CRCs detected by symptoms (P = .01). Cumulative CRC risk at the age of 60 years was similar in the MUT and MSI groups (23.0% combined; 95% confidence interval [CI], 14.8%-31.2%) but considerably lower in the MSS group (1.8%; 95% CI, 0.0%-5.1%). Adenomas at baseline colonoscopy predicted an earlier occurrence of subsequent adenoma (hazard ratio, 2.6; 95% CI, 1.7-4.0) and CRC (hazard ratio, 3.9; 95% CI, 1.7-8.5), providing information about interindividual heterogeneity of adenomas and kinetics of CRC formation.
Annual colonoscopic surveillance is recommended for individuals with HNPCC. Less intense surveillance might be appropriate for MSS families.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 10/2009; 8(2):174-82. · 5.64 Impact Factor
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ABSTRACT: Hereditary non-polyposis colorectal cancer, an autosomal dominant predisposition to colorectal cancer and other malignancies, is caused by inactivating mutations of DNA mismatch repair genes, mainly MLH1 and MSH2. Missense mutations affect protein structure or function, but may also cause aberrant splicing, if located within splice sites (ss) or cis-acting sequences of splicing regulatory proteins, i.e., exonic splicing enhancers or exonic splicing silencers. Despite significant progress of ss scoring algorithms, the prediction for the impact of mutations on splicing is still unsatisfactory. For this study, we assessed ten ss and nine missense mutations outside ss in MLH1 and MSH2, including eleven newly identified mutations, and experimentally analyzed their effect at the RNA level. We additionally tested and compared the reliability of several web-based programs for the prediction of splicing outcome for these mutations.
Journal of Cancer Research and Clinical Oncology 09/2009; 136(1):123-34. · 2.56 Impact Factor
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Gabriela Möslein
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ABSTRACT: Lynch syndrome (synonymous for HNPCC = hereditary non-polyposis colorectal cancer) is characterized by the development of colorectal, endometrial, gastric, and various other cancers, and is caused by a mutation in one of the mismatch repair (MMR) genes. One of the main challenges in the clinical management of Lynch syndrome remains the broad spectrum and heterogeneity among and between affected families. To date, no clinically relevant genotype-phenotype correlation for the two main affected genes hMSH2 and hMLH1 has been established. Clinical management of familial colorectal cancer (CRC) remains a challenge for clinicians. The overlap of syndromes with different underlying genetic causes and the differentiated risk management of colorectal and associated malignancies require state-of-the-art management recommendations.Regarding the identification of Lynch syndrome, the available criteria (revised Bethesda guidelines) appear to be effective for the selection of families for analysis of tumor MMR status. To date, the significant proportion of mutation carriers in Germany are still unknown and diagnosis still relies on patients with index cancers. Taking into account the tremendous importance the identification of MMR mutation carriers implies, future directives could include routine antibody staining for MMR genes in all CRCs. Increasing evidence suggests that microsatellite instability (MSI) and/or immunohistochemical (IHC) are an important prognostic factor and may predict the response to chemotherapy, therefore a broad application of these tools is envisaged in the near future.
08/2009: pages 281 - 294; , ISBN: 9783527627523
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Jim Kaput,
Richard G H Cotton,
Lauren Hardman,
Michael Watson,
Aida I Al Aqeel,
Jumana Y Al-Aama,
Fahd Al-Mulla,
Santos Alonso,
Stefan Aretz,
Arleen D Auerbach, [......],
Mollie Ullman-Cullere,
Joji Utsunomiya,
Henk J van Kranen,
Mauno Vihinen,
Elizabeth Webb,
Thomas K Weber,
Meredith Yeager,
Young I Yeom,
Seon-Hee Yim,
Hyang-Sook Yoo
[show abstract]
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ABSTRACT: 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.
Human Mutation 05/2009; 30(4):496-510. · 5.69 Impact Factor
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Jim Kaput,
Richard G.H. Cotton,
Lauren Hardman,
Michael Watson,
Aida I. Al Aqeel,
Jumana Y. Al-Aama,
Fahd Al-Mulla,
Santos Alonso,
Stefan Aretz,
Arleen D. Auerbach, [......],
Mollie Ullman-Cullere,
Joji Utsunomiya,
Henk J. van Kranen,
Mauno Vihinen,
Elizabeth Webb,
Thomas K. Weber,
Meredith Yeager,
Young I. Yeom,
Seon-Hee Yim,
Hyang-Sook Yoo
[show abstract]
[hide abstract]
ABSTRACT: 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. Hum Mutat 30, 496–510, 2009. © 2009 Wiley-Liss, Inc.
Human Mutation 01/2009; 30(4):496 - 510. · 5.69 Impact Factor
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John Burn,
D Timothy Bishop,
Jukka-Pekka Mecklin,
Finlay Macrae, Gabriela Möslein,
Sylviane Olschwang,
Marie-Luise Bisgaard,
Raj Ramesar,
Diana Eccles,
Eamonn R Maher, [......],
Lucy Side,
Huw J W Thomas,
Rodney J Scott,
Malcolm Dunlop,
Gail Barker,
Faye Elliott,
Jeremy R Jass,
Ricardo Fodde,
Henry T Lynch,
John C Mathers
[show abstract]
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ABSTRACT: Observational and epidemiologic data indicate that the use of aspirin reduces the risk of colorectal neoplasia; however, the effects of aspirin in the Lynch syndrome (hereditary nonpolyposis colon cancer) are not known. Resistant starch has been associated with an antineoplastic effect on the colon.
In a randomized, placebo-controlled trial, we used a two-by-two design to investigate the effects of aspirin, at a dose of 600 mg per day, and resistant starch (Novelose), at a dose of 30 g per day, in reducing the risk of adenoma and carcinoma among persons with the Lynch syndrome.
Among 1071 persons in 43 centers, 62 were ineligible to participate in the study, 72 did not enter the study, and 191 withdrew from the study. These three categories were equally distributed across the study groups. Over a mean period of 29 months (range, 7 to 74), colonic adenoma or carcinoma developed in 141 participants. Of 693 participants randomly assigned to receive aspirin or placebo, neoplasia developed in 66 participants receiving aspirin (18.9%), as compared with 65 receiving placebo (19.0%) (relative risk, 1.0; 95% confidence interval [CI], 0.7 to 1.4). There were no significant differences between the two groups with respect to the development of advanced neoplasia (7.4% and 9.9%, respectively; P=0.33). Among the 727 participants receiving resistant starch or placebo, neoplasia developed in 67 participants receiving starch (18.7%), as compared with 68 receiving placebo (18.4%) (relative risk, 1.0; 95% CI, 0.7 to 1.4). Advanced adenomas and colorectal cancers were evenly distributed in the two groups. The prevalence of serious adverse events was low, and the events were evenly distributed.
The use of aspirin, resistant starch, or both for up to 4 years has no effect on the incidence of colorectal adenoma or carcinoma among carriers of the Lynch syndrome. (Current Controlled Trials number, ISRCTN59521990.)
New England Journal of Medicine 01/2009; 359(24):2567-78. · 53.30 Impact Factor
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Richard G H Cotton,
Arleen D Auerbach,
Myles Axton,
Carol Isaacson Barash,
Samuel F Berkovic,
Anthony J Brookes,
John Burn,
Garry Cutting,
Johan T den Dunnen,
Paul Flicek, [......],
Carolyn S Richards,
Daniela Seminara,
Timothy D Smith,
María-Jesús Sobrido,
Jan Helge Solbakk,
Rudolph E Tanzi,
Sean V Tavtigian,
Graham R Taylor,
Joji Utsunomiya,
Michael Watson
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ABSTRACT: An ambitious plan to collect, curate, and make accessible information on genetic variations affecting human health is beginning to be realized.
Science 12/2008; 322(5903):861-2. · 31.20 Impact Factor
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Annelie Liljegren,
Gail Barker,
Faye Elliott,
Lucio Bertario,
Marie Luise Bisgaard,
Diana Eccles,
Gareth Evans,
Finlay Macrae,
Eamonn Maher,
Annika Lindblom,
Samuel Rotstein,
Bo Nilsson,
Jukka-Pekka Mecklin, Gabriela Möslein,
Jeremy Jass,
Riccardo Fodde,
John Mathers,
John Burn,
D Timothy Bishop
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[hide abstract]
ABSTRACT: To determine the prevalence of adenomatous and hyperplastic polyps in a large cohort of individuals with a germline mutation in a mismatch repair (MMR) gene, the major genetic determinant of hereditary nonpolyposis colorectal cancer (HNPCC). These prevalences have been estimated previously in smaller studies, and the results have been found to be variable.
Colorectal Adenoma/Carcinoma Prevention Programme 2 trial is a chemoprevention trial in people classified as having HNPCC. The 695 patients with a proven germline MMR mutation and documented screening history before the chemoprevention study were the focus of this study. The number, histology, size, and location of polyps found at the participants' first ever colonoscopy were analyzed in a cross-sectional study.
Seventy-four patients (10.6%) were found to have at least one adenoma at first colonoscopy, whereas 37 (5.3%) had at least one hyperplastic polyp. The frequency of an adenoma at first colonoscopy increased from 5.0% (95% CI, 2.8% to 8.3%) in patients younger than 35 years old to 18.9% (95% CI, 9.4% to 32.0%) in patients age at least 55 years (P = .0001 for trend). No such trend was observed for hyperplastic polyps. No sex differences were found for either type of polyp. A marginal association was found between the co-occurrence of adenomas and hyperplastic polyps. Adenomas tended to be more proximally distributed through the colon, whereas hyperplastic polyps tended to be located in the distal colon.
Adenoma prevalence increases with age among MMR mutation carriers, whereas hyperplastic polyp prevalence is consistent. No sex differences were observed for either type of lesion.
Journal of Clinical Oncology 08/2008; 26(20):3434-9. · 18.37 Impact Factor
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ABSTRACT: Expression profiling is a well established tool for the genome-wide analysis of human cancers. However, the high sensitivity of this approach combined with the well known cellular and molecular heterogeneity of cancer often result in extremely complex expression signatures that are difficult to interpret functionally. The majority of sporadic colorectal cancers are triggered by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, leading to the constitutive activation of the Wnt/beta-catenin signaling pathway and formation of adenomas. Despite this common genetic basis, colorectal cancers are very heterogeneous in their degree of differentiation, growth rate, and malignancy potential. Here, we applied a cross-species comparison of expression profiles of intestinal polyps derived from hereditary colorectal cancer patients carrying APC germline mutations and from mice carrying a targeted inactivating mutation in the mouse homologue Apc. This comparative approach resulted in the establishment of a conserved signature of 166 genes that were differentially expressed between adenomas and normal intestinal mucosa in both species. Functional analyses of the conserved genes revealed a general increase in cell proliferation and the activation of the Wnt/beta-catenin signaling pathway. Moreover, the conserved signature was able to resolve expression profiles from hereditary polyposis patients carrying APC germline mutations from those with bi-allelic inactivation of the MYH gene, supporting the usefulness of such comparisons to discriminate among patients with distinct genetic defects.
American Journal Of Pathology 06/2008; 172(5):1363-80. · 4.89 Impact Factor
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Richard G H Cotton,
Arleen D Auerbach,
Myles Axton,
Carol Isaacson Barash,
Samuel F Berkovic,
Anthony J Brookes,
John Burn,
Garry Cutting,
Johan T Den,
Paul Flicek, [......],
S Rajkumar,
Carolyn S Richards,
Daniela Seminara,
Timothy D Smith,
Jan Helge Solbakk,
Rudolph E Tanzi,
Sean V Tavtigian,
Graham R Taylor,
Joji Utsunomiya,
Michael Watson
Science. 01/2008; 322(5903):861-862.
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Nicholas Hearle,
Valérie Schumacher,
Fred H Menko,
Sylviane Olschwang,
Lisa A Boardman,
Johan J P Gille,
Josbert J Keller,
Anne Marie Westerman,
Rodney J Scott,
Wendy Lim, [......],
G Johan A Offerhaus,
Felix W M de Rooij,
J H Paul Wilson,
Anika Hansmann, Gabriela Möslein,
Brigitte Royer-Pokora,
Tilman Vogel,
Robin K S Phillips,
Allan D Spigelman,
Richard S Houlston
[show abstract]
[hide abstract]
ABSTRACT: Although an increased cancer risk in Peutz-Jeghers syndrome is established, data on the spectrum of tumors associated with the disease and the influence of germ-line STK11/LKB1 (serine/threonine kinase) mutation status are limited.
We analyzed the incidence of cancer in 419 individuals with Peutz-Jeghers syndrome, and 297 had documented STK11/LKB1 mutations.
Ninety-six cancers were found among individuals with Peutz-Jeghers syndrome. The risk for developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 2%, 5%, 17%, 31%, 60%, and 85%, respectively. The most common cancers represented in this analysis were gastrointestinal in origin, gastroesophageal, small bowel, colorectal, and pancreatic, and the risk for these cancers at ages 30, 40, 50, and 60 years was 1%, 9%, 15%, and 33%, respectively. In women with Peutz-Jeghers syndrome, the risk of breast cancer was substantially increased, being 8% and 31% at ages 40 and 60 years, respectively. Kaplan-Meier analysis showed that cancer risks were similar in Peutz-Jeghers syndrome patients with identified STK11/LKB1 mutations and those with no detectable mutation (log-rank test of difference chi2 = 0.62; 1 df; P = 0.43). Furthermore, the type or site of STK11/LKB1 mutation did not significantly influence cancer risk.
The results from our study provide quantitative information on the spectrum of cancers and risks of specific cancer types associated with Peutz-Jeghers syndrome.
Clinical Cancer Research 06/2006; 12(10):3209-15. · 7.74 Impact Factor
