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Epidemiological Studies on Peutz-Jeghers Syndrome & Lynch Syndrome

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Epidemiological Studies on Peutz-Jeghers Syndrome & Lynch Syndrome Hereditary colorectal cancer syndromes Epidemiological studies on Peutz-Jeghers syndrome & Lynch syndrome Margot van Lier Colofon ISBN 978-94-6169-031-9 Financial support for printing this thesis was kindly given by Zambon Nederland BV, ABBOTT Immunology, Tramedico, Dr. Falk Pharma Benelux BV, Bayer BV, Merck Sharp & Dohme BV, PENTAX Nederland BV, Gerrit Blaauw fonds, J.E. Jurriaanse Stichting, de Nederlandse Vereni- ging voor Gastroenterologie, the department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, and the Erasmus University, Rotterdam Lay out: Optima Grafische Communicatie, Rotterdam, The Netherlands Printed by: Optima Grafische Communicatie, Rotterdam, The Netherlands Coverdesign, -concept and -illustration: Stan W.H. van Lier http://www.stanvanlier.nl [email protected] © Margot G. F. van Lier, The Netherlands 2011 All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means, without prior permission of the author. Hereditary colorectal cancer syndromes: Epidemiological studies on Peutz-Jeghers syndrome & Lynch syndrome Erfelijke colorectaal kanker syndromen: Epidemiologische studies naar het Peutz-Jeghers syndroom en het Lynch syndroom Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.G. Schmidt en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op 25 maart 2011 om 11.30 uur door Margot Gerarda Franka van Lier geboren te Nijmegen ProMotiecommissiE Promotoren: Prof.dr. E.J. Kuipers Prof.dr. E.W. Steyerberg Overige leden: Prof.dr. M.J. Bruno Prof.dr. J.F. Lange Prof.dr. E.M.H. Mathus-Vliegen Copromotoren: Dr. M.E. van Leerdam Dr. A. Wagner ContEnts Chapter 1. Introduction and outline of the thesis 7 Part i: Peutz-Jeghers syndrome Chapter 2. High cancer risk in Peutz-Jeghers syndrome: A systematic review and 15 surveillance recommendations. Am J Gastroenterol Chapter 3. High cancer risk and increased mortality in patients with Peutz- 31 Jeghers syndrome. Gut Chapter 4. High cumulative risk of intussusception in patients with Peutz- 49 Jeghers syndrome: Time to update surveillance guidelines? Am J Gastroenterol Chapter 5. Endoscopic therapy of small-bowel polyps by double balloon 61 enteroscopy in patients with Peutz-Jeghers syndrome. GI Endoscopy Chapter 6. Quality of life and psychological distress in patients with Peutz- 73 Jeghers syndrome. Clin Genetics Chapter 7. Peutz-Jeghers syndrome and family planning: The attitude towards 87 prenatal diagnosis and preimplantation genetic diagnosis. Submitted Part II: Lynch syndrome Chapter 8. Review on the molecular diagnostics of Lynch syndrome: A central 101 role for the pathology laboratory. J Cell Mol Med Chapter 9. Underutilization of MSI analysis in colorectal cancer patients at high 131 risk for Lynch syndrome. Scand J Gastroenterol Chapter 10. Yield of routine molecular analyses in patients with colorectal cancer 141 ≤ 70 years to detect underlying Lynch syndrome. Manuscript in preparation Chapter 11. Prospective evaluation of molecular screening for Lynch syndrome 157 in patients with endometrial cancer ≤ 70 years. Manuscript in preparation Chapter 12. General discussion and conclusions 173 Summary 187 Samenvatting 191 Publications 197 PhD portfolio 199 Dankwoord 201 Curriculum Vitae 205 5 Introduction and outline of the 1thesis Introduction and outline of the thesis introduCtion Colorectal cancer (CRC) is the second most common malignancy among women after breast 1 Chapter cancer, and the third most common malignancy among men after lung and prostate cancer in the European Union.1 In the Netherlands, approximately 10000 cases are diagnosed each year.2 CRC is moreover associated with high mortality and ranks second to lung cancer as a cause of cancer-related mortality in Europe.1 CRC results from both genetic and environ- mental factors. Genetic factors are a major cause of disease in approximately 20% of CRC cases, with a spectrum ranging from ill-defined familial aggregation without a detectable disease-causing mutation (classified as familial CRC), to well-defined autosomal dominant inherited syndromes.3,4 The well-defined inherited cancer susceptibility syndromes are responsible for approxi- mately 5% of all CRC’s.5 These hereditary cancers represent a significant proportion of all CRC burden, especially since these cancers are often diagnosed at a young age. Hereditary CRC syndromes can be divided into syndromes with and without gastrointestinal polyposis (Table 1). The polyposis syndromes can be further subdivided according to the histology of the polyps; being either hamartomatous or adenomatous polyps. Lynch syndrome, responsible for approximately 3% of all CRCs, is the most common form of hereditary CRC, followed by familial adenomatous polyposis, accounting for nearly 1% of CRC cases. The hamartomatous polyposis syndromes including Peutz-Jeghers syndrome, are rare and together account for less than 1% of all CRCs.6,7 Recognition of hereditary CRC syndromes is of utmost importance in order to provide ad- equate counseling and surveillance to patients and family members at risk. New insights into clinical as well as molecular and genetic characteristics are important to decrease morbidity and mortality associated with these syndromes. Hereditary CRC syndromes that could earlier only be defined on the basis of clinical features and occurrence in pedigrees, can now be table 1. Hereditary colorectal cancer syndromes.8,9 syndrome Gene non-polyposis Lynch syndrome (formerly known as HNPCC) MMR genes Polyposis Adenomatous polyposis - Familial adenomatous polyposis (FAP) / APC Attenuated Familial adenomatous polyposis (aFAP) - MUTYH-associated polyposis (MAP) MYH (biallelic) Hamartomatous polyposis - Peutz-Jeghers syndrome STK11 (LKB1) - Juvenile polyposis SMAD4, PTEN - Cowden syndrome PTEN MMR = Mismatch repair genes, including MLH1, MSH2, MSH6 and PMS2. HNPCC = Hereditary non-polyposis colorectal cancer. 9 Chapter 1 defined on the basis of molecular and genetic characteristics.10 Hereby, dedicated treatment and surveillance can be offered to patients and affected family members. On the other hand, non-carriers can be reassured and dismissed from burdensome surveillance programs. This thesis will focus on two of the abovementioned syndromes: Peutz-Jeghers syndrome and Lynch syndrome. These two genetic cancer susceptibility syndromes are associated with an elevated gastrointestinal cancer risk concerning predominantly CRC, as well as an elevated risk for extra-gastrointestinal malignancies Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant inherited disorder characterized by gastrointestinal hamartomas and mucocutaneous pigmentations.11,12 Jan Peutz, a Dutch physician, was the first to recognize the combination of intestinal polyposis, mucocutaneous pigmentation, and heredity in 1921.11 The hamartomas may cause complications already early in life, including anaemia, bleeding, and intussusception. In 1998 it was discovered that germline mutations in the STK11 gene (Serine Threonine Kinase 11) cause PJS.13,14 The STK11 gene, also known as LKB1 gene, has been designated as a tumor suppressor gene.15 Indeed, it has been recognized that PJS is associated with an increased risk for the development of gastrointestinal and extra-gastrointestinal malignancies. However, as PJS is a rare disorder, it has not been studied as extensively as other hereditary cancer syndromes. The clinical man- agement of PJS patients is thus hampered by a lack of detailed epidemiological and clinical data. Accurate data on for example the intussusception and cancer risk are missing. In order to gain more insight into PJS and to improve counseling and surveillance of PJS patients, we evaluated a large and unique cohort of Dutch PJS patients. We determined cancer, mortality and intussusception risks, and we furthermore studied quality of life, genetic test uptake and decisions regarding family planning. Lynch syndrome (LS) is another and more common autosomal dominant inherited disor- der, not only responsible for 3% of all CRCs6,16, but also for 2% of all endometrial cancers.17 The cancers are generally diagnosed at a young age and multiple synchronous or metachronous malignancies occur in 30% of the patients.5,18,19 In addition, LS is associated with an increased risk for the development of other malignancies including carcinomas of the small intestine, stomach, pancreas and biliary tract, ovaries, brain, upper urinary tract, and skin. LS is caused by germline mutations in one of the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. These mutations lead to microsatellite instability (MSI) in tumor DNA. MSI is the molecular hallmark of LS, and can be detected in more than 90% of all LS associated cancers.20 Previous studies have provided many data on LS, including data on LS-associated cancer risks, the value of colonoscopic surveillance as well as molecular and genetic characteristics. However, one of the most challenging problems regarding LS is its early detection. Early detection of LS is of great importance, particularly in pre-symptomatic mutation carriers but also for symptomatic mutation carriers (i.e. patients with CRC) considering the high risk of metachronous malignancies, since colonoscopic surveillance has proven to reduce CRC morbidity and mortality by 65-70%.21-23 Furthermore, prophylactic surgery may prevent 10 Introduction and outline of the thesis endometrial
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