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1. T.02.1 DELPHI INITIATIVE FOR EARLY-ONSET COLORECTAL CANCER (DIRECT): INTERNATIONAL MANAGEMENT GUIDELINES

Author

Cavestro, G.M., primary, Mannucci, A., additional, Balaguer, F., additional, Heather, H., additional, Kupfer, S., additional, Repici, A., additional, Sartore-Bianchi, A., additional, Seppala, T., additional, Valentini, V., additional, Boland, C., additional, Brand, R., additional, Buffart, T., additional, Burke, C., additional, Caccialanza, R., additional, Cannizzaro, R., additional, Cascinu, S., additional, Cercek, A., additional, Crosbie, E., additional, Danese, S., additional, Dekker, E., additional, Daca-Alvarez, M., additional, Deni, F., additional, Latchford, A., additional, Liska, D., additional, Lynch, P., additional, Malesci, A., additional, Mauri, G., additional, Meldolesi, E., additional, Pal, M., additional, Monahan, K., additional, Moslein, G., additional, Murphy, C., additional, Nass, K., additional, Ng, K., additional, Oliani, C., additional, Papaleo, E., additional, Patel, S., additional, Puzzono, M., additional, Remo, A., additional, Ricciardiello, L., additional, Ripamonti, C., additional, Siena, S., additional, Singh, S., additional, Stadler, Z., additional, Stanich, P., additional, Syngal, S., additional, Turi, S., additional, Urso, E., additional, Valle, L., additional, Vanni, V., additional, Vilar, E., additional, Vitellaro, M., additional, You, Y., additional, Yurgelun, M., additional, Zuppardo, R., additional, and Stoffel, E., additional

Published
2023
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2. Delphi initiative for early-onset colorectal cancer (DIRECt). International Management Guidelines

Author

Cavestro Giulia, M, Mannucci, A, Balaguer, F, Hampel, H, Kupfer, SS, Repici, A, Sartore-Bianchi, A, Seppälä Toni, T, Valentini, V, Boland Clement, R, Brand, RE, Buffart, TE, Burke, CA, Caccialanza, R, Cannizzaro, R, Cascinu, S, Cercek, A, Crosbie, EJ, Danese, S, Dekker, E, Daca-Alvarez, M, Deni, F, Dominguez-Valentin, M, Eng, C, Goel, A, Guillem Josè, G, Houwen, B, Kahi, C, Kalady, MF, Kastrinos, F, Kühn, F, Laghi, L, Latchford, A, Liska, D, Lynch, P, Malesci, A, Mauri, G, Meldolesi, E, Møller, P, Monahan, KJ, Moslein, G, Murphy, CC, Nass, K, Ng, K, Oliani, C, Papaleo, E, Patel, SG, Puzzono, M, Remo, A, Ricciardiello, L, Ripamonti Carla, I, Siena, S, Singh, SK, Stadler, ZK, Stanich, PP, Syngal, S, Turi, S, Urso Emanuele, D, Valle, L, Vanni Valeria, S, Vilar, E, Vitellaro, M, You, Y-QN, Yurgelun, MB, Zuppardo Raffaella, A, Stoffel, EM, Associazione Italiana Familiarità Ereditarietà Tumori, Collaborative Group of the Americas on Inherited Gastrointestinal Cancers, European Hereditary Tumor Group, International Society for Gastrointestinal Hereditary Tumours, Tampere University, Clinical Medicine, Department of Gastroenterology, Gastroenterology and Hepatology, CCA - Cancer Treatment and Quality of Life, CCA - Imaging and biomarkers, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, and Internal medicine

Subjects
Colorectal Cancer, 50 Years, Clinical, Hepatology, Settore MED/06 - Oncologia Medica, 3122 Cancers, Gastroenterology, Young, Recommendation
Abstract

BACKGROUND & AIMS: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. METHODS: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. RESULTS: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. CONCLUSIONS: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC. publishedVersion

Published
2022

3. Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database (Genetics in Medicine, (2020), 22, 1, (15-25), 10.1038/s41436-019-0596-9)

Author

Dominguez-Valentin M., Sampson J. R., Seppala T. T., ten Broeke S. W., Plazzer J. -P., Nakken S., Engel C., Aretz S., Jenkins M. A., Sunde L., Bernstein I., Capella G., Balaguer F., Thomas H., Evans D. G., Burn J., Greenblatt M., Hovig E., de Vos tot Nederveen Cappel W. H., Sijmons R. H., Bertario L., Tibiletti M. G., Cavestro G. M., Lindblom A., Della Valle A., Lopez-Kostner F., Gluck N., Katz L. H., Heinimann K., Vaccaro C. A., Buttner R., Gorgens H., Holinski-Feder E., Morak M., Holzapfel S., Huneburg R., Knebel Doeberitz M., Loeffler M., Rahner N., Schackert H. K., Steinke-Lange V., Schmiegel W., Vangala D., Pylvanainen K., Renkonen-Sinisalo L., Hopper J. L., Win A. K., Haile R. W., Lindor N. M., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J. C., Thibodeau S. N., Wadt K., Therkildsen C., Okkels H., Ketabi Z., Moreira L., Sanchez A., Serra-Burriel M., Pineda M., Navarro M., Blanco I., Green K., Lalloo F., Crosbie E. J., Hill J., Denton O. G., Frayling I. M., Rodland E. A., Vasen H., Mints M., Neffa F., Esperon P., Alvarez K., Kariv R., Rosner G., Pinero T. A., Gonzalez M. L., Kalfayan P., Tjandra D., Winship I. M., Macrae F., Moslein G., Mecklin J. -P., Nielsen M., Moller P., Dominguez-Valentin, M., Sampson, J. R., Seppala, T. T., ten Broeke, S. W., Plazzer, J. -P., Nakken, S., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., Hovig, E., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Bertario, L., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Della Valle, A., Lopez-Kostner, F., Gluck, N., Katz, L. H., Heinimann, K., Vaccaro, C. A., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., Knebel Doeberitz, M., Loeffler, M., Rahner, N., Schackert, H. K., Steinke-Lange, V., Schmiegel, W., Vangala, D., Pylvanainen, K., Renkonen-Sinisalo, L., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Wadt, K., Therkildsen, C., Okkels, H., Ketabi, Z., Moreira, L., Sanchez, A., Serra-Burriel, M., Pineda, M., Navarro, M., Blanco, I., Green, K., Lalloo, F., Crosbie, E. J., Hill, J., Denton, O. G., Frayling, I. M., Rodland, E. A., Vasen, H., Mints, M., Neffa, F., Esperon, P., Alvarez, K., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Tjandra, D., Winship, I. M., Macrae, F., Moslein, G., Mecklin, J. -P., Nielsen, M., and Moller, P.

Abstract

The original version of this Article did not contain details of Dutch Cancer Society (DCS) funding (grant number UL 2017-8223) in the Acknowledgements section. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2020

4. Peutz-Jeghers syndrome: a systematic review and recommendations for management

Author

Beggs, A.D., Latchford, A.R., Vasen, H.F.A., Moslein, G., Alonso, A., Aretz, S., Bertario, L., Blanco, I., Bulow, S., Burn, J., Capella, G., Colas, C., Friedl, W., Moller, P., Hes, F.J., Jarvinen, H., Mecklin, J.-P., Nagengast, F.M., Parc, Y., Phillips, R.K.S., Hyer, W., Ponz de Leon, M., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Tejpar, S., Thomas, H.J.W., Wijnen, J.T., Clark, S.K., and Hodgson, S.V.

Subjects
Peutz-Jeghers syndrome -- Diagnosis, Peutz-Jeghers syndrome -- Care and treatment, Peutz-Jeghers syndrome -- Development and progression, Peutz-Jeghers syndrome -- Risk factors, Medical literature -- Analysis, Health
Published
2010

5. Analysis in the Prospective Lynch Syndrome Database identifies sarcoma as part of the Lynch syndrome tumor spectrum

Author

Dominguez-Valentin M., Sampson J. R., Moller P., Seppala T. T., Plazzer J. -P., Nakken S., Engel C., Aretz S., Jenkins M. A., Sunde L., Bernstein I., Capella G., Balaguer F., Thomas H., Evans D. G., Burn J., Greenblatt M., Hovig E., Nielsen M., de Vos tot Nederveen Cappel W. H., Sijmons R. H., Bertario L., Tibiletti M. G., Cavestro G. M., Lindblom A., Valle A. D., Lopez-Kostner F., Gluck N., Katz L. H., Heinimann K., Vaccaro C. A., Buttner R., Gorgens H., Holinski-Feder E., Morak M., Holzapfel S., Huneburg R., von Knebel Doeberitz M., Loeffler M., Rahner N., Weitz J., Steinke-Lange V., ten Broeke S. W., Schmiegel W., Vangala D., Pylvanainen K., Renkonen-Sinisalo L., Hopper J. L., Win A. K., Haile R. W., Lindor N. M., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J. C., Thibodeau S. N., Jensen L. H., Madsen M. B., Kroldrup L., Nilbert M., Moreira L., Sanchez A., Serra-Burriel M., Pineda M., Navarro M., Vidal J. B., Blanco I., Green K., Lalloo F., Crosbie E. J., Hill J., Denton O. G., Rodland E. A., Vasen H., Mints M., Neffa F., Esperon P., Alvarez K., Kariv R., Rosner G., Pinero T. A., Gonzalez M. L., Kalfayan P., Tjandra D., Winship I. M., Macrae F., Moslein G., Mecklin J. -P., Dominguez-Valentin, M., Sampson, J. R., Moller, P., Seppala, T. T., Plazzer, J. -P., Nakken, S., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., Hovig, E., Nielsen, M., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Bertario, L., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Valle, A. D., Lopez-Kostner, F., Gluck, N., Katz, L. H., Heinimann, K., Vaccaro, C. A., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., von Knebel Doeberitz, M., Loeffler, M., Rahner, N., Weitz, J., Steinke-Lange, V., ten Broeke, S. W., Schmiegel, W., Vangala, D., Pylvanainen, K., Renkonen-Sinisalo, L., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Jensen, L. H., Madsen, M. B., Kroldrup, L., Nilbert, M., Moreira, L., Sanchez, A., Serra-Burriel, M., Pineda, M., Navarro, M., Vidal, J. B., Blanco, I., Green, K., Lalloo, F., Crosbie, E. J., Hill, J., Denton, O. G., Rodland, E. A., Vasen, H., Mints, M., Neffa, F., Esperon, P., Alvarez, K., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Tjandra, D., Winship, I. M., Macrae, F., Moslein, G., and Mecklin, J. -P.

Subjects
Male, Adult, Oncology, Cancer Research, 2019-20 coronavirus outbreak, medicine.medical_specialty, sarcoma, Databases, Factual, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Sarcoma/diagnosis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Medicine, Aged, business.industry, Sarcoma, Syndrome, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, MSH2, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis, Female, 030211 gastroenterology & hepatology, business
Published
2020

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

Author

Vasen, H.F.A., Moslein, G., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Blanco, I., Bulow, S., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I., Friedl, W., Hes, F.J., Hodgson, S., Jarvinen, H., Mecklin, J.-P., Moller, P., Myrhoi, T., Nagengast, F.M., Parc, Y., Phillips, R., Clark, S.K., Ponz de Leon, M., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Tejpar, S., Thomas, H.J.W., and Wijnen, J.

Subjects
Polyposis, Familial -- Care and treatment, Practice guidelines (Medicine) -- Evaluation, Colorectal cancer -- Risk factors, Colorectal cancer -- Prevention, Health
Published
2008

7. No Difference in Colorectal Cancer Incidence or Stage at Detection by Colonoscopy Among 3 Countries With Different Lynch Syndrome Surveillance Policies

Author

Engel, C., Vasen, H.F., Seppala, T., Aretz, S., Bigirwamungu-Bargeman, M., Boer, S.Y. de, Bucksch, K., Buttner, R., Holinski-Feder, E., Holzapfel, S., Huneburg, R., Jacobs, M.A.J.M., Jarvinen, H., Kloor, M., Doeberitz, M.V., Koornstra, J.J., Kouwen, M. van, Langers, A.M., Meeberg, P.C. van de, Morak, M., Moslein, G., Nagengast, F.M., Pylvanainen, K., Rahner, N., Renkonen-Sinisalo, L., Sanduleanu, S., Schackert, H.K., Schmiegel, W., Schulmann, K., Steinke-Lange, V., Strassburg, C.P., Vecht, J., Verhulst, M.L., Cappel, W.D.T.N., Zachariae, S., Mecklin, J.P., Loeffler, M., German HNPCC Consortium, Dutch Lynch Syndrome, Finnish Lynch Syndrome Registry, Gastroenterology and hepatology, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Male, Colorectal cancer, Colonoscopy, FAMILIES, 0302 clinical medicine, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Stage (cooking), Tumor, medicine.diagnostic_test, MISMATCH REPAIR DEFICIENCY, Incidence, Incidence (epidemiology), Gastroenterology, Middle Aged, Lynch syndrome, 3. Good health, PREVALENCE, POLYPOSIS, 030220 oncology & carcinogenesis, CARCINOMAS, Female, 030211 gastroenterology & hepatology, Hereditary Colon Cancer, Colorectal Neoplasms, Adult, medicine.medical_specialty, HNPCC, Genetic Risk Factor, suolistosyövät, perinnöllinen alttius, INTERVAL CANCERS, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Internal medicine, ADENOMAS, medicine, Humans, Lynchin oireyhtymä, neoplasms, paksusuolisyöpä, Neoplasm Staging, Proportional Hazards Models, seulontatutkimus, Hepatology, Proportional hazards model, business.industry, MUTATIONS, MORTALITY, Interval, ta3122, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Confidence interval, digestive system diseases, business, Index Colonoscopy
Abstract

BACKGROUND & AIMS: Patients with Lynch syndrome are at high risk for developing colorectal cancer (CRC). Regular colonoscopic surveillance is recommended, but there is no international consensus on the appropriate interval. We investigated whether shorter intervals are associated with lower CRC incidence and detection at earlier stages by comparing the surveillance policies in Germany, which evaluates patients by colonoscopy annually, in the Netherlands (patients evaluated at 1-2-year intervals), and Finland (patients evaluated at 2-3-year intervals). METHODS: We collected data from 16,327 colonoscopic examinations (conducted from 1984 through 2015) of 2747 patients with Lynch syndrome (pathogenic variants in the MLH1, MSH2, or MSH6 genes) from the German HNPCC Consortium, the Dutch Lynch Syndrome Registry, and the Finnish Lynch Syndrome Registry. Our analysis included 23,309 person-years of cumulative observation time. Time from the index colonoscopy to incident CRC or adenoma was analyzed using the Kaplan-Meier method; groups were compared using the log-rank test. We performed multivariable Cox regression analyses to identify factors associated with CRC risk (diagnosis of CRC before the index colonoscopy, sex, mutation, age, and presence of adenoma at the index colonoscopy). RESULTS: The 10-year cumulative CRC incidence ranged from 4.1% to 18.4% in patients with low-and high-risk profiles, respectively, and varied with age, sex, mutation, and prior detection of CRC or adenoma. Observed colonoscopy intervals were largely in accordance with the country-specific recommendations. We found no significant differences in cumulative CRC incidence or CRC stage at detection among countries. There was no significant association between CRC stage and[GRAPHICS]time since last colonoscopy. CONCLUSIONS: We did not find a significant reduction in CRC incidence or stage of detection in Germany (annual colonoscopic surveillance) than in countries with longer surveillance intervals (the Netherlands, with 1-2-year intervals, and Finland, with 2-3-year intervals). Overall, we did not find a significant association of the interval with CRC risk, although age, sex, mutation, and prior neoplasia were used to individually modify colonoscopy intervals. Studies are needed to develop and validate risk-adapted surveillance strategies and to identify patients who benefit from shorter surveillance intervals.

Published
2018

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

Author

Vasen, H.F.A., Moslein, G., Alonso, A., Bernstein, I., Bertario, L., Blanco, I., Burn, J., Capella, G., Engel, C., Frayling, I., Friedl, W., Hes, F.J., Hodgson, S., Mecklin, J.-P., Moller, P., Nagengast, F., Parc, Y., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., and Wijnen, J.

Subjects
Colorectal cancer -- Care and treatment, Colorectal cancer -- Genetic aspects, Practice guidelines (Medicine) -- Evaluation, Cancer -- Diagnosis, Cancer -- Standards, Health
Published
2007

9. STK11 genotyping and cancer risk in Peutz-Jeghers syndrome

Author

Schumacher, V., Vogel, T., Leube, B., Driemel, C., Goecke, T., Moslein, G., and Royer-Pokora, B.

Subjects
Oncology, Experimental -- Reports, Cancer -- Risk factors, Cancer -- Genetic aspects, Cancer -- Research, Chromosome abnormalities -- Research, Chromosome abnormalities -- Risk factors, Cancer -- Reports, Health
Published
2005

10. Deciphering the Colon Cancer Genes-Report of the InSiGHT-Human Variome Project Workshop, UNESCO, Paris 2010

Author

Kohonen-Corish, M.R.J., Macrae, F., Genuardi, M., Aretz, S., Bapat, B., Bernstein, I.T., Burn, J., Cotton, R.G.H., Dunnen, J.T. den, Frebourg, T., Greenblatt, M.S., Hofstra, R., Holinski-Feder, E., Lappalainen, I., Lindblom, A., Maglott, D., Moller, P., Morreau, H., Moslein, G., Sijmons, R., Spurdle, A.B., Tavtigian, S., Tops, C.M.J., Weber, T.K., Wind, N. de, Woods, M.O., Contributors InSiGHT-HVP Workshop, Faculteit Medische Wetenschappen/UMCG, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
MISMATCH-REPAIR GENES, COLORECTAL-CANCER, SEQUENCE VARIANTS, CLASSIFICATION, MUTATIONS, DATABASE, MLH1, Colorectal cancer, Human Variome Project, Library science, HNPCC, Biology, Settore MED/03 - GENETICA MEDICA, Data submission, Bioinformatics, Genetics, medicine, Pilot program, cancer, Pathogenicity, Genetics (clinical), colon, Cancer, medicine.disease, Tumor Pathology, variant, HVP, InSiGHT
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. Hum Mutat 32: 491-494, 2011. (C) 2011 Wiley-Liss, Inc.

Published
2011

11. Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families

Author

Friedl, W, Caspari, R, Sengteller, M, Uhlhaas, S, Lamberti, C, Jungck, M, Kadmon, M, Wolf, M, Fahnenstich, J, Gebert, J, Moslein, G, Mangold, E, and Propping, P

Subjects
Polyposis, Familial -- Genetic aspects, Gene mutations -- Analysis -- Genetic aspects, Diseases -- Genetic aspects -- United States, Gastrointestinal diseases -- Genetic aspects, Health, Analysis, Genetic aspects
Abstract

Abstract Background and aims--In familial adenomatous polyposis (FAP), correlations between site of mutation in the adenomatous polyposis coil (APC) gene and severity of colonic polyposis or extracolonic manifestations are well [...]

Published
2001

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

Author

Vasen, H.F.A., Blanco, I., Aktan-Collan, K., Gopie, J.P., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I.M., Genuardi, M., Heinimann, K., Hes, F.J., Hodgson, S.V., Karagiannis, J.A., Lalloo, F., Lindblom, A., Mecklin, J.P., Moller, P., Myrhoj, T., Nagengast, F.M., Parc, Y., Leon, M.P. de, Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Sijmons, R.H., Tejpar, S., Thomas, H.J.W., Rahner, N., Wijnen, J.T., Jarvinen, H.J., Moslein, G., Mallorca Grp, Clinical sciences, and Medical Genetics

Subjects
Male, Settore MED/03 - GENETICA MEDICA, 0302 clinical medicine, Public health surveillance, QUALITY-OF-LIFE, Risk Factors, Neoplasms, Medicine, Public Health Surveillance, Lynch syndrome (HNPCC, Gastroenterology, NONPOLYPOSIS COLORECTAL-CANCER, MSH2 MUTATION CARRIERS, Cost-effectiveness analysis, Colonoscopy, Middle Aged, Lynch syndrome, 3. Good health, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Female, Systematic search, Adult, medicine.medical_specialty, MEDLINE, BLADDER-CANCER, COST-EFFECTIVENESS ANALYSIS, guidelines, HNPCC, RC0254, 03 medical and health sciences, Young Adult, Quality of life (healthcare), Translational research [ONCOL 3], Humans, PROPHYLACTIC SALPINGO-OOPHORECTOMY, Aged, Gynecology, business.industry, Endometrial cancer, DRAKE HEALTH REGISTRY, Colonoscopy/standards, ENDOMETRIAL CANCER, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, BODY-MASS INDEX, MSH6, Family medicine, MISMATCH-REPAIR GENES, Colorectal Neoplasms, Hereditary Nonpolyposis/complications, business, Neoplasms/diagnosis
Abstract

Lynch syndrome (LS) is characterised by the\ud development of colorectal cancer, endometrial cancer\ud and various other cancers, and is caused by a mutation\ud in one of the mismatch repair genes: MLH1, MSH2,\ud MSH6 or PMS2. In 2007, a group of European experts\ud (the Mallorca group) published guidelines for the clinical\ud management of LS. Since then substantial new\ud information has become available necessitating an\ud update of the guidelines. In 2011 and 2012 workshops\ud were organised in Palma de Mallorca. A total of 35\ud specialists from 13 countries participated in the\ud meetings. The first step was to formulate important\ud clinical questions. Then a systematic literature search\ud was performed using the Pubmed database and manual\ud searches of relevant articles. During the workshops the\ud outcome of the literature search was discussed in detail.\ud The guidelines described in this paper may be helpful for\ud the appropriate management of families with LS.\ud Prospective controlled studies should be undertaken to\ud improve further the care of these families.

Published
2013

13. Surgical management of the duodenal manifestations of familial adenomatous polyposis

Author

Parc, Y, Mabrut, J. Y., Shields, C, Alonso, A, Aretz, S, Bertario, L, Burn, J, Capella, G, Colas, C, Clark, Sk, Frayling, I, Hes, Fj, Wijnen, J, Vasen, H, Hodgson, S, Nagengast, Fm, Moslein, G, PONZ DE LEON, Maurizio, Mecklin, Jp, Møller, P, Myrhøj, T, Stormorken, A, Tejpar, S., Clinical sciences, and Medical Genetics

Subjects
Adenoma, medicine.medical_specialty, Duodenum, medicine.medical_treatment, Neoplasm Recurrence, Local/etiology, Malignancy, Duodenal Neoplasms/surgery, Familial adenomatous polyposis, Duodenum/surgery, Duodenectomy, Pancreatectomy, Postoperative Complications, Duodenal Neoplasms, Translational research [ONCOL 3], medicine, Carcinoma, Humans, risk factors, Adenoma/surgery, Adenomatous Polyposis Coli, Duodenoscopy, Neoplasm Recurrence, Local, Randomized Controlled Trials as Topic, Risk Factors, Treatment Outcome, medicine.diagnostic_test, business.industry, Ampullectomy, medicine.disease, Pancreaticoduodenectomy, Endoscopy, Surgery, Pancreatectomy/methods, Adenomatous Polyposis Coli/surgery, Postoperative Complications/etiology, Duodenoscopy/methods, business
Abstract

Background Duodenal adenomas develop in patients with familial adenomatous polyposis, incurring a risk of carcinoma. When this risk is high, surgery is indicated. The choice of surgical treatment can be difficult as evidence-based data are lacking. Methods This is a systematic review of the literature on the non-medical management of duodenal lesions arising in the setting of familial adenomatous polyposis. Studies were identified through searching MEDLINE. Studies published between January 1965 and October 2009 were included. Data regarding number of subjects, complications, length of follow-up, recurrence rate and outcome were extracted. Results Transduodenal resection does not differ from an endoscopic approach in terms of recurrence. Ampullectomy has limited application as only papillary lesions are amenable to treatment in this manner. Duodenectomy with pancreas preservation is preferable to pancreaticoduodenectomy unless malignancy is present, or cannot be excluded. Conclusion Surgery should be reserved for advanced or malignant polyps.

Published
2011

14. A Randomized Placebo-Controlled Prevention Trial of Aspirin and/or Resistant Starch in Young People with Familial Adenomatous Polyposis

Author

Burn, J., Bishop, D.T., Chapman, P.D., Elliott, F., Bertario, L., Dunlop, M.G., Eccles, D., Ellis, A., Evans, D.G., Fodde, R., Maher, E.R., Moslein, G., Vasen, H.F.A., Coaker, J., Phillips, R.K.S., Bulow, S., Mathers, J.C., Int CAPP Consortium, and Pathology

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Adolescent, Colorectal cancer, Rectum, Placebo, Gastroenterology, Article, law.invention, Familial adenomatous polyposis, Young Adult, Randomized controlled trial, Double-Blind Method, SDG 3 - Good Health and Well-being, law, Internal medicine, medicine, Clinical endpoint, Humans, Child, Aspirin, large-bowel cancer chain fatty-acids colorectal-cancer cell-proliferation lynch syndrome dietary fiber butyrate risk neoplasia apoptosis, business.industry, Anti-Inflammatory Agents, Non-Steroidal, International Agencies, Starch, medicine.disease, Prognosis, digestive system diseases, Surgery, medicine.anatomical_structure, Oncology, Adenomatous Polyposis Coli, Relative risk, Drug Therapy, Combination, Female, business, medicine.drug
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 Prev Res; 4(5); 655–65. ©2011 AACR.

Published
2011

15. How to catch all those mutations--the report of the third Human Variome Project Meeting, UNESCO Paris, May 2010

Author

Kohonen-Corish, M.R.J., Al-Aama, J.Y., Auerbach, A.D., Axton, M., Barash, C.I., Bernstein, I., Beroud, C., Burn, J., Cunningham, F., Cutting, G.R., Dunnen, J.T. den, Greenblatt, M.S., Kaput, J., Katz, M., Lindblom, A., Macrae, F., Maglott, D., Moslein, G., Povey, S., Ramesar, R., Richards, S., Seminara, D., Sobrido, M.J., Tavtigian, S., Taylor, G., Vihinen, M., Winship, I., Cotton, R.G.H., Contributors Human Variome Project, HNPCC-register, Hvidovre Hospital, University of Copenhagen = Københavns Universitet (KU), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (JHU), Metabolic Unit, Dept Clinical Chemistry, University of Vermont College of Medicine, University of Vermont [Burlington], University of Massachusetts [Amherst] (UMass Amherst), University of Massachusetts System (UMASS), Department of Clinical Genetics, Karolinska University Hospital [Stockholm], Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, National Center for Biotechnology Information (NCBI), Dept of Genetics, Evolution and Environment [London] (UCL-GEE), University College of London [London] (UCL), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Fundacion Publica Galega de Medicina Xenomica, Fundación Pública Galega de Medicina Xenómica, Department of Oncological Sciences, University of Utah-Huntsman Cancer Institute, Imperial College London, Department of Experimental Medical Science, Lund University [Lund], University of Copenhagen = Københavns Universitet (UCPH), IFR3, and Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
education, Human Variome Project, Library science, Human genetic variation, Biology, computer.software_genre, Article, 03 medical and health sciences, 0302 clinical medicine, Health care, Genetics, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Data collection, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 3. Good health, Variome, Incentive, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, Sustainability, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, computer, Data integration
Abstract

International audience; 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.

Published
2010

17. No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

Author

Guy Rosner, Walter Hernán Pavicic, Claudia Perne, Carlos A. Vaccaro, Elke Holinski-Feder, Leticia Moreira, Wouter H. de Vos tot Nederveen Cappel, Stefan Aretz, Einar Andreas Rødland, Polly A. Newcomb, Karin Alvarez, Ariadna Sánchez, Lone Sunde, Wolff Schmiegel, Joan Brunet, Marc S. Greenblatt, Christina Therkildsen, Karl Heinimann, Lior H. Katz, Fiona Lalloo, Jürgen Weitz, Anna Lepistö, Rolf H. Sijmons, Maartje Nielsen, Hans F. A. Vasen, Deepak Vangala, Monika Morak, Jukka-Pekka Mecklin, Toni T. Seppälä, Sigve Nakken, Stefanie Holzapfel, Douglas Tjandra, Finlay A. Macrae, Päivi Peltomäki, Daniel D. Buchanan, Stephen N. Thibodeau, Adriana Della Valle, James Hill, Annika Lindblom, Bernardo Bonanni, Reinhard Büttner, Francisco López-Köstner, Giulia Martina Cavestro, John Burn, Emma J Crosbie, Lucio Bertario, Sanne W. ten Broeke, D. G. R. Evans, Kate Green, Verena Steinke-Lange, Eivind Hovig, Miquel Serra-Burriel, Francesc Balaguer, Kirsi Pylvänäinen, Gabriela Möslein, Revital Kariv, Thomas Hansen, Maria Grazia Tibiletti, Tamara Alejandra Piñero, Nils Rahner, Magnus von Knebel Doeberitz, Ingrid Winship, Nathan Gluck, Lars Joachim Lindberg, Christoph Engel, Mev Dominguez-Valentin, John-Paul Plazzer, Julian R. Sampson, Marta Pineda, John L. Hopper, Pablo Kalfayan, Heike Görgens, Aung Ko Win, Steven Gallinger, Loic Le Marchand, Mark A. Jenkins, Markus Loeffler, Noralane M. Lindor, Inge Bernstein, Pål Møller, Laura Renkonen-Sinisalo, Florencia Neffa, Huw Thomas, Gabriel Capellá, Jane C. Figueiredo, Miriam Mints, Patricia Esperon, Matilde Navarro, Robert Hüneburg, Guided Treatment in Optimal Selected Cancer Patients (GUTS), HUS Abdominal Center, Department of Surgery, Genome-Scale Biology (GSB) Research Program, II kirurgian klinikka, ATG - Applied Tumor Genomics, Research Programs Unit, Clinicum, Department of Medical and Clinical Genetics, Dominguez-Valentin, M., Plazzer, J. -P., Sampson, J. R., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Macrae, F., Winship, I. M., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Nielsen, M., Bertario, L., Bonanni, B., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Della Valle, A., Lopez-Kostner, F., Alvarez, K., Gluck, N., Katz, L., Heinimann, K., Vaccaro, C. A., Nakken, S., Hovig, E., Green, K., Lalloo, F., Hill, J., Vasen, H. F. A., Perne, C., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., Doeberitz, M. V. K., Loeffler, M., Rahner, N., Weitz, J., Steinke-Lange, V., Schmiegel, W., Vangala, D., Crosbie, E. J., Pineda, M., Navarro, M., Brunet, J., Moreira, L., Sanchez, A., Serra-Burriel, M., Mints, M., Kariv, R., Rosner, G., Pinero, T. A., Pavicic, W. H., Kalfayan, P., Ten Broeke, S. W., Mecklin, J. -P., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Peltomaki, P., Hopper, J. L., Win, A. K., Buchanan, D. D., Lindor, N. M., Gallinger, S., Marchand, L. L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Therkildsen, C., Hansen, T. V. O., Lindberg, L., Rodland, E. A., Neffa, F., Esperon, P., Tjandra, D., Moslein, G., Seppala, T. T., and Moller, P.

Subjects
cancer incidence, 0302 clinical medicine, Malalties hereditàries, Missense mutation, 8Q23.3, Càncer, Cancer, Genetics, 0303 health sciences, medicine.diagnostic_test, Factors de risc en les malalties, MISMATCH REPAIR GENES, MLH1, General Medicine, Penetrance, Lynch syndrome, 3. Good health, syöpägeenit, 030220 oncology & carcinogenesis, Medicine, syöpätaudit, ilmaantuvuus, Genetic diseases, congenital, hereditary, and neonatal diseases and abnormalities, missense, 11Q23.1, Risk factors in diseases, CANCER-RISK, Article, aberrant splicing, 03 medical and health sciences, AGE, medicine, Genetic predisposition, ddc:610, MSH2, Lynchin oireyhtymä, penetrance, 030304 developmental biology, Genetic testing, truncating, perinnölliset taudit, business.industry, MUTATIONS, HMSH2, nutritional and metabolic diseases, medicine.disease, digestive system diseases, 3121 General medicine, internal medicine and other clinical medicine, business
Abstract

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Published
2021

18. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study

Author

Seçil Aksoy, Michael O. Woods, Heinric Williams, Bruno Buecher, Finlay A. Macrae, Lotte N. Krogh, Jay Qiu, Wan K.W. Juhari, Jan T. Lowery, Anne-Marie Gerdes, Magnus von Knebel Doeberitz, Luigi Ricciardiello, Karsten Schulmann, Jose Luis Soto, Kristina Lagerstedt-Robinson, Kiwamu Akagi, Raj Ramesar, Uffe Birk Jensen, Angel Alonso, Robert Hüneburg, Olivier Caron, Michel Longy, Jan Lubinski, Kate Green, Annabel Goodwin, D. Gareth Evans, Julie Wods, Leigha Senter, Matthew F. Kalady, Mark Clendenning, Barbara A. Leggett, Ravindran Ankathil, Swati G. Patel, Julian Barwell, Katherine M. Tucker, Grant Lee, Pascaline Berthet, Dawn M. Nixon, Sonia S. Kupfer, Naohiro Tomita, Susan Parry, Trinidad Caldés, Robert W. Haile, Edenir Inêz Palmero, Karin Alvarez, Cassandra B. Nichols, Mark A. Jenkins, N. Jewel Samadder, Loic LeMarchand, John Burn, Francisco Lopez, Rodney J. Scott, Pierre Laurent-Puig, Julie Arnold, Christina Therkildsen, Hans K. Schackert, Pilar Garre, Reinhard Buettner, Adriana Della Valle, Patricia Esperon, Wolff Schmiegel, Karl Heinimann, Inge Bernstein, Matthias Kloor, Nicoline Hoogerbrugge, Rui Manuel Reis, Fränzel J.B. Van Duijnhoven, Christoph Engel, Mohd Nizam Zahary, Sylviane Olschwang, Sapna Syngal, Valérie Bonadona, Nicholas Pachter, Matilde Navarro, Albert de la Chapelle, Beate Betz, Jukka-Pekka Mecklin, Catherine Noguès, Elena M. Stoffel, Toni T. Seppälä, Chrystelle Colas, Anneke Lucassen, Allan D. Spigelman, Youenn Drouet, Elisa J. Cops, Uri Ladabaum, Steve Thibodeau, Jeffrey N. Weitzel, Fiona Lalloo, Patrick J. Morrison, Maurizio Genuardi, Kohji Tanakaya, Patrick M. Lynch, Frederik J. Hes, William D. Foulkes, Carmen Guillén-Ponce, Jenny von Salomé, Emilia Rogoża-Janiszewska, Andrew Latchford, John L. Hopper, Carrie Snyder, Verónica Barca-Tierno, Gabriela Möslein, Lauren M. Gima, Melissa C. Southey, Paul A. James, Marion Dhooge, Claudia Perne, Steven Gallinger, Heather Hampel, Amanda B. Spurdle, Ingrid Winship, Emmanuelle Fourme, Rish K. Pai, Daniela Turchetti, Marta Pineda, Jürgen Weitz, James Hill, Daniel D. Buchanan, Carlos A. Vaccaro, Noralane M. Lindor, Rachel Pearlman, Pål Møller, Christian P. Strassburg, Jane C. Figueiredo, Aída Falcón de Vargas, Silke Zachariae, Karolin Bucksch, Joanne Ngeow, Silke Redler, Henrik Okkels, Maija R.J. Kohonen-Corish, Hans F. A. Vasen, Verena Steinke-Lange, Roselyne Guimbaud, Deepak Vangala, Isabelle Coupier, Nils Rahner, Berrin Tunca, Sanne W. Bajwa-ten Broeke, Niels de Wind, Sophie Lejeune, José Gaston Guillem, Karin Wadt, Polly A. Newcomb, Elke Holinski-Feder, Florencia Neffa, Rodrigo Santa Cruz Guindalini, Paul E. Wise, Julian R. Sampson, Graham Casey, Lene Juel Rasmussen, Rolf H. Sijmons, Tadeusz Dębniak, Ann-Sofie Backman, Joji Utsunomiya, Melyssa Aronson, Aung Ko Win, Yves-Jean Bignon, Judy W. C. Ho, Robyn L. Ward, Mev Dominguez-Valentin, Karolina Malińska, Elizabeth E. Half, John-Paul Plazzer, Marjolijn J. L. Ligtenberg, Rachel Austin, Nicola K. Poplawski, Marcia Cruz-Correa, Nagahide Matsubara, Charlotte Kvist Lautrup, Thomas Hansen, Tatsuro Yamaguchi, Thomas John, David J. Amor, Ilana Solomon, Yun-Hee Choi, Meghan J. van Wanzeele, Rakefet Shtoyerman, Vanessa Huntley, Maartje Nielsen, Deborah Neklason, Kevin J. Monahan, Gülçin Tezcan, Stefan Aretz, Talya Boisjoli, Sophie Giraud, Thierry Frebourg, Christophe Rosty, Heike Görgens, Lone Sunde, Allyson Templeton, Jacob Nattermann, Mala Pande, Joan Brunet, Nancy Uhrhammer, James M. Church, Florencia Spirandelli, Laurent Briollais, James G. Dowty, Jeanette C. Reece, Rachel Susman, Fay Kastrinos, Kirsi Pylvänäinen, Gabriel Capellá, Helène Schuster, Min H. Chew, Markus Loeffler, Christine Lasset, Michael J. Hall, Capuccine Delnatte, Floor A. Duijkers, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Digital Precision Cancer Medicine (iCAN), ATG - Applied Tumor Genomics, HUS Abdominal Center, Clinical sciences, Medical Genetics, Win A.K., Dowty J.G., Reece J.C., Lee G., Templeton A.S., Plazzer J.-P., Buchanan D.D., Akagi K., Aksoy S., Alonso A., Alvarez K., Amor D.J., Ankathil R., Aretz S., Arnold J.L., Aronson M., Austin R., Backman A.-S., Bajwa-ten Broeke S.W., Barca-Tierno V., Barwell J., Bernstein I., Berthet P., Betz B., Bignon Y.-J., Boisjoli T., Bonadona V., Briollais L., Brunet J., Bucksch K., Buecher B., Buettner R., Burn J., Caldes T., Capella G., Caron O., Casey G., Chew M.H., Choi Y.-H., Church J., Clendenning M., Colas C., Cops E.J., Coupier I., Cruz-Correa M., de la Chapelle A., de Wind N., Debniak T., Della Valle A., Delnatte C., Dhooge M., Dominguez-Valentin M., Drouet Y., Duijkers F.A., Engel C., Esperon P., Evans D.G., Falcon de Vargas A., Figueiredo J.C., Foulkes W., Fourme E., Frebourg T., Gallinger S., Garre P., Genuardi M., Gerdes A.-M., Gima L.M., Giraud S., Goodwin A., Gorgens H., Green K., Guillem J., Guillen-Ponce C., Guimbaud R., Guindalini R.S.C., Half E.E., Hall M.J., Hampel H., Hansen T.V.O., Heinimann K., Hes F.J., Hill J., Ho J.W.C., Holinski-Feder E., Hoogerbrugge N., Huneburg R., Huntley V., James P.A., Jensen U.B., John T., Juhari W.K.W., Kalady M., Kastrinos F., Kloor M., Kohonen-Corish M.R., Krogh L.N., Kupfer S.S., Ladabaum U., Lagerstedt-Robinson K., Lalloo F., Lasset C., Latchford A., Laurent-Puig P., Lautrup C.K., Leggett B.A., Lejeune S., LeMarchand L., Ligtenberg M., Lindor N., Loeffler M., Longy M., Lopez F., Lowery J., Lubinski J., Lucassen A.M., Lynch P.M., Malinska K., Matsubara N., Mecklin J.-P., Moller P., Monahan K., Morrison P.J., Nattermann J., Navarro M., Neffa F., Neklason D., Newcomb P.A., Ngeow J., Nichols C., Nielsen M., Nixon D.M., Nogues C., Okkels H., Olschwang S., Pachter N., Pai R.K., Palmero E.I., Pande M., Parry S., Patel S.G., Pearlman R., Perne C., Pineda M., Poplawski N.K., Pylvanainen K., Qiu J., Rahner N., Ramesar R., Rasmussen L.J., Redler S., Reis R.M., Ricciardiello L., Rogoza-Janiszewska E., Rosty C., Samadder N.J., Sampson J.R., Schackert H.K., Schmiegel W., Schulmann K., Schuster H., Scott R., Senter L., Seppala T.T., Shtoyerman R., Sijmons R.H., Snyder C., Solomon I.B., Soto J.L., Southey M.C., Spigelman A., Spirandelli F., Spurdle A.B., Steinke-Lange V., Stoffel E.M., Strassburg C.P., Sunde L., Susman R., Syngal S., Tanakaya K., Tezcan G., Therkildsen C., Thibodeau S., Tomita N., Tucker K.M., Tunca B., Turchetti D., Uhrhammer N., Utsunomiya J., Vaccaro C., van Duijnhoven F.J.B., van Wanzeele M.J., Vangala D.B., Vasen H.F.A., von Knebel Doeberitz M., von Salome J., Wadt K.A.W., Ward R.L., Weitz J., Weitzel J.N., Williams H., Winship I., Wise P.E., Wods J., Woods M.O., Yamaguchi T., Zachariae S., Zahary M.N., Hopper J.L., Haile R.W., Macrae F.A., Moslein G., and Jenkins M.A.

Subjects
0301 basic medicine, Proband, Oncology, Male, Heredity, DNA mismatch repair, [SDV]Life Sciences [q-bio], SUSCEPTIBILITY, Settore MED/03 - GENETICA MEDICA, 0302 clinical medicine, Residence Characteristics, Risk Factors, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], PMS2, ComputingMilieux_MISCELLANEOUS, MLH1, Age Factors, Middle Aged, Penetrance, Lynch syndrome, 3. Good health, Pedigree, Phenotype, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis, Female, Adult, medicine.medical_specialty, PENETRANCE, congenital, hereditary, and neonatal diseases and abnormalities, GENES, 3122 Cancers, colorectal cancer, BREAST, Risk Assessment, 03 medical and health sciences, Sex Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Retrospective Studies, business.industry, MUTATIONS, Cancer, medicine.disease, digestive system diseases, MSH2, MSH6, MODEL, INDIVIDUALS, 030104 developmental biology, Lynch Syndrome, Gene-Environment Interaction, business
Abstract

Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

Published
2021

19. Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants:a Prospective Lynch Syndrome Database report

Author

Einar Andreas Rødland, Joan B. Vida, Heike Görgens, Eivind Hovig, Kirsi Pylvänäinen, Monika Morak, Wouter H. de Vos tot Nederveen Cappel, Lone Sunde, Mark A. Jenkins, Lucio Bertario, Patricia Esperon, Reinhard Büttner, Finlay A. Macrae, Inge Bernstein, Marc S. Greenblatt, Wolff Schmiegel, Giulia Martina Cavestro, Maria Grazia Tibiletti, Silke Redler, Zohreh Ketabi, Karl Heinimann, Fiona Lalloo, Huw Thomas, Christina Therkildsen, Deepak Vangala, Magnus von Knebel Doeberitz, Matilde Navarro, Erik Rokkones, Douglas Tjandra, D. G. Evans, Marta Pineda, Marian J.E. Mourits, Lior H. Katz, Bernardo Bonanni, Pablo Kalfayan, Stephen N. Thibodeau, Loic Le Marchand, Revital Kariv, Maartje Nielsen, Emma J Crosbie, Oliver G. Denton, Stefanie Holzapfel, Guy Rosner, Mev Dominguez-Valentin, John Burn, Verena Steinke-Lange, Carlos A. Vaccaro, Gabriela Möslein, Elke Holinski-Feder, Gabriel Capellá, Johanna Tecklenburg, Karin Wadt, Kate Green, Christoph Engel, Miriam Mints, Anna Lepistö, Tamara Alejandra Piñero, Jukka-Pekka Mecklin, John L. Hopper, Robert Hüneburg, Markus Loeffler, Florencia Neffa, Toni T. Seppälä, Claudia Perne, Polly A. Newcomb, Karin Alvarez, Adriana Della Valle, Julian R. Sampson, Sanne W. ten Broeke, Francisco Lopez-Koestner, John-Paul Plazzer, James Hill, Hans Georg Strauß, Ingrid Winship, Nathan Gluck, Aung Ko Win, Jane C. Figueiredo, Jürgen Weitz, Hans F. A. Vasen, Rolf H. Sijmons, Walter Hernán Pavicic, Stefan Aretz, Steven Gallinger, Noralane M. Lindor, Pål Møller, Laura Renkonen-Sinisalo, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Seppala, T. T., Dominguez-Valentin, M., Crosbie, E. J., Engel, C., Aretz, S., Macrae, F., Winship, I., Capella, G., Thomas, H., Hovig, E., Nielsen, M., Sijmons, R. H., Bertario, L., Bonanni, B., Tibiletti, M. G., Cavestro, G. M., Mints, M., Gluck, N., Katz, L., Heinimann, K., Vaccaro, C. A., Green, K., Lalloo, F., Hill, J., Schmiegel, W., Vangala, D., Perne, C., Strauss, H. -G., Tecklenburg, J., Holinski-Feder, E., Steinke-Lange, V., Mecklin, J. -P., Plazzer, J. -P., Pineda, M., Navarro, M., Vida, J. B., Kariv, R., Rosner, G., Pinero, T. A., Pavicic, W., Kalfayan, P., ten Broeke, S. W., Jenkins, M. A., Sunde, L., Bernstein, I., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Della Valle, A., Lopez-Koestner, F., Alvarez, K., Buttner, R., Gorgens, H., Morak, M., Holzapfel, S., Huneburg, R., von Knebel Doeberitz, M., Loeffler, M., Redler, S., Weitz, J., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Hopper, J. L., Win, A. K., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Therkildsen, C., Wadt, K. A. W., Mourits, M. J. E., Ketabi, Z., Denton, O. G., Rodland, E. A., Vasen, H., Neffa, F., Esperon, P., Tjandra, D., Moslein, G., Rokkones, E., Sampson, J. R., Evans, D. G., Moller, P., Genome-Scale Biology (GSB) Research Program, HUS Abdominal Center, Clinicum, II kirurgian klinikka, Department of Surgery, and Doctoral Programme in Clinical Research

Subjects
0301 basic medicine, Cancer Research, Oophorectomy, Databases, Factual, Colorectal cancer, SURGERY, medicine.medical_treatment, Càncer d'ovari, computer.software_genre, DNA Mismatch Repair, 0302 clinical medicine, Endometrial cancer, munasarjasyöpä, Medicine, Prospective Studies, Colectomy, Salpingo-oophorectomy/methods, Database, Manchester Cancer Research Centre, COLON-CANCER, MLH1, WOMEN, Middle Aged, Prognosis, Lynch syndrome, 3. Good health, kohdunrungon syöpä, Oncology, COLECTOMY, 030220 oncology & carcinogenesis, Female, Biomarkers, Tumor/genetics, Adult, Heterozygote, Genital Neoplasms, Female, Salpingo-oophorectomy, Hysterectomy, 03 medical and health sciences, Genital Neoplasms, Female/prevention & control, Ovarian cancer, Colorectal Neoplasms, Hereditary Nonpolyposis/genetics, Biomarkers, Tumor, Mortalitat, Humans, Hysterectomy/methods, Mortality, Lynchin oireyhtymä, Risk-reducing surgery, Aged, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, Cancer, MSH6, 3126 Surgery, anesthesiology, intensive care, radiology, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, MSH2, 030104 developmental biology, Cross-Sectional Studies, PMS2, Càncer d'endometri, Mutation, kohdunpoisto, business, computer, Follow-Up Studies
Abstract

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd.

Published
2021

20. Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report

Author

Eivind Hovig, Bernardo Bonanni, Monika Morak, Mark A. Jenkins, Patricia Esperon, Toni T. Seppälä, Lone Sunde, Pablo Kalfayan, Gabriel Capellá, Inge Bernstein, Matilde Navarro, Marc S. Greenblatt, John Burn, Zohreh Ketabi, Johanna Tecklenburg, Francisco Lopez-Koestner, Miriam Mints, Heike Görgens, Neil A J Ryan, Kate Green, Annika Auranen, Douglas Tjandra, Robert W. Haile, Marta Pineda, Tamara Alejandra Piñero, Stefan Aretz, Robert Hüneburg, Verena Steinke-Lange, Markus Loeffler, Christina Therkildsen, John L. Hopper, Deepak Vangala, Huw Thomas, Reinhard Büttner, James Hill, Einar Andreas Rødland, Revital Kariv, Maria Grazia Tibiletti, Sigve Nakken, Stefanie Holzapfel, D. Gareth Evans, Oliver G. Denton, Julian R. Sampson, Henrik Okkels, Joan Vidal, Loic Le Marchand, Hans Georg Strauß, Gabriela Möslein, Claudia Perne, Ingrid Winship, Nathan Gluck, Jane C. Figueiredo, Mev Dominguez-Valentin, Wolff Schmiegel, Karl Heinimann, Kirsi Pylvänäinen, Karin Alvarez, Maartje Nielsen, Wouter H. de Vos tot Nederveen Cappel, Fiona Lalloo, Aung Ko Win, Guy Rosner, Carlos A. Vaccaro, Polly A. Newcomb, Elke Holinski-Feder, John-Paul Plazzer, Lior H. Katz, Christoph Engel, Anna Lepistö, Jukka-Pekka Mecklin, Giulia Martina Cavestro, Adriana Della Valle, Finlay A. Macrae, Sanne W. ten Broeke, Florencia Neffa, Rolf H. Sijmons, María Laura Gonzalez, Nils Rahner, Jürgen Weitz, Hans F. A. Vasen, Stephen N. Thibodeau, Emma J Crosbie, Lucio Bertario, Steven Gallinger, Noralane M. Lindor, Pål Møller, Laura Renkonen-Sinisalo, Magnus von Knebel Doeberitz, Dominguez-Valentin, M., Crosbie, E. J., Engel, C., Aretz, S., Macrae, F., Winship, I., Capella, G., Thomas, H., Nakken, S., Hovig, E., Nielsen, M., Sijmons, R. H., Bertario, L., Bonanni, B., Tibiletti, M. G., Cavestro, G. M., Mints, M., Gluck, N., Katz, L., Heinimann, K., Vaccaro, C. A., Green, K., Lalloo, F., Hill, J., Schmiegel, W., Vangala, D., Perne, C., Strauss, H. -G., Tecklenburg, J., Holinski-Feder, E., Steinke-Lange, V., Mecklin, J. -P., Plazzer, J. -P., Pineda, M., Navarro, M., Vidal, J. B., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Ryan, N., ten Broeke, S. W., Jenkins, M. A., Sunde, L., Bernstein, I., Burn, J., Greenblatt, M., de Vos tot Nederveen Cappel, W. H., Della Valle, A., Lopez-Koestner, F., Alvarez, K., Buttner, R., Gorgens, H., Morak, M., Holzapfel, S., Huneburg, R., von Knebel Doeberitz, M., Loeffler, M., Rahner, N., Weitz, J., Pylvanainen, K., Renkonen-Sinisalo, L., Lepisto, A., Auranen, A., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Therkildsen, C., Okkels, H., Ketabi, Z., Denton, O. G., Rodland, E. A., Vasen, H., Neffa, F., Esperon, P., Tjandra, D., Moslein, G., Sampson, J. R., Evans, D. G., Seppala, T. T., Moller, P., ATG - Applied Tumor Genomics, HUS Abdominal Center, II kirurgian klinikka, Department of Surgery, Clinicum, Helsinki University Hospital Area, and University of Helsinki

Subjects
0301 basic medicine, medicine.medical_treatment, DNA Mismatch Repair, Gynecologic surgery, 0302 clinical medicine, Malalties hereditàries, Prospective Studies, Prospective cohort study, Genetics (clinical), Mismatch Repair Endonuclease PMS2, Incidence (epidemiology), Middle Aged, 16. Peace & justice, Lynch syndrome, 3. Good health, 030220 oncology & carcinogenesis, Female, syöpätaudit, MutL Protein Homolog 1, Genetic diseases, Heterozygote, medicine.medical_specialty, Salpingo-oophorectomy, Cirurgia ginecològica, Hysterectomy, Article, 03 medical and health sciences, Càncer colorectal, CAPP2, medicine, Humans, Lynchin oireyhtymä, Gynecology, perinnölliset taudit, HEREDITARY COLORECTAL-CANCER, business.industry, Endometrial cancer, Cancer, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Colorectal cancer, ASPIRIN, 030104 developmental biology, Clinical research, 3121 General medicine, internal medicine and other clinical medicine, kohdunpoisto, 3111 Biomedicine, Ovarian cancer, business
Abstract

Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR ( path_MMR ) variants. Methods The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. Results Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1 , path_MSH2 , path_MSH6 , and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. Conclusion Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

Published
2021

21. The Management of Peutz–Jeghers Syndrome: European Hereditary Tumour Group (EHTG) Guideline †

Author

Anja Wagner, Emma J Crosbie, Annika Auranen, Marta Puzzono, Marco J. Bruno, Andrew Latchford, Giulia Martina Cavestro, Monique E. van Leerdam, Ingrid Winship, Anne Goverde, Stefan Aretz, Gabriela Möslein, Anne Marie Jelsig, Anna Lepistö, Veronica Zuber, Wagner, A., Aretz, S., Auranen, A., Bruno, M. J., Cavestro, G. M., Crosbie, E. J., Goverde, A., Jelsig, A. M., Latchford, A., van Leerdam, M. E., Lepisto, A., Puzzono, M., Winship, I., Zuber, V., Moslein, G., Clinical Genetics, and Gastroenterology & Hepatology

Subjects
medicine.medical_specialty, MEDLINE, Delphi method, lcsh:Medicine, Peutz–Jeghers syndrome, Review, Guideline, Practical guideline, 03 medical and health sciences, 0302 clinical medicine, Medicine, Grading (education), business.industry, lcsh:R, STK11, Subject (documents), General Medicine, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Family medicine, Keywords: Peutz–Jeghers syndrome, 030211 gastroenterology & hepatology, business, Variable number, guideline
Abstract

The scientific data to guide the management of Peutz–Jeghers syndrome (PJS) are sparse. The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to update the previous guideline from 2010 and formulate a revised practical guideline for colleagues managing PJS patients. Methods: Literature searches were performed using MEDLINE, Embase, and Cochrane. Evidence levels and recommendation strengths were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). A Delphi process was followed, with consensus being reached when ≥80% of the voting guideline committee members agreed. Recommendations and statements: The only recent guidelines available were for gastrointestinal and pancreatic management. These were reviewed and endorsed after confirming that no more recent relevant papers had been published. Literature searches were performed for additional questions and yielded a variable number of relevant papers depending on the subject addressed. Additional recommendations and statements were formulated. Conclusions: A decade on, the evidence base for recommendations remains poor, and collaborative studies are required to provide better data about this rare condition. Within these restrictions, multisystem, clinical management recommendations for PJS have been formulated.

Published
2021

22. Correction:Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

Author

Gabriel Capellá, Patricia Esperon, Christoph Engel, Rolf H. Sijmons, María Laura Gonzalez, Matilde Navarro, Francisco López-Köstner, Julian R. Sampson, Miquel Serra-Burriel, Karin Alvarez, Ingrid Winship, Nathan Gluck, Lone Sunde, Reinhard Büttner, Giulia Martina Cavestro, Wouter H. de Vos tot Nederveen Cappel, Jukka-Pekka Mecklin, Marc S. Greenblatt, Kate Green, Robert Hüneburg, Markus Loeffler, Maria Grazia Tibiletti, Tamara Alejandra Piñero, Florencia Neffa, Lucio Bertario, Ariadna Sánchez, Verena Steinke-Lange, Christina Therkildsen, Jane C. Figueiredo, Douglas Tjandra, Magnus von Knebel Doeberitz, Lior H. Katz, Steven Gallinger, Noralane M. Lindor, Gabriela Möslein, Adriana Della Valle, John L. Hopper, Einar Andreas Rødland, Miriam Mints, Annika Lindblom, Ian M. Frayling, Polly A. Newcomb, Pål Møller, Sanne W. ten Broeke, Laura Renkonen-Sinisalo, Sigve Nakken, Stefanie Holzapfel, Finlay A. Macrae, Stefan Aretz, Nils Rahner, Karin Wadt, Robert W. Haile, Francesc Balaguer, Revital Kariv, Stephen N. Thibodeau, Huw D. Thomas, Emma J Crosbie, Deepak Vangala, Monika Morak, Ignacio Blanco, Hans K. Schackert, Henrik Okkels, Mev Dominguez-Valentin, Oliver G. Denton, John-Paul Plazzer, Zohreh Ketabi, James Hill, Loic Le Marchand, Mark A. Jenkins, Inge Bernstein, D. Gareth Evans, Heike Görgens, Marta Pineda, John Burn, Kirsi Pylvänäinen, Eivind Hovig, Hans F. A. Vasen, Pablo Kalfayan, Toni T. Seppälä, Aung Ko Win, Maartje Nielsen, Wolff Schmiegel, Guy Rosner, Karl Heinimann, Fiona Lalloo, Carlos A. Vaccaro, Elke Holinski-Feder, Leticia Moreira, HUS Abdominal Center, Clinicum, II kirurgian klinikka, University of Helsinki, Department of Surgery, ATG - Applied Tumor Genomics, Research Programs Unit, Dominguez-Valentin, M., Sampson, J. R., Seppala, T. T., ten Broeke, S. W., Plazzer, J. -P., Nakken, S., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., Hovig, E., de Vos tot Nederveen Cappel, W. H., Sijmons, R. H., Bertario, L., Tibiletti, M. G., Cavestro, G. M., Lindblom, A., Della Valle, A., Lopez-Kostner, F., Gluck, N., Katz, L. H., Heinimann, K., Vaccaro, C. A., Buttner, R., Gorgens, H., Holinski-Feder, E., Morak, M., Holzapfel, S., Huneburg, R., Knebel Doeberitz, M., Loeffler, M., Rahner, N., Schackert, H. K., Steinke-Lange, V., Schmiegel, W., Vangala, D., Pylvanainen, K., Renkonen-Sinisalo, L., Hopper, J. L., Win, A. K., Haile, R. W., Lindor, N. M., Gallinger, S., Le Marchand, L., Newcomb, P. A., Figueiredo, J. C., Thibodeau, S. N., Wadt, K., Therkildsen, C., Okkels, H., Ketabi, Z., Moreira, L., Sanchez, A., Serra-Burriel, M., Pineda, M., Navarro, M., Blanco, I., Green, K., Lalloo, F., Crosbie, E. J., Hill, J., Denton, O. G., Frayling, I. M., Rodland, E. A., Vasen, H., Mints, M., Neffa, F., Esperon, P., Alvarez, K., Kariv, R., Rosner, G., Pinero, T. A., Gonzalez, M. L., Kalfayan, P., Tjandra, D., Winship, I. M., Macrae, F., Moslein, G., Mecklin, J. -P., Nielsen, M., Moller, P., and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Oncology, Male, Colorectal cancer, Lynch syndrome, Penetrance, DNA Mismatch Repair, 0302 clinical medicine, Databases, Genetic, Malalties hereditàries, Prospective Studies, Càncer, PMS2, Genetics (clinical), Mismatch Repair Endonuclease PMS2, Cancer, 0303 health sciences, Sex Characteristics, Factors de risc en les malalties, 1184 Genetics, developmental biology, physiology, MLH1, Middle Aged, 16. Peace & justice, 3. Good health, DNA-Binding Proteins, MutS Homolog 2 Protein, syöpägeenit, MSH2, 030220 oncology & carcinogenesis, MSH6, 030211 gastroenterology & hepatology, DNA mismatch repair, Female, geneettiset tekijät, MutL Protein Homolog 1, Genetic diseases, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Risk factors in diseases, suolistosyövät, MUTATION CARRIERS, Risk Assessment, Article, sukupuoli, Age and gender, 03 medical and health sciences, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Lynchin oireyhtymä, Gene, 030304 developmental biology, Aged, business.industry, Endometrial cancer, Correction, nutritional and metabolic diseases, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Survival Analysis, digestive system diseases, Mutation, 3111 Biomedicine, ikä, business, Ovarian cancer
Abstract

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender.

Published
2020

23. Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database.

Author

Dominguez-Valentin M, Haupt S, Seppälä TT, Sampson JR, Sunde L, Bernstein I, Jenkins MA, Engel C, Aretz S, Nielsen M, Capella G, Balaguer F, Evans DG, Burn J, Holinski-Feder E, Bertario L, Bonanni B, Lindblom A, Levi Z, Macrae F, Winship I, Plazzer JP, Sijmons R, Laghi L, Della Valle A, Heinimann K, Dębniak T, Fruscio R, Lopez-Koestner F, Alvarez-Valenzuela K, Katz LH, Laish I, Vainer E, Vaccaro C, Carraro DM, Monahan K, Half E, Stakelum A, Winter D, Kennelly R, Gluck N, Sheth H, Abu-Freha N, Greenblatt M, Rossi BM, Bohorquez M, Cavestro GM, Lino-Silva LS, Horisberger K, Tibiletti MG, Nascimento ID, Thomas H, Rossi NT, Apolinário da Silva L, Zaránd A, Ruiz-Bañobre J, Heuveline V, Mecklin JP, Pylvänäinen K, Renkonen-Sinisalo L, Lepistö A, Peltomäki P, Therkildsen C, Madsen MG, Burgdorf SK, Hopper JL, Win AK, Haile RW, Lindor N, Gallinger S, Le Marchand L, Newcomb PA, Figueiredo J, Buchanan DD, Thibodeau SN, von Knebel Doeberitz M, Loeffler M, Rahner N, Schröck E, Steinke-Lange V, Schmiegel W, Vangala D, Perne C, Hüneburg R, Redler S, Büttner R, Weitz J, Pineda M, Duenas N, Vidal JB, Moreira L, Sánchez A, Hovig E, Nakken S, Green K, Lalloo F, Hill J, Crosbie E, Mints M, Goldberg Y, Tjandra D, Ten Broeke SW, Kariv R, Rosner G, Advani SH, Thomas L, Shah P, Shah M, Neffa F, Esperon P, Pavicic W, Torrezan GT, Bassaneze T, Martin CA, Moslein G, and Moller P

Abstract

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants ( path_MMR ) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time., Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender., Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers., Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome., Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017., Competing Interests: R.B. has received honoraria for lectures and advisory boards from AbbVie, Amgen, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Illumina, Lilly, Merck-Serono, MSD, Novartis, Qiagen, Pfizer, Roche, and Targos MP Inc. R.B. is a Co-Founder and Scientific Advisor for Targos Mol. Pathology Inc. Kassel/Germany. T.T.S. is the CEO and co-owner of Healthfund Finland Oy and reports consultation fees from Boehringer Ingelheim Finland and Amgen. FB is supported by JANSSEN PHARMACEUTICALS (clinical trial for Familial Adenomatous polyposis). RH is supported by the 10.13039/501100002424Fujifilm Germany and Janssen-Pharmaceuticals. LK is consultant of Sandoz, Novartis and Abbott. GM reports consultancy fees from Johnson & Johnson., (© 2023 The Author(s).)

Published
2023
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24. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium.

Author

Møller P, Seppälä T, Dowty JG, Haupt S, Dominguez-Valentin M, Sunde L, Bernstein I, Engel C, Aretz S, Nielsen M, Capella G, Evans DG, Burn J, Holinski-Feder E, Bertario L, Bonanni B, Lindblom A, Levi Z, Macrae F, Winship I, Plazzer JP, Sijmons R, Laghi L, Valle AD, Heinimann K, Half E, Lopez-Koestner F, Alvarez-Valenzuela K, Scott RJ, Katz L, Laish I, Vainer E, Vaccaro CA, Carraro DM, Gluck N, Abu-Freha N, Stakelum A, Kennelly R, Winter D, Rossi BM, Greenblatt M, Bohorquez M, Sheth H, Tibiletti MG, Lino-Silva LS, Horisberger K, Portenkirchner C, Nascimento I, Rossi NT, da Silva LA, Thomas H, Zaránd A, Mecklin JP, Pylvänäinen K, Renkonen-Sinisalo L, Lepisto A, Peltomäki P, Therkildsen C, Lindberg LJ, Thorlacius-Ussing O, von Knebel Doeberitz M, Loeffler M, Rahner N, Steinke-Lange V, Schmiegel W, Vangala D, Perne C, Hüneburg R, de Vargas AF, Latchford A, Gerdes AM, Backman AS, Guillén-Ponce C, Snyder C, Lautrup CK, Amor D, Palmero E, Stoffel E, Duijkers F, Hall MJ, Hampel H, Williams H, Okkels H, Lubiński J, Reece J, Ngeow J, Guillem JG, Arnold J, Wadt K, Monahan K, Senter L, Rasmussen LJ, van Hest LP, Ricciardiello L, Kohonen-Corish MRJ, Ligtenberg MJL, Southey M, Aronson M, Zahary MN, Samadder NJ, Poplawski N, Hoogerbrugge N, Morrison PJ, James P, Lee G, Chen-Shtoyerman R, Ankathil R, Pai R, Ward R, Parry S, Dębniak T, John T, van Overeem Hansen T, Caldés T, Yamaguchi T, Barca-Tierno V, Garre P, Cavestro GM, Weitz J, Redler S, Büttner R, Heuveline V, Hopper JL, Win AK, Lindor N, Gallinger S, Le Marchand L, Newcomb PA, Figueiredo J, Buchanan DD, Thibodeau SN, Ten Broeke SW, Hovig E, Nakken S, Pineda M, Dueñas N, Brunet J, Green K, Lalloo F, Newton K, Crosbie EJ, Mints M, Tjandra D, Neffa F, Esperon P, Kariv R, Rosner G, Pavicic WH, Kalfayan P, Torrezan GT, Bassaneze T, Martin C, Moslein G, Ahadova A, Kloor M, Sampson JR, and Jenkins MA

Abstract

Objective: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants., Methods: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path&#95;MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path&#95;MMR carriers who were first- or second-degree relatives of Lynch syndrome probands., Results: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path&#95;MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path&#95;MSH2 50% and 39%; for path&#95;MSH6 13% and 17% and for path&#95;PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups., Conclusions: Prospectively observed CRC incidences (PLSD) in path&#95;MLH1 and path&#95;MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path&#95;MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path&#95;PMS2 carriers subjected to colonoscopy, but not significantly so., (© 2022. The Author(s).)

Published
2022
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25. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X.

Author

Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, Gallinger S, Bapat B, Aronson M, Hopper J, Jass J, LeMarchand L, Grove J, Potter J, Newcomb P, Terdiman JP, Conrad P, Moslein G, Goldberg R, Ziogas A, Anton-Culver H, de Andrade M, Siegmund K, Thibodeau SN, Boardman LA, and Seminara D

Subjects
Adaptor Proteins, Signal Transducing, Adult, Aged, Base Pair Mismatch genetics, Carrier Proteins, Colorectal Neoplasms classification, Colorectal Neoplasms epidemiology, Colorectal Neoplasms, Hereditary Nonpolyposis classification, Colorectal Neoplasms, Hereditary Nonpolyposis epidemiology, DNA-Binding Proteins genetics, Female, Heterozygote, Humans, Male, Mass Screening, Microsatellite Repeats, Middle Aged, MutL Protein Homolog 1, MutS Homolog 2 Protein, Neoplasm Proteins genetics, Neoplasms epidemiology, Neoplasms genetics, Neoplastic Syndromes, Hereditary classification, Neoplastic Syndromes, Hereditary epidemiology, Neoplastic Syndromes, Hereditary genetics, Nuclear Proteins, Pedigree, Proto-Oncogene Proteins genetics, Risk Assessment, SEER Program, Chromosomal Instability, Colorectal Neoplasms genetics, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA Repair genetics, Mutation genetics
Abstract

Context: Approximately 60% of families that meet the Amsterdam-I criteria (AC-I) for hereditary nonpolyposis colorectal cancer (HNPCC) have a hereditary abnormality in a DNA mismatch repair (MMR) gene. Cancer incidence in AC-I families with MMR gene mutations is reported to be very high, but cancer incidence for individuals in AC-I families with no evidence of an MMR defect is unknown., Objective: To determine if cancer risks in AC-I families with no apparent deficiency in DNA MMR are different from cancer risks in AC-I families with DNA MMR abnormalities., Design, Setting, and Participants: Identification (1997-2001) of 161 AC-I pedigrees from multiple population- and clinic-based sources in North America and Germany, with families grouped into those with (group A) or without (group B) MMR deficiency by tumor testing. A total of 3422 relatives were included in the analyses., Main Outcome Measures: Cancer incidence in groups A and B (excluding the 3 affected members used to define each pedigree as AC-I) and computed age- and sex-adjusted standardized incidence ratios (SIRs) using Surveillance, Epidemiology, and End Results data., Results: Group A families from both population- and clinic-based series showed increased incidence of the HNPCC-related cancers. Group B families showed increased incidence only for colorectal cancer (SIR, 2.3; 95% confidence interval, 1.7-3.0) and to a lesser extent than group A (SIR, 6.1; 95% confidence interval, 5.2-7.2) (P<.001)., Conclusions: Families who fulfill AC-I criteria but who have no evidence of a DNA MMR defect do not share the same cancer incidence as families with HNPCC-Lynch syndrome (ie, hereditary MMR deficiency). Relatives in such families have a lower incidence of colorectal cancer than those in families with HNPCC-Lynch syndrome, and incidence may not be increased for other cancers. These families should not be described or counseled as having HNPCC-Lynch syndrome. To facilitate distinguishing these entities, the designation of "familial colorectal cancer type X" is suggested to describe this type of familial aggregation of colorectal cancer.

Published
2005
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26. Familial adenomatous polyposis: results after ileal pouch-anal anastomosis in teenagers.

Author

Parc YR, Moslein G, Dozois RR, Pemberton JH, Wolff BG, and King JE

Subjects
Adenomatous Polyposis Coli complications, Adolescent, Fecal Incontinence etiology, Female, Humans, Logistic Models, Male, Postoperative Complications, Rectal Neoplasms complications, Reoperation, Retrospective Studies, Treatment Outcome, Adenomatous Polyposis Coli surgery, Proctocolectomy, Restorative, Quality of Life
Abstract

Purpose: Virtually all untreated patients with familial adenomatous polyposis develop colorectal carcinoma. Thus, prophylactic colectomy is indicated. Detractors of ileal pouch-anal anastomosis prefer ileorectal anastomosis for teenagers because of the potential negative impact of ileal pouch-anal anastomosis on quality of life. The aim of this study was to assess the effects on quality of life of ileal pouch-anal anastomosis in teenagers with familial adenomatous polyposis., Methods: Between 1981 and 1998, 48 teenagers underwent ileal pouch-anal anastomosis for familial adenomatous polyposis. One patient had proctectomy and ileal pouch-anal anastomosis after previous ileorectal anastomosis. A temporary diverting loop ileostomy was established in 42 patients (87.5 percent). One patient had colonic carcinoma diagnosed preoperatively. Two other patients were found to have unsuspected rectal cancer at surgery. Mean follow-up (+/- standard deviation) in 43 patients was 80.5 +/- 42 months., Results: There was no immediate postoperative mortality. Postoperative complications included pelvic sepsis (3 patients; 1 requiring reoperation) and bleeding (1 patient; no surgery required). One patient died of metastatic colonic carcinoma. Ten patients required reoperation, seven had bowel obstruction, one had portal hypertension, and two required an ileostomy. The mean (+/- standard deviation) daytime and nighttime stool frequency was 4 +/- 1.5 and 1 +/- 1, respectively. One patient reported daytime and nighttime incontinence, and two patients reported nighttime incontinence only. No patient experienced impotence or retrograde ejaculation. Social, sexual, sport, housework, recreation, family, travel, and work activities were improved or unchanged in 82.5, 87, 80, 90, 80, 92.5, 77.5, and 89 percent of patients, respectively. Three male patients fathered children, and three female patients had a total of six children after normal pregnancies and deliveries., Conclusion: The impact of ileal pouch-anal anastomosis on quality of life was favorable in the majority of teenagers. The risk of rectal cancer should be the major consideration before proposing an operation to teenagers with familial adenomatous polyposis.

Published
2000
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27. Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes.

Author

Thibodeau SN, French AJ, Roche PC, Cunningham JM, Tester DJ, Lindor NM, Moslein G, Baker SM, Liskay RM, Burgart LJ, Honchel R, and Halling KC

Subjects
Adaptor Proteins, Signal Transducing, Carrier Proteins, Humans, Immunohistochemistry, MutL Protein Homolog 1, MutS Homolog 2 Protein, Neoplasm Proteins analysis, Nuclear Proteins, Proto-Oncogene Proteins analysis, Colorectal Neoplasms genetics, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA Repair genetics, DNA-Binding Proteins, Microsatellite Repeats, Mutation, Neoplasm Proteins genetics, Proto-Oncogene Proteins genetics
Abstract

To date, at least four genes involved in DNA mismatch repair (MMR) have been demonstrated to be altered in the germline of patients with hereditary nonpolyposis colon cancer: hMSH2, hMLH1, hPMS1, and hPMS2. Additionally, loss of MMR function has been demonstrated to lead to the phenomenon of microsatellite instability (MIN) in tumors from these patients. In this study, we have examined the protein expression pattern of hMSH2 and hMLH1 by immunohistochemistry in paraffin-embedded tumors from 7 patients with MIN+ sporadic cancer, 13 patients with familial colorectal cancer, and 12 patients meeting the strict Amsterdam criteria for hereditary nonpolyposis colon cancer. The relationship between the expression of these two gene products, the presence of germline or somatic mutations, and the presence of tumor MIN was examined. Nineteen of the 28 tumors studied demonstrated MIN, whereas mutations in hMLH1 and hMSH2 were detected in 6 and 2 patients, respectively. Of the eight MIN+/mutation+ cases, the absence of protein expression was observed for the corresponding gene product in all but one case (missense mutation in hMLH1). However, seven MIN+/mutation- cases also showed no expression of either hMLH1 (n = 5), hMSH2 (n = 1), or both (n = 1), whereas four MIN+/mutation- cases demonstrated normal expression for both. None of the MIN-/mutation- cases (n = 9) demonstrated an altered expression pattern for either protein. These data suggest that examination of protein expression by immunohistochemistry may be a rapid method for prescreening tumors for mutations in the MMR genes.

Published
1996

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