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1. 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, T, Sampson, J, Sunde, L, Bernstein, I, Jenkins, M, Engel, C, Aretz, S, Nielsen, M, Capella, G, Balaguer, F, Evans, D, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Dębniak, T, Fruscio, R, Lopez-Koestner, F, Alvarez-Valenzuela, K, Katz, L, Laish, I, Vainer, E, Vaccaro, C, Carraro, D, Monahan, K, Half, E, Stakelum, A, Winter, D, Kennelly, R, Gluck, N, Sheth, H, Abu-Freha, N, Greenblatt, M, Rossi, B, Bohorquez, M, Cavestro, G, Lino-Silva, L, Horisberger, K, Tibiletti, M, Nascimento, I, Thomas, H, Rossi, N, Apolinário da Silva, L, Zaránd, A, Ruiz-Bañobre, J, Heuveline, V, Mecklin, J, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, P, Therkildsen, C, Madsen, M, Burgdorf, S, Hopper, J, Win, A, Haile, R, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, P, Figueiredo, J, Buchanan, D, Thibodeau, S, 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, J, Moreira, L, Sánchez, A, Hovig, E, Nakken, S, Green, K, Lalloo, F, Hill, J, Crosbie, E, Mints, M, Goldberg, Y, Dominguez-Valentin M., Haupt S., Seppälä T. T., Sampson J. R., Sunde L., Bernstein I., Jenkins M. A., Engel C., Aretz S., Nielsen M., Capella G., Balaguer F., Evans D. G., Burn J., Holinski-Feder E., Bertario L., Bonanni B., Lindblom A., Levi Z., Macrae F., Winship I., Plazzer J. P., Sijmons R., Laghi L., Della Valle A., Heinimann K., Dębniak T., Fruscio R., Lopez-Koestner F., Alvarez-Valenzuela K., Katz L. H., Laish I., Vainer E., Vaccaro C., Carraro D. M., Monahan K., Half E., Stakelum A., Winter D., Kennelly R., Gluck N., Sheth H., Abu-Freha N., Greenblatt M., Rossi B. M., Bohorquez M., Cavestro G. M., Lino-Silva L. S., Horisberger K., Tibiletti M. G., Nascimento I. d., Thomas H., Rossi N. T., Apolinário da Silva L., Zaránd A., Ruiz-Bañobre J., Heuveline V., Mecklin J. P., Pylvänäinen K., Renkonen-Sinisalo L., Lepistö A., Peltomäki P., Therkildsen C., Madsen M. G., Burgdorf S. K., Hopper J. L., Win A. K., Haile R. W., Lindor N., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J., Buchanan D. D., Thibodeau S. N., 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 J. B., Moreira L., Sánchez A., Hovig E., Nakken S., Green K., Lalloo F., Hill J., Crosbie E., Mints M., Goldberg Y., Dominguez-Valentin, M, Haupt, S, Seppälä, T, Sampson, J, Sunde, L, Bernstein, I, Jenkins, M, Engel, C, Aretz, S, Nielsen, M, Capella, G, Balaguer, F, Evans, D, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Dębniak, T, Fruscio, R, Lopez-Koestner, F, Alvarez-Valenzuela, K, Katz, L, Laish, I, Vainer, E, Vaccaro, C, Carraro, D, Monahan, K, Half, E, Stakelum, A, Winter, D, Kennelly, R, Gluck, N, Sheth, H, Abu-Freha, N, Greenblatt, M, Rossi, B, Bohorquez, M, Cavestro, G, Lino-Silva, L, Horisberger, K, Tibiletti, M, Nascimento, I, Thomas, H, Rossi, N, Apolinário da Silva, L, Zaránd, A, Ruiz-Bañobre, J, Heuveline, V, Mecklin, J, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, P, Therkildsen, C, Madsen, M, Burgdorf, S, Hopper, J, Win, A, Haile, R, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, P, Figueiredo, J, Buchanan, D, Thibodeau, S, 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, J, Moreira, L, Sánchez, A, Hovig, E, Nakken, S, Green, K, Lalloo, F, Hill, J, Crosbie, E, Mints, M, Goldberg, Y, Dominguez-Valentin M., Haupt S., Seppälä T. T., Sampson J. R., Sunde L., Bernstein I., Jenkins M. A., Engel C., Aretz S., Nielsen M., Capella G., Balaguer F., Evans D. G., Burn J., Holinski-Feder E., Bertario L., Bonanni B., Lindblom A., Levi Z., Macrae F., Winship I., Plazzer J. P., Sijmons R., Laghi L., Della Valle A., Heinimann K., Dębniak T., Fruscio R., Lopez-Koestner F., Alvarez-Valenzuela K., Katz L. H., Laish I., Vainer E., Vaccaro C., Carraro D. M., Monahan K., Half E., Stakelum A., Winter D., Kennelly R., Gluck N., Sheth H., Abu-Freha N., Greenblatt M., Rossi B. M., Bohorquez M., Cavestro G. M., Lino-Silva L. S., Horisberger K., Tibiletti M. G., Nascimento I. d., Thomas H., Rossi N. T., Apolinário da Silva L., Zaránd A., Ruiz-Bañobre J., Heuveline V., Mecklin J. P., Pylvänäinen K., Renkonen-Sinisalo L., Lepistö A., Peltomäki P., Therkildsen C., Madsen M. G., Burgdorf S. K., Hopper J. L., Win A. K., Haile R. W., Lindor N., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J., Buchanan D. D., Thibodeau S. N., 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 J. B., Moreira L., Sánchez A., Hovig E., Nakken S., Green K., Lalloo F., Hill J., Crosbie E., Mints M., and Goldberg Y.
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 ackno
Published: 2023

2. Die Sequenzvarianten Arg72Pro des Tumorsuppressorgens p53 und Arg462Gln des Prostatakarzinom-Suszeptibilitätsgens RNASEL haben einen additiven Effekt auf das Erkrankungsalter von HNPCC-Patienten

Author: Deutsches HNPCC-Konsortium, Krüger, Stefan, Engel, C., Bier, A., Silber, A. -S., Görgens, H., Mangold, E., Pagenstecher, C., Holinski-Feder, E., von Knebel Doeberitz, M., Royer-Pokora, B., Dechant, S., Pox, C., Rahner, N., Müller, A., Schackert, H. K., Steinau, H. -U., editor, Schackert, H. K., editor, and Bauer, H., editor
Published: 2007
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3. 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, J.G., Haupt, S., Dominguez-Valentin, M., Sunde, L., Bernstein, I., Engel, C., Aretz, S., Nielsen, M., Capella, G., Evans, D.G., Burn, J., Holinski-Feder, E., Bertario, L., Bonanni, B., Lindblom, A., Levi, Z., Macrae, F., Winship, I., Plazzer, J.P., Sijmons, R., Laghi, L., Valle, A.D., Heinimann, K., Half, E., Lopez-Koestner, F., Alvarez-Valenzuela, K., Scott, R.J., Katz, L., Laish, I., Vainer, E., Vaccaro, C.A., Carraro, D.M., Gluck, N., Abu-Freha, N., Stakelum, A., Kennelly, R., Winter, D., Rossi, B.M., Greenblatt, M., Bohorquez, M., Sheth, H., Tibiletti, M.G., Lino-Silva, L.S., Horisberger, K., Portenkirchner, C., Nascimento, I., Rossi, N.T., Silva, L.A. da, Thomas, H, Zaránd, A., Mecklin, J.P., Pylvänäinen, K., Renkonen-Sinisalo, L., Lepisto, A., Peltomäki, P., Therkildsen, C., Lindberg, L.J., Thorlacius-Ussing, O., Doeberitz, M. von Knebel, Loeffler, M., Rahner, N., Steinke-Lange, V., Schmiegel, W., Vangala, D., Perne, C., Hüneburg, R., Vargas, A.F. de, Latchford, A., Gerdes, A.M., Backman, A.S., Guillén-Ponce, C., Snyder, C., Lautrup, C.K., Amor, D., Palmero, E., Stoffel, E., Duijkers, F., Hall, M.J., Hampel, H., Williams, H., Okkels, H., Lubiński, J., Reece, J., Ngeow, J., Guillem, J.G., Arnold, J., Wadt, K., Monahan, K., Senter, L., Rasmussen, L.J., Hest, L.P. van, Ricciardiello, L., Kohonen-Corish, M.R.J., Ligtenberg, M.J.L., Southey, M., Aronson, M., Zahary, M.N., Samadder, N.J., Hoogerbrugge, N., Sampson, J.R., Jenkins, M.A., Møller, P., Seppälä, T., Dowty, J.G., Haupt, S., Dominguez-Valentin, M., Sunde, L., Bernstein, I., Engel, C., Aretz, S., Nielsen, M., Capella, G., Evans, D.G., Burn, J., Holinski-Feder, E., Bertario, L., Bonanni, B., Lindblom, A., Levi, Z., Macrae, F., Winship, I., Plazzer, J.P., Sijmons, R., Laghi, L., Valle, A.D., Heinimann, K., Half, E., Lopez-Koestner, F., Alvarez-Valenzuela, K., Scott, R.J., Katz, L., Laish, I., Vainer, E., Vaccaro, C.A., Carraro, D.M., Gluck, N., Abu-Freha, N., Stakelum, A., Kennelly, R., Winter, D., Rossi, B.M., Greenblatt, M., Bohorquez, M., Sheth, H., Tibiletti, M.G., Lino-Silva, L.S., Horisberger, K., Portenkirchner, C., Nascimento, I., Rossi, N.T., Silva, L.A. da, Thomas, H, Zaránd, A., Mecklin, J.P., Pylvänäinen, K., Renkonen-Sinisalo, L., Lepisto, A., Peltomäki, P., Therkildsen, C., Lindberg, L.J., Thorlacius-Ussing, O., Doeberitz, M. von Knebel, Loeffler, M., Rahner, N., Steinke-Lange, V., Schmiegel, W., Vangala, D., Perne, C., Hüneburg, R., Vargas, A.F. de, Latchford, A., Gerdes, A.M., Backman, A.S., Guillén-Ponce, C., Snyder, C., Lautrup, C.K., Amor, D., Palmero, E., Stoffel, E., Duijkers, F., Hall, M.J., Hampel, H., Williams, H., Okkels, H., Lubiński, J., Reece, J., Ngeow, J., Guillem, J.G., Arnold, J., Wadt, K., Monahan, K., Senter, L., Rasmussen, L.J., Hest, L.P. van, Ricciardiello, L., Kohonen-Corish, M.R.J., Ligtenberg, M.J.L., Southey, M., Aronson, M., Zahary, M.N., Samadder, N.J., Hoogerbrugge, N., Sampson, J.R., and Jenkins, M.A.
Abstract: Item does not contain fulltext
Published: 2022

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

Author: Moller, P, Seppala, 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, J-P, Sijmons, R, Laghi, L, Della Valle, A, 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, Zarand, A, Mecklin, J-P, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Peltomaki, 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, Hueneburg, R, de Vargas, AF, Latchford, A, Gerdes, A-M, Backman, A-S, Guillen-Ponce, C, Snyder, C, Lautrup, CK, Amor, D, Palmero, E, Stoffel, E, Duijkers, F, Hall, MJ, Hampel, H, Williams, H, Okkels, H, Lubinski, 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, Debniak, T, John, T, van Overeem Hansen, T, Caldes, T, Yamaguchi, T, Barca-Tierno, V, Garre, P, Cavestro, GM, Weitz, J, Redler, S, Buettner, 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, Duenas, 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, Jenkins, MA, Moller, P, Seppala, 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, J-P, Sijmons, R, Laghi, L, Della Valle, A, 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, Zarand, A, Mecklin, J-P, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Peltomaki, 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, Hueneburg, R, de Vargas, AF, Latchford, A, Gerdes, A-M, Backman, A-S, Guillen-Ponce, C, Snyder, C, Lautrup, CK, Amor, D, Palmero, E, Stoffel, E, Duijkers, F, Hall, MJ, Hampel, H, Williams, H, Okkels, H, Lubinski, 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, Debniak, T, John, T, van Overeem Hansen, T, Caldes, T, Yamaguchi, T, Barca-Tierno, V, Garre, P, Cavestro, GM, Weitz, J, Redler, S, Buettner, 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, Duenas, 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_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_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_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_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_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.
Published: 2022

5. Recommendations to improve identification of hereditary and familial colorectal cancer in Europe

Author: Vasen, H. F. A., Möslein, G., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Blanco, I., Bulow, S., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I., Rahner, N., Hes, F. J., Hodgson, S., Mecklin, J.-P., Møller, P., Myrhøj, T., Nagengast, F. M., Parc, Y., Ponz de Leon, M., Renkonen-Sinisalo, L., Sampson, J. R., Stormorken, A., Tejpar, S., Thomas, H. J. W., Wijnen, J., Lubinski, J., Järvinen, H., Claes, E., Heinimann, K., Karagiannis, J. A., Lindblom, A., Dove-Edwin, I., and Müller, H.
Published: 2010
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6. 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
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7. 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

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

Author: Dominguez-Valentin, M, Crosbie, EJ, Engel, C, Aretz, S, Macrae, F, Winship, I, Capella, G, Thomas, H, Nakken, S, Hovig, E, Nielsen, M, Sijmons, RH, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Mints, M, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, 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, Brunet Vidal, J, Kariv, R, Rosner, G, Alejandra Pinero, T, Laura Gonzalez, M, Kalfayan, P, Ryan, N, Ten Broeke, SW, Jenkins, MA, Sunde, L, Bernstein, I, Burn, J, Greenblatt, M, Cappel, WHDVTN, Della Valle, A, Lopez-Koestner, F, Alvarez, K, Buettner, R, Goergens, H, Morak, M, Holzapfel, S, Hueneburg, R, Doeberitz, MVK, Loeffler, M, Rahner, N, Weitz, J, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Auranen, A, Hopper, JL, Win, AK, Haile, RW, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Therkildsen, C, Okkels, H, Ketabi, Z, Denton, OG, Rodland, EA, Vasen, H, Neffa, F, Esperon, P, Tjandra, D, Moeslein, G, Sampson, JR, Evans, DG, Seppala, TT, Moller, P, Dominguez-Valentin, M, Crosbie, EJ, Engel, C, Aretz, S, Macrae, F, Winship, I, Capella, G, Thomas, H, Nakken, S, Hovig, E, Nielsen, M, Sijmons, RH, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Mints, M, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, 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, Brunet Vidal, J, Kariv, R, Rosner, G, Alejandra Pinero, T, Laura Gonzalez, M, Kalfayan, P, Ryan, N, Ten Broeke, SW, Jenkins, MA, Sunde, L, Bernstein, I, Burn, J, Greenblatt, M, Cappel, WHDVTN, Della Valle, A, Lopez-Koestner, F, Alvarez, K, Buettner, R, Goergens, H, Morak, M, Holzapfel, S, Hueneburg, R, Doeberitz, MVK, Loeffler, M, Rahner, N, Weitz, J, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Auranen, A, Hopper, JL, Win, AK, Haile, RW, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Therkildsen, C, Okkels, H, Ketabi, Z, Denton, OG, Rodland, EA, Vasen, H, Neffa, F, Esperon, P, Tjandra, D, Moeslein, G, Sampson, JR, Evans, DG, Seppala, TT, and Moller, P
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

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

Author: Dominguez-Valentin, M, Plazzer, J-P, Sampson, JR, Engel, C, Aretz, S, Jenkins, MA, Sunde, L, Bernstein, I, Capella, G, Balaguer, F, Macrae, F, Winship, IM, Thomas, H, Evans, DG, Burn, J, Greenblatt, M, Cappel, WHDVTN, Sijmons, RH, Nielsen, M, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Lindblom, A, Della Valle, A, Lopez-Kostner, F, Alvarez, K, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, Nakken, S, Hovig, E, Green, K, Lalloo, F, Hill, J, Vasen, HFA, Perne, C, Buettner, R, Goergens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Hueneburg, R, Doeberitz, MVK, Loeffler, M, Rahner, N, Weitz, J, Steinke-Lange, V, Schmiegel, W, Vangala, D, Crosbie, EJ, Pineda, M, Navarro, M, Brunet, J, Moreira, L, Sanchez, A, Serra-Burriel, M, Mints, M, Kariv, R, Rosner, G, Pinero, TA, Pavicic, WH, Kalfayan, P, ten Broeke, SW, Mecklin, J-P, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Peltomaki, P, Hopper, JL, Win, AK, Buchanan, DD, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Therkildsen, C, Hansen, TVO, Lindberg, L, Rodland, EA, Neffa, F, Esperon, P, Tjandra, D, Moslein, G, Seppala, TT, Moller, P, Dominguez-Valentin, M, Plazzer, J-P, Sampson, JR, Engel, C, Aretz, S, Jenkins, MA, Sunde, L, Bernstein, I, Capella, G, Balaguer, F, Macrae, F, Winship, IM, Thomas, H, Evans, DG, Burn, J, Greenblatt, M, Cappel, WHDVTN, Sijmons, RH, Nielsen, M, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Lindblom, A, Della Valle, A, Lopez-Kostner, F, Alvarez, K, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, Nakken, S, Hovig, E, Green, K, Lalloo, F, Hill, J, Vasen, HFA, Perne, C, Buettner, R, Goergens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Hueneburg, R, Doeberitz, MVK, Loeffler, M, Rahner, N, Weitz, J, Steinke-Lange, V, Schmiegel, W, Vangala, D, Crosbie, EJ, Pineda, M, Navarro, M, Brunet, J, Moreira, L, Sanchez, A, Serra-Burriel, M, Mints, M, Kariv, R, Rosner, G, Pinero, TA, Pavicic, WH, Kalfayan, P, ten Broeke, SW, Mecklin, J-P, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Peltomaki, P, Hopper, JL, Win, AK, Buchanan, DD, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Therkildsen, C, Hansen, TVO, Lindberg, L, Rodland, EA, Neffa, F, Esperon, P, Tjandra, D, Moslein, G, Seppala, TT, and Moller, P
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

10. Pathogenic PTPN11 variants involving the poly-glutamine Gln255-Gln256-Gln257 stretch highlight the relevance of helix B in SHP2's functional regulation

Author: Martinelli, S, Pannone, L, Lissewski, C, Brinkmann, J, Flex, E, Schanze, D, Calligari, P, Anselmi, M, Pantaleoni, F, Canale, Vc, Radio, Fc, Ioannides, A, Rahner, N, Schanze, I, Josifova, D, Bocchinfuso, G, Ryten, M, Stella, L, Tartaglia, M, and Zenker, M
Subjects: Settore CHIM/02, ERK phosphorylation studies, in vitro phosphatase assay, Noonan syndrome, SHP2, molecular dynamics simulations, PTPN11
Published: 2020

11. MSH6 mutation in Muir–Torre syndrome: could this be a rare finding?

Author: MANGOLD, E., RAHNER, N., FRIEDRICHS, N., BUETTNER, R., PAGENSTECHER, C., ARETZ, S., FRIEDL, W., RUZICKA, T., PROPPING, P., RÜTTEN, A., and KRUSE, R.
Published: 2007

12. Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome

Author: Engel, C., Ahadova, A., Seppälä, T.T., Aretz, S., Bigirwamungu-Bargeman, M., Bläker, H., Bucksch, K., Büttner, R., Cappel, W.T. de Vos Tot Nede, Endris, V., Holinski-Feder, E., Holzapfel, S., Hüneburg, R., Jacobs, M., Koornstra, J.J., Langers, A.M., Lepistö, A., Morak, M., Möslein, G., Peltomäki, P., Pylvänäinen, K., Rahner, N., Renkonen-Sinisalo, L., Schulmann, K., Steinke-Lange, V., Stenzinger, A., Strassburg, C.P., Meeberg, P.C. van de, Kouwen, M.C.A. van, Leerdam, M. van, Vangala, D.B., Vecht, J., Verhulst, M.L., Doeberitz, M. von Knebel, Weitz, J., Zachariae, S., Loeffler, M., Mecklin, J.P., Kloor, M., Vasen, H.F., Engel, C., Ahadova, A., Seppälä, T.T., Aretz, S., Bigirwamungu-Bargeman, M., Bläker, H., Bucksch, K., Büttner, R., Cappel, W.T. de Vos Tot Nede, Endris, V., Holinski-Feder, E., Holzapfel, S., Hüneburg, R., Jacobs, M., Koornstra, J.J., Langers, A.M., Lepistö, A., Morak, M., Möslein, G., Peltomäki, P., Pylvänäinen, K., Rahner, N., Renkonen-Sinisalo, L., Schulmann, K., Steinke-Lange, V., Stenzinger, A., Strassburg, C.P., Meeberg, P.C. van de, Kouwen, M.C.A. van, Leerdam, M. van, Vangala, D.B., Vecht, J., Verhulst, M.L., Doeberitz, M. von Knebel, Weitz, J., Zachariae, S., Loeffler, M., Mecklin, J.P., Kloor, M., and Vasen, H.F.
Abstract: Contains fulltext : 220040.pdf (Publisher’s version ) (Closed access), BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are
Published: 2020

13. Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database (vol 22, pg 15, 2020)

Author: Dominguez-Valentin, M, Sampson, JR, Seppala, TT, ten Broeke, SW, Plazzer, J-P, Nakken, S, Engel, C, Aretz, S, Jenkins, MA, Sunde, L, Bernstein, I, Capella, G, Balaguer, F, Thomas, H, Evans, DG, Burn, J, Greenblatt, M, Hovig, E, de Vos tot Nederveen Cappel, WH, Sijmons, RH, Bertario, L, Tibiletti, MG, Cavestro, GM, Lindblom, A, Della Valle, A, Lopez-Kostner, F, Gluck, N, Katz, LH, Heinimann, K, Vaccaro, CA, Buttner, R, Gorgens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Huneburg, R, Knebel Doeberitz, MV, Loeffler, M, Rahner, N, Schackert, HK, Steinke-Lange, V, Schmiegel, W, Vangala, D, Pylvanainen, K, Renkonen-Sinisalo, L, Hopper, JL, Win, AK, Haile, RW, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, 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, EJ, Hill, J, Denton, OG, Frayling, IM, Rodland, EA, Vasen, H, Mints, M, Neffa, F, Esperon, P, Alvarez, K, Kariv, R, Rosner, G, Pinero, TA, Gonzalez, ML, Kalfayan, P, Tjandra, D, Winship, IM, Macrae, F, Moslein, G, Mecklin, J-P, Nielsen, M, Moller, P, Dominguez-Valentin, M, Sampson, JR, Seppala, TT, ten Broeke, SW, Plazzer, J-P, Nakken, S, Engel, C, Aretz, S, Jenkins, MA, Sunde, L, Bernstein, I, Capella, G, Balaguer, F, Thomas, H, Evans, DG, Burn, J, Greenblatt, M, Hovig, E, de Vos tot Nederveen Cappel, WH, Sijmons, RH, Bertario, L, Tibiletti, MG, Cavestro, GM, Lindblom, A, Della Valle, A, Lopez-Kostner, F, Gluck, N, Katz, LH, Heinimann, K, Vaccaro, CA, Buttner, R, Gorgens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Huneburg, R, Knebel Doeberitz, MV, Loeffler, M, Rahner, N, Schackert, HK, Steinke-Lange, V, Schmiegel, W, Vangala, D, Pylvanainen, K, Renkonen-Sinisalo, L, Hopper, JL, Win, AK, Haile, RW, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, 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, EJ, Hill, J, Denton, OG, Frayling, IM, Rodland, EA, Vasen, H, Mints, M, Neffa, F, Esperon, P, Alvarez, K, Kariv, R, Rosner, G, Pinero, TA, Gonzalez, ML, Kalfayan, P, Tjandra, D, Winship, IM, Macrae, F, Moslein, G, Mecklin, J-P, Nielsen, M, and Moller, P
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2020

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

Author: Dominguez-Valentin, M, Sampson, JR, Seppala, TT, ten Broeke, SW, Plazzer, J-P, Nakken, S, Engel, C, Aretz, S, Jenkins, MA, Sunde, L, Bernstein, I, Capella, G, Balaguer, F, Thomas, H, Evans, DG, Burn, J, Greenblatt, M, Hovig, E, de Vos Tot Nederveen Cappel, WH, Sijmons, RH, Bertario, L, Tibiletti, MG, Cavestro, GM, Lindblom, A, Della Valle, A, Lopez-Kostner, F, Gluck, N, Katz, LH, Heinimann, K, Vaccaro, CA, Buettner, R, Goergens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Hueneburg, R, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schackert, HK, Steinke-Lange, V, Schmiegel, W, Vangala, D, Pylvanainen, K, Renkonen-Sinisalo, L, Hopper, JL, Win, AK, Haile, RW, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, 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, EJ, Hill, J, Denton, OG, Frayling, IM, Rodland, EA, Vasen, H, Mints, M, Neffa, F, Esperon, P, Alvarez, K, Kariv, R, Rosner, G, Pinero, TA, Gonzalez, ML, Kalfayan, P, Tjandra, D, Winship, IM, Macrae, F, Moeslein, G, Mecklin, J-P, Nielsen, M, Moller, P, Dominguez-Valentin, M, Sampson, JR, Seppala, TT, ten Broeke, SW, Plazzer, J-P, Nakken, S, Engel, C, Aretz, S, Jenkins, MA, Sunde, L, Bernstein, I, Capella, G, Balaguer, F, Thomas, H, Evans, DG, Burn, J, Greenblatt, M, Hovig, E, de Vos Tot Nederveen Cappel, WH, Sijmons, RH, Bertario, L, Tibiletti, MG, Cavestro, GM, Lindblom, A, Della Valle, A, Lopez-Kostner, F, Gluck, N, Katz, LH, Heinimann, K, Vaccaro, CA, Buettner, R, Goergens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Hueneburg, R, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schackert, HK, Steinke-Lange, V, Schmiegel, W, Vangala, D, Pylvanainen, K, Renkonen-Sinisalo, L, Hopper, JL, Win, AK, Haile, RW, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, 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, EJ, Hill, J, Denton, OG, Frayling, IM, Rodland, EA, Vasen, H, Mints, M, Neffa, F, Esperon, P, Alvarez, K, Kariv, R, Rosner, G, Pinero, TA, Gonzalez, ML, Kalfayan, P, Tjandra, D, Winship, IM, Macrae, F, Moeslein, G, Mecklin, J-P, Nielsen, M, and Moller, P
Abstract: PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.
Published: 2020

15. 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
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16. The Apparent Genetic Anticipation in PMS2-Associated Lynch Syndrome Families Is Explained by Birth-cohort Effect

Author: Broeke, S.W. ten, Rodriguez-Girondo, M., Suerink, M., Aretz, S., Bernstein, I., Capella, G., Engel, C., Gomez-Garcia, E.B., Hest, L.P. van, Doeberitz, M. von Knebel, Lagerstedt-Robinson, K., Letteboer, T.G., Moller, P., Os, T.A. van, Pineda, M., Rahner, N., Olderode-Berends, M.J., Salome, J. von, Schackert, H.K., Spruijt, L., Steinke-Lange, V., Wagner, A., Tops, C.M., Nielsen, M., Broeke, S.W. ten, Rodriguez-Girondo, M., Suerink, M., Aretz, S., Bernstein, I., Capella, G., Engel, C., Gomez-Garcia, E.B., Hest, L.P. van, Doeberitz, M. von Knebel, Lagerstedt-Robinson, K., Letteboer, T.G., Moller, P., Os, T.A. van, Pineda, M., Rahner, N., Olderode-Berends, M.J., Salome, J. von, Schackert, H.K., Spruijt, L., Steinke-Lange, V., Wagner, A., Tops, C.M., and Nielsen, M.
Abstract: Contains fulltext : 206727.pdf (publisher's version ) (Closed access), BACKGROUND: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families. METHODS: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias. RESULTS: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648-2.619) and HR = 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively]. CONCLUSIONS: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome. IMPACT: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition.
Published: 2019

17. Cancer Risks for PMS2-Associated Lynch Syndrome (vol 29, pg 2961, 2018)

Author: ten Broeke, SW, van der Klift, HM, Tops, CMJ, Aretz, S, Bernstein, I, Buchanan, DD, de la Chapelle, A, Capella, G, Clendenning, M, Engel, C, Gallinger, S, Garcia, EG, Figueiredo, JC, Haile, R, Hampel, HL, van Hest, L, Hopper, JL, Hoogerbrugge, N, Doeberitz, MVK, Le Marchand, L, Letteboer, TGW, Jenkins, MA, Lindblom, A, Lindor, NM, Mensenkamp, AR, Moller, P, Newcomb, PA, van Os, TAM, Pearlman, R, Pineda, M, Rahner, N, Redeker, EJW, Olderode-Berends, MJW, Rosty, C, Schackert, HK, Scott, R, Senter, L, Spruijt, L, Steinke-Lange, V, Suerink, M, Thibodeau, S, Vos, YJ, Wagner, A, Winship, I, Hes, FJ, Vasen, HFA, Wijnen, JT, Nielsen, M, Win, AK, ten Broeke, SW, van der Klift, HM, Tops, CMJ, Aretz, S, Bernstein, I, Buchanan, DD, de la Chapelle, A, Capella, G, Clendenning, M, Engel, C, Gallinger, S, Garcia, EG, Figueiredo, JC, Haile, R, Hampel, HL, van Hest, L, Hopper, JL, Hoogerbrugge, N, Doeberitz, MVK, Le Marchand, L, Letteboer, TGW, Jenkins, MA, Lindblom, A, Lindor, NM, Mensenkamp, AR, Moller, P, Newcomb, PA, van Os, TAM, Pearlman, R, Pineda, M, Rahner, N, Redeker, EJW, Olderode-Berends, MJW, Rosty, C, Schackert, HK, Scott, R, Senter, L, Spruijt, L, Steinke-Lange, V, Suerink, M, Thibodeau, S, Vos, YJ, Wagner, A, Winship, I, Hes, FJ, Vasen, HFA, Wijnen, JT, Nielsen, M, and Win, AK
Abstract: This corrects the article "Cancer Risks for PMS2-Associated Lynch Syndrome" in volume 36 on page 2961.
Published: 2019

18. Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report

Author: Seppala, TT, Ahadova, A, Dominguez-Valentin, M, Macrae, F, Evans, DG, Therkildsen, C, Sampson, J, Scott, R, Burn, J, Moeslein, G, Bernstein, I, Holinski-Feder, E, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Lautrup, CK, Lindblom, A, Plazzer, J-P, Winship, I, Tjandra, D, Katz, LH, Aretz, S, Hueneburg, R, Holzapfel, S, Heinimann, K, Della Valle, A, Neffa, F, Gluck, N, Cappel, WHDVTN, Vasen, H, Morak, M, Steinke-Lange, V, Engel, C, Rahner, N, Schmiegel, W, Vangala, D, Thomas, H, Green, K, Lalloo, F, Crosbie, EJ, Hill, J, Capella, G, Pineda, M, Navarro, M, Blanco, I, ten Broeke, S, Nielsen, M, Ljungmann, K, Nakken, S, Lindor, N, Frayling, I, Hovig, E, Sunde, L, Kloor, M, Mecklin, J-P, Kalager, M, Moller, P, Seppala, TT, Ahadova, A, Dominguez-Valentin, M, Macrae, F, Evans, DG, Therkildsen, C, Sampson, J, Scott, R, Burn, J, Moeslein, G, Bernstein, I, Holinski-Feder, E, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Lautrup, CK, Lindblom, A, Plazzer, J-P, Winship, I, Tjandra, D, Katz, LH, Aretz, S, Hueneburg, R, Holzapfel, S, Heinimann, K, Della Valle, A, Neffa, F, Gluck, N, Cappel, WHDVTN, Vasen, H, Morak, M, Steinke-Lange, V, Engel, C, Rahner, N, Schmiegel, W, Vangala, D, Thomas, H, Green, K, Lalloo, F, Crosbie, EJ, Hill, J, Capella, G, Pineda, M, Navarro, M, Blanco, I, ten Broeke, S, Nielsen, M, Ljungmann, K, Nakken, S, Lindor, N, Frayling, I, Hovig, E, Sunde, L, Kloor, M, Mecklin, J-P, Kalager, M, and Moller, P
Abstract: BACKGROUND: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. METHODS: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. RESULTS: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). CONCLUSIONS: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situa
Published: 2019

19. Genetic testing for hereditary breast and ovarian cancer using the GC-HBOC TruRisk® gene panel

Author: Honisch, E, additional, Vesper, AS, additional, Rahner, N, additional, Niederacher, D, additional, and Fehm, T, additional
Published: 2018
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20. Cancer Risks for PMS2-Associated Lynch Syndrome

Author: ten Broeke, SW, van der Klift, HM, Tops, CMJ, Aretz, S, Bernstein, I, Buchanan, DD, de la Chapelle, A, Capella, G, Clendenning, M, Engel, C, Gallinger, S, Gomez Garcia, E, Figueiredo, JC, Haile, R, Hampel, HL, Hopper, JL, Hoogerbrugge, N, Doeberitz, MVK, Le Marchand, L, Letteboer, TGW, Jenkins, MA, Lindblom, A, Lindor, NM, Mensenkamp, AR, Moller, P, Newcomb, PA, van Os, TAM, Pearlman, R, Pineda, M, Rahner, N, Redeker, EJW, Olderode-Berends, MJW, Rosty, C, Schackert, HK, Scott, R, Senter, L, Spruijt, L, Steinke-Lange, V, Suerink, M, Thibodeau, S, Vos, YJ, Wagner, A, Winship, I, Hes, FJ, Vasen, HFA, Wijnen, JT, Nielsen, M, Win, AK, ten Broeke, SW, van der Klift, HM, Tops, CMJ, Aretz, S, Bernstein, I, Buchanan, DD, de la Chapelle, A, Capella, G, Clendenning, M, Engel, C, Gallinger, S, Gomez Garcia, E, Figueiredo, JC, Haile, R, Hampel, HL, Hopper, JL, Hoogerbrugge, N, Doeberitz, MVK, Le Marchand, L, Letteboer, TGW, Jenkins, MA, Lindblom, A, Lindor, NM, Mensenkamp, AR, Moller, P, Newcomb, PA, van Os, TAM, Pearlman, R, Pineda, M, Rahner, N, Redeker, EJW, Olderode-Berends, MJW, Rosty, C, Schackert, HK, Scott, R, Senter, L, Spruijt, L, Steinke-Lange, V, Suerink, M, Thibodeau, S, Vos, YJ, Wagner, A, Winship, I, Hes, FJ, Vasen, HFA, Wijnen, JT, Nielsen, M, and Win, AK
Abstract: PURPOSE: Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants. METHODS: A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance. RESULTS: In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer. CONCLUSION: Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.
Published: 2018

21. Klassische Chromoendoskopie erhöht die Adenomdetektionsrate im Vergleich zur Standardkoloskopie bei Lynch-Syndrom – eine Multicenterstudie

Author: Hüneburg, R, additional, van Heteren, P, additional, Holzapfel, S, additional, Weismüller, TJ, additional, Engel, C, additional, Rahner, N, additional, Möslein, G, additional, Schmiegel, W, additional, Büttner, R, additional, Loeffler, M, additional, Aretz, S, additional, Strassburg, CP, additional, and Nattermann, J, additional
Published: 2017
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22. 38-jährige Patientin mit DCIS links und Nachweis eines Mosaiks einer pathogenen ATM-Mutation

Author: Jäger, B, additional, Honisch, E, additional, Niederacher, D, additional, Ruhl, D, additional, Rahner, N, additional, Fehm, T, additional, and Vesper, AS, additional
Published: 2017
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23. Multi-Genanalyse mit dem TruRisk™-Genpanel beim familiären Brust- und Eierstockkrebs

Author: Kaleta, T, additional, Niederacher, D, additional, Honisch, E, additional, Rahner, N, additional, Cierna, B, additional, Loosen, K, additional, Fehm, T, additional, and Vesper, AS, additional
Published: 2017
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24. Mutation analysis and association studies of the neurofilament L, M and H genes in German Parkinson's disease patients

Author: Krueger, R., Rahner, N., Fischer, C., Schulte, T., Holzmann, C., Epplen, J.T., Schoels, L., and Riess, O.
Subjects: Human genetics -- Research, Human chromosome abnormalities -- Research, Genetic disorders -- Research, Mutation (Biology) -- Analysis, Parkinson's disease -- Genetic aspects, Cytoplasmic filaments -- Genetic aspects, Biological sciences
Published: 2001

25. The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers

Author: Suerink, M., Klift, H.M. van der, Broeke, S.W. ten, Dekkers, O.M., Bernstein, I., Capella Munar, G., Garcia, E., Hoogerbrugge, N., Letteboer, T.G., Menko, F.H., Lindblom, A., Mensenkamp, A., Moller, P., Os, T.A. van, Rahner, N., Redeker, B.J., Olderode-Berends, M.J., Spruijt, L., Vos, Y.J., Wagner, A., Morreau, H., Hes, F.J., Vasen, H.F.A., Tops, C.M., Wijnen, J.T., Nielsen, M., Suerink, M., Klift, H.M. van der, Broeke, S.W. ten, Dekkers, O.M., Bernstein, I., Capella Munar, G., Garcia, E., Hoogerbrugge, N., Letteboer, T.G., Menko, F.H., Lindblom, A., Mensenkamp, A., Moller, P., Os, T.A. van, Rahner, N., Redeker, B.J., Olderode-Berends, M.J., Spruijt, L., Vos, Y.J., Wagner, A., Morreau, H., Hes, F.J., Vasen, H.F.A., Tops, C.M., Wijnen, J.T., and Nielsen, M.
Abstract: Item does not contain fulltext, PURPOSE: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype. METHODS: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally. RESULTS: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC. CONCLUSIONS: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-of-origin effect.Genet Med 18 4, 405-409.
Published: 2016

26. BRCA-Mutationsnachweis an einem ausgesuchten Patientinnenkollektiv mit Triple-negativem Mammakarzinom und negativer Familienanamnese

Author: Kaleta, T, primary, Niederacher, D, additional, Rahner, N, additional, Loosen, K, additional, Cierna, B, additional, Ruhl, D, additional, Fehm, T, additional, and Vesper, AS, additional
Published: 2016
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27. Next-Gen-Sequencing basierte Multi-Genanalyse (TruRisk™-Genpanel) beim familiären Brust- und Eierstockkrebs

Author: Kaleta, T, primary, Vesper, AS, additional, Rahner, N, additional, Loosen, K, additional, Cierna, B, additional, Ruhl, D, additional, Fehm, T, additional, and Niederacher, D, additional
Published: 2016
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28. 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

29. Mutation and association analyses of the candidate genes ESR1, ESR2, MAX, PCNA, and KAT2A in patients with unexplained MSH2-deficient tumors

Author: Rahner, N., Brockschmidt, F.F., Steinke, V., Kahl, P., Becker, T., Vasen, H.F., Wijnen, J.T., Tops, C.J., Holinski-Feder, E., Ligtenberg, M.J.L., Spruijt, L., Gorgens, H., Stemmler, S., Kloor, M., Dietmaier, W., Schumacher, J., Nothen, Markus, Propping, P., Hoogerbrugge, N., Genetica & Celbiologie, Klinische Genetica, and RS: GROW - School for Oncology and Reproduction
Subjects: Cancer Research, Candidate gene, congenital, hereditary, and neonatal diseases and abnormalities, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], HNPCC, Single-nucleotide polymorphism, KAT2A, Biology, MLH1, Immunoenzyme Techniques, Germline mutation, Translational research [ONCOL 3], Proliferating Cell Nuclear Antigen, Genetics, medicine, Estrogen Receptor beta, Humans, PCNA, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], Genetics (clinical), Histone Acetyltransferases, ESR, Hereditary cancer and cancer-related syndromes [ONCOL 1], Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Estrogen Receptor alpha, nutritional and metabolic diseases, medicine.disease, Prognosis, Colorectal Neoplasms, Hereditary Nonpolyposis, Lynch syndrome, digestive system diseases, Association study, MutS Homolog 2 Protein, Mutation analysis, Oncology, MSH2, Case-Control Studies, Mutation, Mutation testing, DNA mismatch repair, Follow-Up Studies, Microsatellite Repeats, MAX
Abstract: Item does not contain fulltext Lynch syndrome (Hereditary non-polyposis colorectal cancer/HNPCC) is a cancer susceptibility syndrome which is caused by germline mutations in DNA mismatch repair (MMR) genes, in particular MLH1 and MSH2. A pathogenic germline mutation in the respective MMR gene is suggested by the finding of a loss of a mismatch repair protein in tumor tissue on immunohistochemical staining combined with an early age of onset and/or the familial occurrence of colorectal cancer. Pathogenic germline mutations are identifiable in around 60% of patients suspected of Lynch syndrome, depending on the familial occurrence. The aim of the present study was to identify novel susceptibility genes for Lynch syndrome. 64 Healthy controls and 64 Lynch syndrome patients with no pathogenic MSH2 mutation but a loss of MSH2 expression in their tumor tissue were screened for rare and disease causing germline mutations in the functional candidate genes ESR1, ESR2, MAX, PCNA, and KAT2A. Thirty variants were identified, and these were then genotyped in an independent sample of 36 mutation negative Lynch syndrome patients and 234 controls. Since a trend towards association was observed for KAT2A, an additional set of 21 tagging SNPs was analyzed at this locus in a final case-control sample of 142 mutation negative Lynch syndrome patients and 298 controls. The mutation analysis failed to reveal any rare disease-causing mutations. No association was found at the single-marker or haplotypic level for any common disease-modifying variant. The present results suggest that neither rare nor common genetic variants in ESR1, ESR2, MAX, PCNA, or KAT2A contribute to the development of Lynch syndrome. 01 maart 2012
Published: 2012

30. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk

Author: Broeke, S.W. ten, Brohet, R.M., Tops, C.M., Klift, H.M. van der, Velthuizen, M.E., Bernstein, I., Capella Munar, G., Garcia, E., Hoogerbrugge, N., Letteboer, T.G., Menko, F.H., Lindblom, A., Mensenkamp, A.R., Moller, P., Os, T.A. van, Rahner, N., Redeker, B.J., Sijmons, R.H., Spruijt, L., Suerink, M., Vos, Y.J., Wagner, A., Hes, F.J., Vasen, H.F.A., Nielsen, M., Wijnen, J.T., Broeke, S.W. ten, Brohet, R.M., Tops, C.M., Klift, H.M. van der, Velthuizen, M.E., Bernstein, I., Capella Munar, G., Garcia, E., Hoogerbrugge, N., Letteboer, T.G., Menko, F.H., Lindblom, A., Mensenkamp, A.R., Moller, P., Os, T.A. van, Rahner, N., Redeker, B.J., Sijmons, R.H., Spruijt, L., Suerink, M., Vos, Y.J., Wagner, A., Hes, F.J., Vasen, H.F.A., Nielsen, M., and Wijnen, J.T.
Abstract: Item does not contain fulltext, PURPOSE: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. METHODS: Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers. RESULTS: The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P < .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis. CONCLUSION: CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.
Published: 2015

31. BRCA-Mutations-Nachweis an einem ausgesuchten Patientinnenkollektiv mit Triple-negativem Mammakarzinom und negativer Familienanamnese

Author: Vesper, A, primary, Niederacher, D, additional, Rahner, N, additional, Kaleta, T, additional, and Fehm, T, additional
Published: 2015
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32. The additive effect of p53 Arg72Pro and RNASEL Arg462Gln genotypes on age of disease onset in hereditary nonpolyposis colorectal cancer (HNPCC) patients with pathogenic germline mutations in MSH2/MLH1

Author: Schackert, HK, Engel, C, Bier, A, Silber, AS, Görgens, H, Mangold, E, Pagenstecher, C, Holinski-Feder, E, von Knebel Doeberitz, M, Möslein, G, Dechant, S, Pox, C, Rahner, N, Müller, A, and Krüger, S
Subjects: ddc: 610
Published: 2006

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

Author: Vasen, H.F., 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., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Sijmons, R.H., Tejpar, S., Thomas, H.J., Rahner, N., Wijnen, J.T., Jarvinen, H.J., Moslein, G., et al., Vasen, H.F., 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., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Sijmons, R.H., Tejpar, S., Thomas, H.J., Rahner, N., Wijnen, J.T., Jarvinen, H.J., Moslein, G., and et al.
Abstract: Item does not contain fulltext, Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.
Published: 2013

34. 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, Maurizio, 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., De Leon, M. P., 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., Maurizio Genuardi. (ORCID:0000-0002-7410-8351), 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, Maurizio, 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., De Leon, M. P., 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., and Maurizio Genuardi. (ORCID:0000-0002-7410-8351)
Abstract: Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families
Published: 2013

35. Risks of less common cancers in proven mutation carriers with lynch syndrome

Author: Engel, C., Loeffler, M., Steinke, V., Rahner, N., Holinski-Feder, E., Dietmaier, W., Schackert, H.K., Goergens, H., von Knebel Doeberitz, M., Goecke, T.O., Schmiegel, W., Buettner, R., Moeslein, G., Letteboer, T.G., Garcia, E.G., Hes, F.J., Hoogerbrugge, N., Menko, F.H., van Os, T.A., Sijmons, R.H., Wagner, A., Kluijt, I., Propping, P., Vasen, H.F., Engel, C., Loeffler, M., Steinke, V., Rahner, N., Holinski-Feder, E., Dietmaier, W., Schackert, H.K., Goergens, H., von Knebel Doeberitz, M., Goecke, T.O., Schmiegel, W., Buettner, R., Moeslein, G., Letteboer, T.G., Garcia, E.G., Hes, F.J., Hoogerbrugge, N., Menko, F.H., van Os, T.A., Sijmons, R.H., Wagner, A., Kluijt, I., Propping, P., and Vasen, H.F.
Abstract: Item does not contain fulltext, PURPOSE Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6. PATIENTS AND METHODS Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk. Results The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers. CONCLUSION The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.
Published: 2012

36. Risks of less common cancers in proven mutation carriers with lynch syndrome

Author: Engel, C. (Christoph), Loeffler, M. (Markus), Steinke, V. (Verena), Rahner, N. (Nils), Holinski-Feder, E. (Elke), Dietmaier, W. (Wolfgang), Schackert, H.K. (Hans), Goergens, H. (Heike), Von Knebel Doeberitz, M. (Magnus), Goecke, T.O. (Timm), Schmiegel, W. (W.), Buettner, R. (Reinhard), Moeslein, G. (Gabriela), Letteboer, T.G.W. (Tom), Gómez García, E.B. (Encarna), Hes, F.J. (Frederik), Hoogerbrugge, N. (Nicoline), Menko, F. (Fred), Os, T.A.M. (Theo) van, Sijmons, R.H. (Rolf), Wagner, A. (Anja), Kluijt, I. (Irma), Propping, P. (Peter), Vasen, H. (Hans), Engel, C. (Christoph), Loeffler, M. (Markus), Steinke, V. (Verena), Rahner, N. (Nils), Holinski-Feder, E. (Elke), Dietmaier, W. (Wolfgang), Schackert, H.K. (Hans), Goergens, H. (Heike), Von Knebel Doeberitz, M. (Magnus), Goecke, T.O. (Timm), Schmiegel, W. (W.), Buettner, R. (Reinhard), Moeslein, G. (Gabriela), Letteboer, T.G.W. (Tom), Gómez García, E.B. (Encarna), Hes, F.J. (Frederik), Hoogerbrugge, N. (Nicoline), Menko, F. (Fred), Os, T.A.M. (Theo) van, Sijmons, R.H. (Rolf), Wagner, A. (Anja), Kluijt, I. (Irma), Propping, P. (Peter), and Vasen, H. (Hans)
Abstract: Purpose: Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6. Patients and Methods: Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk. Results: The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers. Conclusion: The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.
Published: 2012
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37. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study

Author: Kempers, M.J.E., Kuiper, R.P., Ockeloen, C.W., Chappuis, P.O., Hutter, P., Rahner, N., Schackert, H.K., Steinke, V., Holinski-Feder, E., Morak, M., Kloor, M., Buttner, R., Verwiel, E.T.P., Krieken, J.H. van, Nagtegaal, I.D., Goossens, M., Post, R.S. van der, Niessen, R.C., Sijmons, R.H., Kluijt, I., Hogervorst, F.B.L., Leter, E.M., Gille, J.J.P., Aalfs, C.M., Redeker, E.J., Hes, F.J., Tops, C.M., Nesselrooij, B.P. van, Gijn, M.E. van, Gomez Garcia, E.B., Eccles, D.M., Bunyan, D.J., Syngal, S., Stoffel, E.M., Culver, J.O., Palomares, M.R., Graham, T., Velsher, L., Papp, J., Olah, E., Chan, T.L., Leung, S.Y., Geurts van Kessel, A.H.M., Kiemeney, L.A.L.M., Hoogerbrugge, N., Ligtenberg, M.J.L., Kempers, M.J.E., Kuiper, R.P., Ockeloen, C.W., Chappuis, P.O., Hutter, P., Rahner, N., Schackert, H.K., Steinke, V., Holinski-Feder, E., Morak, M., Kloor, M., Buttner, R., Verwiel, E.T.P., Krieken, J.H. van, Nagtegaal, I.D., Goossens, M., Post, R.S. van der, Niessen, R.C., Sijmons, R.H., Kluijt, I., Hogervorst, F.B.L., Leter, E.M., Gille, J.J.P., Aalfs, C.M., Redeker, E.J., Hes, F.J., Tops, C.M., Nesselrooij, B.P. van, Gijn, M.E. van, Gomez Garcia, E.B., Eccles, D.M., Bunyan, D.J., Syngal, S., Stoffel, E.M., Culver, J.O., Palomares, M.R., Graham, T., Velsher, L., Papp, J., Olah, E., Chan, T.L., Leung, S.Y., Geurts van Kessel, A.H.M., Kiemeney, L.A.L.M., Hoogerbrugge, N., and Ligtenberg, M.J.L.
Abstract: Contains fulltext : 97324.pdf (publisher's version ) (Closed access), BACKGROUND: Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions. METHODS: We obtained clinical data for 194 carriers of a 3' end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM-MSH2 deletion. FINDINGS: 93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65-85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM-MSH2 deletion (69% [95% CI 47-91], p=0.8609) or mutations in MSH2 (77% [64-90], p=0.5892) or MLH1 (79% [68-90], p=0.5492), but was higher than noted for carriers of MSH6 mutation (50% [38-62], p<0.0001). By contrast, women with EPCAM deletions had a 12% [0-27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM-MSH2 deletion (55% [20-90], p<0.0001) or of a mutation in MSH2 (51% [33-69], p=0.0006) or MSH6 (34% [20-48], p=0.0309), but did not differ significantly from that noted for MLH1 (33% [15-51], p=0.1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer. INTERPR
Published: 2011

38. Recurrence and variability of germline EPCAM deletions in Lynch syndrome

Author: Kuiper, R.P., Vissers, L.E.L.M., Venkatachalam, R., Bodmer, D., Hoenselaar, E., Goossens, M., Haufe, A., Kamping, E.J., Niessen, R.C., Hogervorst, F.B.L., Gille, J.J.P., Redeker, B., Tops, C.M., Gijn, M.E. van, Ouweland, A.M. van den, Rahner, N., Steinke, V., Kahl, P., Holinski-Feder, E., Morak, M., Kloor, M., Stemmler, S., Betz, B., Hutter, P., Bunyan, D.J., Syngal, S., Culver, J.O., Graham, T., Chan, T.L., Nagtegaal, I.D., Krieken, J.H. van, Schackert, H.K., Hoogerbrugge, N., Geurts van Kessel, A.H.M., Ligtenberg, M.J.L., Kuiper, R.P., Vissers, L.E.L.M., Venkatachalam, R., Bodmer, D., Hoenselaar, E., Goossens, M., Haufe, A., Kamping, E.J., Niessen, R.C., Hogervorst, F.B.L., Gille, J.J.P., Redeker, B., Tops, C.M., Gijn, M.E. van, Ouweland, A.M. van den, Rahner, N., Steinke, V., Kahl, P., Holinski-Feder, E., Morak, M., Kloor, M., Stemmler, S., Betz, B., Hutter, P., Bunyan, D.J., Syngal, S., Culver, J.O., Graham, T., Chan, T.L., Nagtegaal, I.D., Krieken, J.H. van, Schackert, H.K., Hoogerbrugge, N., Geurts van Kessel, A.H.M., and Ligtenberg, M.J.L.
Abstract: Contains fulltext : 96266.pdf (publisher's version ) (Closed access), Recently, we identified 3' end deletions in the EPCAM gene as a novel cause of Lynch syndrome. These truncating EPCAM deletions cause allele-specific epigenetic silencing of the neighboring DNA mismatch repair gene MSH2 in tissues expressing EPCAM. Here we screened a cohort of unexplained Lynch-like families for the presence of EPCAM deletions. We identified 27 novel independent MSH2-deficient families from multiple geographical origins with varying deletions all encompassing the 3' end of EPCAM, but leaving the MSH2 gene intact. Within The Netherlands and Germany, EPCAM deletions appeared to represent at least 2.8% and 1.1% of the confirmed Lynch syndrome families, respectively. MSH2 promoter methylation was observed in epithelial tissues of all deletion carriers tested, thus confirming silencing of MSH2 as the causative defect. In a total of 45 families, 19 different deletions were found, all including the last two exons and the transcription termination signal of EPCAM. All deletions appeared to originate from Alu-repeat mediated recombination events. In 17 cases regions of microhomology around the breakpoints were found, suggesting nonallelic homologous recombination as the most likely mechanism. We conclude that 3' end EPCAM deletions are a recurrent cause of Lynch syndrome, which should be implemented in routine Lynch syndrome diagnostics.
Published: 2011

39. Recommendations to improve identification of hereditary and familial colorectal cancer in Europe.

Author: Vasen, H.F., Moslein, G., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Blanco, I., Bulow, S., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I., Rahner, N., Hes, F.J., Hodgson, S., Mecklin, J.P., Moller, P., Myrhoj, T., Nagengast, F.M., Parc, Y., Ponz de Leon, M., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Tejpar, S., Thomas, H.J., Wijnen, J., Lubinski, J., Jarvinen, H., Claes, E., Heinimann, K., Karagiannis, J.A., Lindblom, A., Dove-Edwin, I., Muller, H., Vasen, H.F., Moslein, G., Alonso, A., Aretz, S., Bernstein, I., Bertario, L., Blanco, I., Bulow, S., Burn, J., Capella, G., Colas, C., Engel, C., Frayling, I., Rahner, N., Hes, F.J., Hodgson, S., Mecklin, J.P., Moller, P., Myrhoj, T., Nagengast, F.M., Parc, Y., Ponz de Leon, M., Renkonen-Sinisalo, L., Sampson, J.R., Stormorken, A., Tejpar, S., Thomas, H.J., Wijnen, J., Lubinski, J., Jarvinen, H., Claes, E., Heinimann, K., Karagiannis, J.A., Lindblom, A., Dove-Edwin, I., and Muller, H.
Abstract: 1 juni 2010, Item does not contain fulltext, Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify
Published: 2010

40. Recommendations to improve identification of hereditary and familial colorectal cancer in Europe

Author: Vasen, H F A, Möslein, G, Alonso, A, Aretz, S, Bernstein, I, Bertario, L, Blanco, I, Bulow, S, Burn, J, Capella, G, Colas, C, Engel, C, Frayling, I, Rahner, N, Hes, F J, Hodgson, S, Mecklin, J-P, Møller, P, Myrhøj, T, Nagengast, F M, Parc, Y, Ponz de Leon, M, Renkonen-Sinisalo, L, Sampson, J R, Stormorken, A, Tejpar, S, Thomas, H J W, Wijnen, J, Lubinski, J, Järvinen, H, Claes, E, Heinimann, K, Karagiannis, J A, Lindblom, A, Dove-Edwin, I, Müller, H, Vasen, H F A, Möslein, G, Alonso, A, Aretz, S, Bernstein, I, Bertario, L, Blanco, I, Bulow, S, Burn, J, Capella, G, Colas, C, Engel, C, Frayling, I, Rahner, N, Hes, F J, Hodgson, S, Mecklin, J-P, Møller, P, Myrhøj, T, Nagengast, F M, Parc, Y, Ponz de Leon, M, Renkonen-Sinisalo, L, Sampson, J R, Stormorken, A, Tejpar, S, Thomas, H J W, Wijnen, J, Lubinski, J, Järvinen, H, Claes, E, Heinimann, K, Karagiannis, J A, Lindblom, A, Dove-Edwin, I, and Müller, H
Abstract: Udgivelsesdato: 2010-Jun, Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify
Published: 2010

41. S3-Leitlinie Kolorektales Karzinom Version 1.0 - Juni 2013 AWMF-Registernummer: 021/007OL

Author: Pox, C., additional, Aretz, S., additional, Bischoff, S., additional, Graeven, U., additional, Hass, M., additional, Heußner, P., additional, Hohenberger, W., additional, Holstege, A., additional, Hübner, J., additional, Kolligs, F., additional, Kreis, M., additional, Lux, P., additional, Ockenga, J., additional, Porschen, R., additional, Post, S., additional, Rahner, N., additional, Reinacher-Schick, A., additional, Riemann, J., additional, Sauer, R., additional, Sieg, A., additional, Scheppach, W., additional, Schmitt, W., additional, Schmoll, H., additional, Schulmann, K., additional, Tannapfel, A., additional, and Schmiegel, W., additional
Published: 2013
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42. Entwicklung eines Zweit-Malignoms (aggressiven diffusen großzelligen B-Zell-NHL) bei einer gesunden BRCA1-Mutationsträgerin

Author: Langer, E, primary, Ortmann, U, additional, Rahner, N, additional, Cierna, B, additional, Niederacher, D, additional, Zwiefel, K, additional, Janni, W, additional, and Mohrmann, S, additional
Published: 2012
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43. Constitutional mismatch repair deficiency and childhood leukemia/lymphoma - report on a novel biallelic MSH6 mutation

Author: Ripperger, T., primary, Beger, C., additional, Rahner, N., additional, Sykora, K. W., additional, Bockmeyer, C. L., additional, Lehmann, U., additional, Kreipe, H. H., additional, and Schlegelberger, B., additional
Published: 2009
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44. Recommendations to improve identification of hereditary and familial colorectal cancer in Europe

Author: Vasen, H. F. A., primary, Möslein, G., additional, Alonso, A., additional, Aretz, S., additional, Bernstein, I., additional, Bertario, L., additional, Blanco, I., additional, Bulow, S., additional, Burn, J., additional, Capella, G., additional, Colas, C., additional, Engel, C., additional, Frayling, I., additional, Rahner, N., additional, Hes, F. J., additional, Hodgson, S., additional, Mecklin, J.-P., additional, Møller, P., additional, Myrhøj, T., additional, Nagengast, F. M., additional, Parc, Y., additional, Ponz de Leon, M., additional, Renkonen-Sinisalo, L., additional, Sampson, J. R., additional, Stormorken, A., additional, Tejpar, S., additional, Thomas, H. J. W., additional, Wijnen, J., additional, Lubinski, J., additional, Järvinen, H., additional, Claes, E., additional, Heinimann, K., additional, Karagiannis, J. A., additional, Lindblom, A., additional, Dove-Edwin, I., additional, and Müller, H., additional
Published: 2009
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45. Flache Adenome sind die vorherrschende Läsion bei HNPCC Familien

Author: Hüneburg, R, primary, Lammert, F, additional, Rabe, C, additional, Rahner, N, additional, Kahl, P, additional, Büttner, R, additional, Propping, P, additional, Sauerbruch, T, additional, and Lamberti, C, additional
Published: 2009
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46. Chromocolonoscopy detects more adenomas than white light colonoscopy or narrow band imaging colonoscopy in hereditary nonpolyposis colorectal cancer screening

Author: Hüneburg, R., primary, Lammert, F., additional, Rabe, C., additional, Rahner, N., additional, Kahl, P., additional, Büttner, R., additional, Propping, P., additional, Sauerbruch, T., additional, and Lamberti, C., additional
Published: 2009
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47. Wertigkeit der Chromokoloskopie im Vergleich zur narrow-band-imaging Koloskopie in der Vorsorge von HNPCC Familien

Author: Hüneburg, R, primary, Lamberti, C, additional, Lammert, F, additional, Rabe, C, additional, Rahner, N, additional, Büttner, R, additional, Propping, P, additional, and Sauerbruch, T, additional
Published: 2007
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48. Coexisting somatic promoter hypermethylation and pathogenicMLH1 germline mutation in Lynch syndrome

Author: Rahner, N, primary, Friedrichs, N, additional, Steinke, V, additional, Aretz, S, additional, Friedl, W, additional, Buettner, R, additional, Mangold, E, additional, Propping, P, additional, and Walldorf, C, additional
Published: 2007
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49. MSH6 mutation in Muir?Torre syndrome: could this be a rare finding?

Author: Mangold, E., primary, Rahner, N., additional, Friedrichs, N., additional, Buettner, R., additional, Pagenstecher, C., additional, Aretz, S., additional, Friedl, W., additional, Ruzicka, T., additional, Propping, P., additional, Rütten, A., additional, and Kruse, R., additional
Published: 2007
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50. Coexisting somatic promoter hypermethylation and pathogenic MLH1 germline mutation in Lynch syndrome.

Author: Rahner, N, Friedrichs, N, Steinke, V, Aretz, S, Friedl, W, Buettner, R, Mangold, E, Propping, P, and Walldorf, C
Abstract: Somatic epimutations in the MLH1 promoter mimic the phenotype of Lynch syndrome. To date, no somatic hypermethylation of the MLH1 promoter in the carrier of a pathogenic MLH1 germline mutation has been identified, prompting the recommendation that a germline mutation in MLH1 should only be sought in the absence of tumour tissue methylation. We aimed to determine whether methylation of the MLH1 promoter may coexist in carriers of a pathogenic germline mutation in MLH1. We examined the methylation status of the MLH1 promoter in 123 tumour tissue samples, demonstrating high microsatellite instability and loss of expression of a mismatch repair protein (60 cases with MLH1 germline mutation, 25 cases without mutation, 38 cases with MSH2 mutations), using combined bisulphite restriction analysis (COBRA) and SNaPshot analysis. Methylation of the MLH1 promoter was found in two patients with pathogenic germline mutations, one a carrier of a MLH1 mutation and the other a carrier of a MSH2 mutation. Our results demonstrate that methylation of the MLH1 promoter region does not exclude the presence of a germline mutation in a mismatch repair (MMR) gene. Hypermethylation of the MLH1 promoter may be present in most cases of sporadic colorectal cancers, but this does not exclude a diagnosis of Lynch syndrome. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
Published: 2008
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