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1. Monoallelic NTHL1 Loss-of-Function Variants and Risk of Polyposis and Colorectal Cancer

Author

Boot, Arnoud, Stojovska, Marija Staninova, Mahmood, Khalid, Clendenning, Mark, de Miranda, Noel, Dymerska, Dagmara, Egmond, Demi van, Gallinger, Steven, Georgeson, Peter, Hoogerbrugge, Nicoline, Hopper, John L., Jansen, Erik A.M., Jenkins, Mark A., Joo, Jihoon E., Kuiper, Roland P., Ligtenberg, Marjolijn J.L., Lubinski, Jan, Macrae, Finlay A., Morreau, Hans, Newcomb, Polly, Nielsen, Maartje, Palles, Claire, Park, Daniel J., Pope, Bernard J., Rosty, Christophe, Ruiz Ponte, Clara, Schackert, Hans K., Sijmons, Rolf H., Tomlinson, Ian P., Tops, Carli M.J., Vreede, Lilian, Walker, Romy, Win, Aung K., Elsayed, Fadwa A., Grolleman, Judith E., Ragunathan, Abiramy, Buchanan, Daniel D., van Wezel, Tom, and de Voer, Richarda M.

Published
2020
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2. 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, Mev, Sampson, Julian R., Seppälä, Toni T., ten Broeke, Sanne W., Plazzer, John-Paul, Nakken, Sigve, Engel, Christoph, Aretz, Stefan, Jenkins, Mark A., Sunde, Lone, Bernstein, Inge, Capella, Gabriel, Balaguer, Francesc, Thomas, Huw, Evans, D. Gareth, Burn, John, Greenblatt, Marc, Hovig, Eivind, de Vos tot Nederveen Cappel, Wouter H., Sijmons, Rolf H., Bertario, Lucio, Tibiletti, Maria Grazia, Cavestro, Giulia Martina, Lindblom, Annika, Della Valle, Adriana, Lopez-Köstner, Francisco, Gluck, Nathan, Katz, Lior H., Heinimann, Karl, Vaccaro, Carlos A., Büttner, Reinhard, Görgens, Heike, Holinski-Feder, Elke, Morak, Monika, Holzapfel, Stefanie, Hüneburg, Robert, Knebel Doeberitz, Magnus von, Loeffler, Markus, Rahner, Nils, Schackert, Hans K., Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Pylvänäinen, Kirsi, Renkonen-Sinisalo, Laura, Hopper, John L., Win, Aung Ko, Haile, Robert W., Lindor, Noralane M., Gallinger, Steven, Le Marchand, Loïc, Newcomb, Polly A., Figueiredo, Jane C., Thibodeau, Stephen N., Wadt, Karin, Therkildsen, Christina, Okkels, Henrik, Ketabi, Zohreh, Moreira, Leticia, Sánchez, Ariadna, Serra-Burriel, Miquel, Pineda, Marta, Navarro, Matilde, Blanco, Ignacio, Green, Kate, Lalloo, Fiona, Crosbie, Emma J., Hill, James, Denton, Oliver G., Frayling, Ian M., Rødland, Einar Andreas, Vasen, Hans, Mints, Miriam, Neffa, Florencia, Esperon, Patricia, Alvarez, Karin, Kariv, Revital, Rosner, Guy, Pinero, Tamara Alejandra, Gonzalez, María Laura, Kalfayan, Pablo, Tjandra, Douglas, Winship, Ingrid M., Macrae, Finlay, Möslein, Gabriela, Mecklin, Jukka-Pekka, Nielsen, Maartje, and Møller, Pål

Published
2020
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3. Germline deletions in the tumour suppressor gene FOCAD are associated with polyposis and colorectal cancer development

Author

Weren, Robbert DA, Venkatachalam, Ramprasath, Cazier, Jean-Baptiste, Farin, Henner F, Kets, C Marleen, de Voer, Richarda M, Vreede, Lilian, Verwiel, Eugène TP, van Asseldonk, Monique, Kamping, Eveline J, Kiemeney, Lambertus A, Neveling, Kornelia, Aben, Katja KH, Carvajal-Carmona, Luis, Nagtegaal, Iris D, Schackert, Hans K, Clevers, Hans, van de Wetering, Marc, Tomlinson, Ian P, Ligtenberg, Marjolijn JL, Hoogerbrugge, Nicoline, Geurts van Kessel, Ad, and Kuiper, Roland P

Subjects
Prevention, Human Genome, Digestive Diseases, Genetics, Cancer, Colo-Rectal Cancer, Aetiology, 2.1 Biological and endogenous factors, Adenomatous Polyposis Coli, Adult, Case-Control Studies, Chromosomes, Human, Pair 9, Colorectal Neoplasms, DNA Copy Number Variations, Epithelial Cells, Female, Gene Deletion, Gene Expression Regulation, Neoplastic, Germ-Line Mutation, Heterozygote, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Open Reading Frames, Tumor Suppressor Proteins, polyposis and colorectal cancer, cancer predisposition, FOCAD, copy number variation, gene expression, Clinical Sciences, Pathology
Abstract

Heritable genetic variants can significantly affect the lifetime risk of developing cancer, including polyposis and colorectal cancer (CRC). Variants in genes currently known to be associated with a high risk for polyposis or CRC, however, explain only a limited number of hereditary cases. The identification of additional genetic causes is, therefore, crucial to improve CRC prevention, detection and treatment. We have performed genome-wide and targeted DNA copy number profiling and resequencing in early-onset and familial polyposis/CRC patients, and show that deletions affecting the open reading frame of the tumour suppressor gene FOCAD are recurrent and significantly enriched in CRC patients compared with unaffected controls. All patients carrying FOCAD deletions exhibited a personal or family history of polyposis. RNA in situ hybridization revealed FOCAD expression in epithelial cells in the colonic crypt, the site of tumour initiation, as well as in colonic tumours and organoids. Our data suggest that monoallelic germline deletions in the tumour suppressor gene FOCAD underlie moderate genetic predisposition to the development of polyposis and CRC.

Published
2015

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

Author

Engel, Christoph, Vasen, Hans F., Seppälä, Toni, Aretz, Stefan, Bigirwamungu-Bargeman, Marloes, de Boer, Sybrand Y., Bucksch, Karolin, Büttner, Reinhard, Holinski-Feder, Elke, Holzapfel, Stefanie, Hüneburg, Robert, Jacobs, Maarten A.J.M., Järvinen, Heikki, Kloor, Matthias, von Knebel Doeberitz, Magnus, Koornstra, Jan J., van Kouwen, Mariette, Langers, Alexandra M., van de Meeberg, Paul C., Morak, Monika, Möslein, Gabriela, Nagengast, Fokko M., Pylvänäinen, Kirsi, Rahner, Nils, Renkonen-Sinisalo, Laura, Sanduleanu, Silvia, Schackert, Hans K., Schmiegel, Wolff, Schulmann, Karsten, Steinke-Lange, Verena, Strassburg, Christian P., Vecht, Juda, Verhulst, Marie-Louise, de Vos tot Nederveen Cappel, Wouter, Zachariae, Silke, Mecklin, Jukka-Pekka, and Loeffler, Markus

Published
2018
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5. Correction: 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, Mev, Sampson, Julian R., Seppälä, Toni T., ten Broeke, Sanne W., Plazzer, John-Paul, Nakken, Sigve, Engel, Christoph, Aretz, Stefan, Jenkins, Mark A., Sunde, Lone, Bernstein, Inge, Capella, Gabriel, Balaguer, Francesc, Thomas, Huw, Evans, D. Gareth, Burn, John, Greenblatt, Marc, Hovig, Eivind, de Vos tot Nederveen Cappel, Wouter H., Sijmons, Rolf H., Bertario, Lucio, Tibiletti, Maria Grazia, Cavestro, Giulia Martina, Lindblom, Annika, Della Valle, Adriana, Lopez-Köstner, Francisco, Gluck, Nathan, Katz, Lior H., Heinimann, Karl, Vaccaro, Carlos A., Büttner, Reinhard, Görgens, Heike, Holinski-Feder, Elke, Morak, Monika, Holzapfel, Stefanie, Hüneburg, Robert, Knebel Doeberitz, Magnus von, Loeffler, Markus, Rahner, Nils, Schackert, Hans K., Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Pylvänäinen, Kirsi, Renkonen-Sinisalo, Laura, Hopper, John L., Win, Aung Ko, Haile, Robert W., Lindor, Noralane M., Gallinger, Steven, Le Marchand, Loïc, Newcomb, Polly A., Figueiredo, Jane C., Thibodeau, Stephen N., Wadt, Karin, Therkildsen, Christina, Okkels, Henrik, Ketabi, Zohreh, Moreira, Leticia, Sánchez, Ariadna, Serra-Burriel, Miquel, Pineda, Marta, Navarro, Matilde, Blanco, Ignacio, Green, Kate, Lalloo, Fiona, Crosbie, Emma J., Hill, James, Denton, Oliver G., Frayling, Ian M., Rødland, Einar Andreas, Vasen, Hans, Mints, Miriam, Neffa, Florencia, Esperon, Patricia, Alvarez, Karin, Kariv, Revital, Rosner, Guy, Pinero, Tamara Alejandra, Gonzalez, María Laura, Kalfayan, Pablo, Tjandra, Douglas, Winship, Ingrid M., Macrae, Finlay, Möslein, Gabriela, Mecklin, Jukka-Pekka, Nielsen, Maartje, and Møller, Pål

Published
2020
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6. Germline Mutations in the Spindle Assembly Checkpoint Genes BUB1 and BUB3 Are Risk Factors for Colorectal Cancer

Author

de Voer, Richarda M., Geurts van Kessel, Ad, Weren, Robbert D.A., Ligtenberg, Marjolijn J.L., Smeets, Dominique, Fu, Lei, Vreede, Lilian, Kamping, Eveline J., Verwiel, Eugène T.P., Hahn, Marc–Manuel, Ariaans, Maayke, Spruijt, Liesbeth, van Essen, Ton, Houge, Gunnar, Schackert, Hans K., Sheng, Jian Q., Venselaar, Hanka, van Ravenswaaij–Arts, Conny M.A., van Krieken, J. Han J.M., Hoogerbrugge, Nicoline, and Kuiper, Roland P.

Published
2013
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7. A variant allele of Growth Factor Independence 1 (GFI1) is associated with acute myeloid leukemia

Author

Khandanpour, Cyrus, Thiede, Christian, Valk, Peter J.M., Sharif-Askari, Ehssan, Nückel, Holger, Lohmann, Dietmar, Horsthemke, Bernhard, Siffert, Winfried, Neubauer, Andreas, Grzeschik, Karl-Heinz, Bloomfield, Clara D., Marcucci, Guido, Maharry, Kati, Slovak, Marilyn L., van der Reijden, Bert A., Jansen, Joop H., Schackert, Hans K., Afshar, Khashayar, Schnittger, Susanne, Peeters, Justine K., Kroschinsky, Frank, Ehninger, Gerhard, Lowenberg, Bob, Dührsen, Ulrich, and Möröy, Tarik

Published
2010
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8. Variation in the Risk of Colorectal Cancer for Lynch Syndrome: A retrospective family cohort study

Author

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

Subjects
Article
Abstract

BACKGROUND: Current clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the average age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate how much penetrance varies between carriers of pathogenic variants in the same gene by sex and continent of residence of the carrier. METHODS: We studied 79,809 relatives from 5,255 families, of at least three relatives, in which at least one was a confirmed carrier of a pathogenic or likely pathogenic variant in a mismatch repair gene (1,829 MLH1, 2,179 MSH2, 798 MSH6, 449 PMS2), recruited in 15 countries from North America, Europe and Australasia by the collaborative centres of the International Mismatch Repair Consortium. We used modified segregation analysis conditioned on ascertainment to estimate the average penetrance and modelled unmeasured polygenic factors to estimate the variation in penetrance of colorectal cancer. The existence of familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested using a Wald p-value for the null hypothesis that the polygenic standard deviation is zero. FINDINGS: There was strong evidence of the existence of familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was more prominent for MLH1 and MSH2 variant carriers; depending on gene, sex, and continent, with 7–56% of carriers having a risk of colorectal cancer to age 80 of less than 20%, and 9–44% having a risk of more than 80%, while only 10–19% had a risk of 40–60%. INTERPRETATION: Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessment for precision prevention and early detection of colorectal cancer for Lynch syndrome.

Published
2021

13. Value of uppergastrointestinalendoscopy for gastric cancer surveillance in patients with Lynch syndrome

Author

Ladigan-Badura, Swetlana, Vangala, Deepak B., Engel, Christoph, Bucksch, Karolin, Hueneburg, Robert, Perne, Claudia, Nattermann, Jacob, Steinke-Lange, Verena, Rahner, Nils, Schackert, Hans K., Weitz, Juergen, Kloor, Matthias, Kuhlkamp, Judith, Moeslein, Gabriela, Strassburg, Christian, Morak, Monika, Holinski-Feder, Elke, Buettner, Reinhard, Aretz, Stefan, Loeffler, Markus, Schmiegel, Wolff, Pox, Christian, Schulmann, Karsten, Ladigan-Badura, Swetlana, Vangala, Deepak B., Engel, Christoph, Bucksch, Karolin, Hueneburg, Robert, Perne, Claudia, Nattermann, Jacob, Steinke-Lange, Verena, Rahner, Nils, Schackert, Hans K., Weitz, Juergen, Kloor, Matthias, Kuhlkamp, Judith, Moeslein, Gabriela, Strassburg, Christian, Morak, Monika, Holinski-Feder, Elke, Buettner, Reinhard, Aretz, Stefan, Loeffler, Markus, Schmiegel, Wolff, Pox, Christian, and Schulmann, Karsten

Abstract

In our study, we evaluated the effectiveness of upper gastrointestinal (GI) endoscopy as an instrument for early gastric cancer (GC) detection in Lynch syndrome (LS) patients by analyzing data from the registry of theGerman Consortium for Familial Intestinal Cancer. In a prospective, multicenter cohort study, 1128 out of 2009 registered individuals with confirmed LS underwent 5176 upper GI endoscopies. Compliance was good since 77.6% of upper GI endoscopies were completed within the recommended interval of 1 to 3 years. Forty-nine GC events were observed in 47 patients.MLH1(n = 21) andMSH2(n = 24) mutations were the most prevalent. GCs in patients undergoing regular surveillance were diagnosed significantly more often in an early-stage disease (UICC I) than GCs detected through symptoms (83% vs 25%;P= .0231). Thirty-two (68%) patients had a negative family history of GC. The median age at diagnosis was 51 years (range 28-66). Of all GC patients, 13 were diagnosed at an age younger than 45. Our study supports the recommendation of regular upper GI endoscopy surveillance for LS patients beginning no later than at the age of 30.

Published
2021

14. Value of upper gastrointestinal endoscopy for gastric cancer surveillance in patients with Lynch syndrome

Author

Ladigan-Badura, Swetlana, Vangala, Deepak B., Engel, Christoph, Bucksch, Karolin, Hueneburg, Robert, Perne, Claudia, Nattermann, Jacob, Steinke-Lange, Verena, Rahner, Nils, Schackert, Hans K., Weitz, Jürgen, Kloor, Matthias, Kuhlkamp, Judith, Nguyen, Huu Phuc, Moeslein, Gabriela, Strassburg, Christian, Morak, Monika, Holinski-Feder, Elke, Buettner, Reinhard, Aretz, Stefan, Loeffler, Markus, Schmiegel, Wolff, Pox, Christian, Schulmann, Karsten, for Familial Intestinal Cancer, German Consortium, Ladigan-Badura, Swetlana, Vangala, Deepak B., Engel, Christoph, Bucksch, Karolin, Hueneburg, Robert, Perne, Claudia, Nattermann, Jacob, Steinke-Lange, Verena, Rahner, Nils, Schackert, Hans K., Weitz, Jürgen, Kloor, Matthias, Kuhlkamp, Judith, Nguyen, Huu Phuc, Moeslein, Gabriela, Strassburg, Christian, Morak, Monika, Holinski-Feder, Elke, Buettner, Reinhard, Aretz, Stefan, Loeffler, Markus, Schmiegel, Wolff, Pox, Christian, Schulmann, Karsten, and for Familial Intestinal Cancer, German Consortium

Abstract

In our study, we evaluated the effectiveness of upper gastrointestinal (GI) endoscopy as an instrument for early gastric cancer (GC) detection in Lynch syndrome (LS) patients by analyzing data from the registry of the German Consortium for Familial Intestinal Cancer. In a prospective, multicenter cohort study, 1128 out of 2009 registered individuals with confirmed LS underwent 5176 upper GI endoscopies. Compliance was good since 77.6% of upper GI endoscopies were completed within the recommended interval of 1 to 3 years. Forty-nine GC events were observed in 47 patients. MLH1 (n = 21) and MSH2 (n = 24) mutations were the most prevalent. GCs in patients undergoing regular surveillance were diagnosed significantly more often in an early-stage disease (UICC I) than GCs detected through symptoms (83% vs 25%; P = .0231). Thirty-two (68%) patients had a negative family history of GC. The median age at diagnosis was 51 years (range 28-66). Of all GC patients, 13 were diagnosed at an age younger than 45. Our study supports the recommendation of regular upper GI endoscopy surveillance for LS patients beginning no later than at the age of 30. What's new? Risk of gastric cancer (GC) is significantly increased among patients with Lynch syndrome (LS). GC screening in LS patients, however, is fraught with uncertainty, particularly regarding the use of esophagogastroduodenoscopy (EGD). The authors of this study investigated the use of EGD for regular GC surveillance in a German cohort of LS patients. Regular surveillance by EGD resulted in more frequent diagnosis and significant down-staging of GC, relative to detection via symptoms alone. In most cases, family history of GC was negative. This study supports recommendations for regular gastroscopic surveillance in LS patients starting by age 30.

Published
2021

16. Genome-wide analysis associates familial colorectal cancer with increases in copy number variations and a rare structural variation at 12p12.3

Author

Yang, Rongxi, Chen, Bowang, Pfütze, Katrin, Buch, Stephan, Steinke, Verena, Holinski-Feder, Elke, Stöcker, Sarah, von Schönfels, Witigo, Becker, Thomas, Schackert, Hans K., Royer-Pokora, Brigitte, Kloor, Matthias, Schmiegel, Wolff H., Büttner, Reinhard, Engel, Christoph, Lascorz Puertolas, Jesus, Försti, Asta, Kunkel, Nelli, Bugert, Peter, Schreiber, Stefan, Krawczak, Michael, Schafmayer, Clemens, Propping, Peter, Hampe, Jochen, Hemminki, Kari, and Burwinkel, Barbara

Published
2014
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22. Monoallelic NTHL1 Loss-of-Function Variants and Risk of Polyposis and Colorectal Cancer

Author

Elsayed, Fadwa A., primary, Grolleman, Judith E., additional, Ragunathan, Abiramy, additional, Buchanan, Daniel D., additional, van Wezel, Tom, additional, de Voer, Richarda M., additional, Boot, Arnoud, additional, Stojovska, Marija Staninova, additional, Mahmood, Khalid, additional, Clendenning, Mark, additional, de Miranda, Noel, additional, Dymerska, Dagmara, additional, Egmond, Demi van, additional, Gallinger, Steven, additional, Georgeson, Peter, additional, Hoogerbrugge, Nicoline, additional, Hopper, John L., additional, Jansen, Erik A.M., additional, Jenkins, Mark A., additional, Joo, Jihoon E., additional, Kuiper, Roland P., additional, Ligtenberg, Marjolijn J.L., additional, Lubinski, Jan, additional, Macrae, Finlay A., additional, Morreau, Hans, additional, Newcomb, Polly, additional, Nielsen, Maartje, additional, Palles, Claire, additional, Park, Daniel J., additional, Pope, Bernard J., additional, Rosty, Christophe, additional, Ruiz Ponte, Clara, additional, Schackert, Hans K., additional, Sijmons, Rolf H., additional, Tomlinson, Ian P., additional, Tops, Carli M.J., additional, Vreede, Lilian, additional, Walker, Romy, additional, and Win, Aung K., additional

Published
2020
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23. Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility

Author

Lascorz, Jesús, Försti, Asta, Chen, Bowang, Buch, Stephan, Steinke, Verena, Rahner, Nils, Holinski-Feder, Elke, Morak, Monika, Schackert, Hans K., Görgens, Heike, Schulmann, Karsten, Goecke, Timm, Kloor, Matthias, Engel, Cristoph, Büttner, Reinhard, Kunkel, Nelli, Weires, Marianne, Hoffmeister, Michael, Pardini, Barbara, Naccarati, Alessio, Vodickova, Ludmila, Novotny, Jan, Schreiber, Stefan, Krawczak, Michael, Bröring, Clemens D., Völzke, Henry, Schafmayer, Clemens, Vodicka, Pavel, Chang-Claude, Jenny, Brenner, Hermann, Burwinkel, Barbara, Propping, Peter, Hampe, Jochen, and Hemminki, Kari

Published
2010
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25. Efficacy of Annual Colonoscopic Surveillance in Individuals With Hereditary Nonpolyposis Colorectal Cancer

Author

Engel, Christoph, Rahner, Nils, Schulmann, Karsten, Holinski–Feder, Elke, Goecke, Timm O., Schackert, Hans K., Kloor, Matthias, Steinke, Verena, Vogelsang, Holger, Möslein, Gabriela, Görgens, Heike, Dechant, Stefan, von Knebel Doeberitz, Magnus, Rüschoff, Josef, Friedrichs, Nicolaus, Büttner, Reinhard, Loeffler, Markus, Propping, Peter, and Schmiegel, Wolff

Published
2010
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26. HNPCC-associated small bowel cancer: Clinical and molecular characteristics

Author

Schulmann, Karsten, Brasch, Frank E., Kunstmann, Erdmute, Engel, Christoph, Pagenstecher, Constanze, Vogelsang, Holger, Krüger, Stefan, Vogel, Tilman, Knaebel, Hanns-Peter, Rüschoff, Josef, Hahn, Stephan A., Knebel-Doeberitz, Magnus V., Moeslein, Gabriela, Meltzer, Stephen J., Schackert, Hans K., Tympner, Christiane, Mangold, Elisabeth, and Schmiegel, Wolff

Published
2005
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28. An unusual case of Cowden syndrome associated with ganglioneuromatous polyposis

Author

Pistorius, Steffen, Klink, Barbara, Pablik, Jessica, Rump, Andreas, Aust, Daniela, Garzarolli, Marlene, Schrock, Evelin, and Schackert, Hans K.

Subjects
Diagnosis, Care and treatment, Case studies, Familial polyposis -- Case studies -- Diagnosis -- Care and treatment, Multiple hamartoma syndrome -- Case studies -- Diagnosis -- Care and treatment, Polyposis, Familial -- Case studies -- Diagnosis -- Care and treatment
Abstract

Author(s): Steffen Pistorius[sup.1,6] , Barbara Klink[sup.2,7] , Jessica Pablik[sup.3] , Andreas Rump[sup.2] , Daniela Aust[sup.3,7] , Marlene Garzarolli[sup.4] , Evelin Schröck[sup.2,7] and Hans K. Schackert[sup.5,6,7] Background Ganglioneuromatous polyposis (GP) is [...]

Published
2016
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29. 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, Mev, Sampson, Julian R., Seppälä, Toni T., ten Broeke, Sanne W., Plazzer, John Paul, Nakken, Sigve, Engel, Christoph, Aretz, Stefan, Jenkins, Mark A., Sunde, Lone, Bernstein, Inge, Capella, Gabriel, Balaguer, Francesc, Thomas, Huw, Evans, D. Gareth, Burn, John, Greenblatt, Marc, Hovig, Eivind, de Vos tot Nederveen Cappel, Wouter H., Sijmons, Rolf H., Bertario, Lucio, Tibiletti, Maria Grazia, Cavestro, Giulia Martina, Lindblom, Annika, Della Valle, Adriana, Lopez-Köstner, Francisco, Gluck, Nathan, Katz, Lior H., Heinimann, Karl, Vaccaro, Carlos A., Büttner, Reinhard, Görgens, Heike, Holinski-Feder, Elke, Morak, Monika, Holzapfel, Stefanie, Hüneburg, Robert, Knebel Doeberitz, Magnus von, Loeffler, Markus, Rahner, Nils, Schackert, Hans K., Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Pylvänäinen, Kirsi, Renkonen-Sinisalo, Laura, Hopper, John L., Win, Aung Ko, Haile, Robert W., Lindor, Noralane M., Gallinger, Steven, Le Marchand, Loïc, Newcomb, Polly A., Figueiredo, Jane C., Thibodeau, Stephen N., Wadt, Karin, Therkildsen, Christina, Okkels, Henrik, Ketabi, Zohreh, Moreira, Leticia, Sánchez, Ariadna, Serra-Burriel, Miquel, Pineda, Marta, Navarro, Matilde, Blanco, Ignacio, Green, Kate, Lalloo, Fiona, Crosbie, Emma J., Hill, James, Denton, Oliver G., Frayling, Ian M., Rødland, Einar Andreas, Vasen, Hans, Mints, Miriam, Neffa, Florencia, Esperon, Patricia, Alvarez, Karin, Kariv, Revital, Rosner, Guy, Pinero, Tamara Alejandra, Gonzalez, María Laura, Kalfayan, Pablo, Tjandra, Douglas, Winship, Ingrid M., Macrae, Finlay, Möslein, Gabriela, Mecklin, Jukka Pekka, Nielsen, Maartje, Møller, Pål, Dominguez-Valentin, Mev, Sampson, Julian R., Seppälä, Toni T., ten Broeke, Sanne W., Plazzer, John Paul, Nakken, Sigve, Engel, Christoph, Aretz, Stefan, Jenkins, Mark A., Sunde, Lone, Bernstein, Inge, Capella, Gabriel, Balaguer, Francesc, Thomas, Huw, Evans, D. Gareth, Burn, John, Greenblatt, Marc, Hovig, Eivind, de Vos tot Nederveen Cappel, Wouter H., Sijmons, Rolf H., Bertario, Lucio, Tibiletti, Maria Grazia, Cavestro, Giulia Martina, Lindblom, Annika, Della Valle, Adriana, Lopez-Köstner, Francisco, Gluck, Nathan, Katz, Lior H., Heinimann, Karl, Vaccaro, Carlos A., Büttner, Reinhard, Görgens, Heike, Holinski-Feder, Elke, Morak, Monika, Holzapfel, Stefanie, Hüneburg, Robert, Knebel Doeberitz, Magnus von, Loeffler, Markus, Rahner, Nils, Schackert, Hans K., Steinke-Lange, Verena, Schmiegel, Wolff, Vangala, Deepak, Pylvänäinen, Kirsi, Renkonen-Sinisalo, Laura, Hopper, John L., Win, Aung Ko, Haile, Robert W., Lindor, Noralane M., Gallinger, Steven, Le Marchand, Loïc, Newcomb, Polly A., Figueiredo, Jane C., Thibodeau, Stephen N., Wadt, Karin, Therkildsen, Christina, Okkels, Henrik, Ketabi, Zohreh, Moreira, Leticia, Sánchez, Ariadna, Serra-Burriel, Miquel, Pineda, Marta, Navarro, Matilde, Blanco, Ignacio, Green, Kate, Lalloo, Fiona, Crosbie, Emma J., Hill, James, Denton, Oliver G., Frayling, Ian M., Rødland, Einar Andreas, Vasen, Hans, Mints, Miriam, Neffa, Florencia, Esperon, Patricia, Alvarez, Karin, Kariv, Revital, Rosner, Guy, Pinero, Tamara Alejandra, Gonzalez, María Laura, Kalfayan, Pablo, Tjandra, Douglas, Winship, Ingrid M., Macrae, Finlay, Möslein, Gabriela, Mecklin, Jukka Pekka, Nielsen, Maartje, and Møller, Pål

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

33. Germline truncating-mutations in BRCA1 and MSH6 in a patient with early onset endometrial cancer

Author

Kast Karin, Neuhann Teresa M, Görgens Heike, Becker Kerstin, Keller Katja, Klink Barbara, Aust Daniela, Distler Wolfgang, Schröck Evelin, and Schackert Hans K

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Hereditary Breast and Ovarian Cancer Syndrome (HBOCS) and Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC, Lynch Syndrome) are two tumor predisposition syndromes responsible for the majority of hereditary breast and colorectal cancers. Carriers of both germline mutations in breast cancer genes BRCA1 or BRCA2 and in mismatch repair (MMR) genes MLH1, MSH2, MSH6 or PMS2 are very rare. Case presentation We identified germline mutations in BRCA1 and in MSH6 in a patient with increased risk for HBOC diagnosed with endometrial cancer at the age of 46 years. Conclusions Although carriers of mutations in both MMR and BRCA genes are rare in Caucasian populations and anamnestical and histopathological findings may guide clinicians to identify these families, both syndromes can only be diagnosed through a complete gene analysis of the respective genes.

Published
2012
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34. Role of germline aberrations affecting,andin gastric cancer susceptibility

Author

Weren, Robbert D A, van der Post, Rachel S, Vogelaar, Ingrid P, van Krieken, J Han, Spruijt, Liesbeth, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Aalfs, Cora M, van Hest, Liselotte P, Oliveira, Carla, Kamping, Eveline J, Schackert, Hans K, Ranzani, Guglielmina N, Gómez García, Encarna B, Hes, Frederik J, Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G E M, Sijmons, Rolf H, Wagner, Anja, van der Kolk, Lizet E, Cats, Annemieke, Bjørnevoll, Inga, Hoogerbrugge, Nicoline, Ligtenberg, Marjolijn J L, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Journal Article
Abstract

BACKGROUND: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germlineCDH1mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genesCTNNA1,MAP3K6orMYD88. METHODS: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without aCDH1germline mutation for germline variants affectingCTNNA1,MAP3K6andMYD88using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes. RESULTS: Predicted deleterious germline variants were not encountered inMYD88, but recurrently observed inCTNNA1(n=2) andMAP3K6(n=3) in our cohort of patients with GC. In contrast to deleterious variants inCTNNA1, deleterious variants inMAP3K6also occur frequently in the general population. CONCLUSIONS: Based on our resultsMAP3K6should no longer be considered a GC predisposition gene, whereas deleteriousCTNNA1variants are confirmed as an infrequent cause of GC susceptibility. BiallelicMYD88germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.

Published
2018

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

Author

ten Broeke, Sanne W., primary, Rodríguez-Girondo, Mar, additional, Suerink, Manon, additional, Aretz, Stefan, additional, Bernstein, Inge, additional, Capellá, Gabriel, additional, Engel, Christoph, additional, Gomez-Garcia, Encarna B., additional, van Hest, Liselot P., additional, von Knebel Doeberitz, Magnus, additional, Lagerstedt-Robinson, Kristina, additional, Letteboer, Tom G.W., additional, Moller, Pal, additional, van Os, Theo A., additional, Pineda, Marta, additional, Rahner, Nils, additional, Olderode-Berends, Maran J.W., additional, von Salomé, Jenny, additional, Schackert, Hans K., additional, Spruijt, Liesbeth, additional, Steinke-Lange, Verena, additional, Wagner, Anja, additional, Tops, Carli M.J., additional, and Nielsen, Maartje, additional

Published
2019
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36. Polymorphisms of genes coding for ghrelin and its receptor in relation to colorectal cancer risk: a two-step gene-wide case-control study

Author

Engel Christoph, Kloor Matthias, Betz Beate, Kötting Judith, Görgens Heike, Schackert Hans K, Morak Monika, Holinski-Feder Elke, Rahner Nils, Steinke Verena, Novotny Jan, Vodickova Ludmila, Naccarati Alessio, Pardini Barbara, Campa Daniele, Büttner Reinhard, Propping Peter, Försti Asta, Hemminki Kari, Barale Roberto, Vodicka Pavel, and Canzian Federico

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Abstract Background Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), has two major functions: the stimulation of the growth hormone production and the stimulation of food intake. Accumulating evidence also indicates a role of ghrelin in cancer development. Methods We conducted a case-control study to examine the association of common genetic variants in the genes coding for ghrelin (GHRL) and its receptor (GHSR) with colorectal cancer risk. Pairwise tagging was used to select the 11 polymorphisms included in the study. The selected polymorphisms were genotyped in 680 cases and 593 controls from the Czech Republic. Results We found two SNPs associated with lower risk of colorectal cancer, namely SNPs rs27647 and rs35683. We replicated the two hits, in additional 569 cases and 726 controls from Germany. Conclusion A joint analysis of the two populations indicated that the T allele of rs27647 SNP exerted a protective borderline effect (Ptrend = 0.004).

Published
2010
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37. Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes

Author

Kayser, Katrin, Degenhardt, Franziska, Holzapfel, Stefanie, Horpaopan, Sukanya, Peters, Sophia, Spier, Isabel, Morak, Monika, Vangala, Deepak, Rahner, Nils, von Knebel-Doeberitz, Magnus, Schackert, Hans K., Engel, Christoph, Büttner, Reinhard, Wijnen, Juul, Doerks, Tobias, Bork, Peer, Moebus, Susanne, Herms, Stefan, Fischer, Sascha, Hoffmann, Per, Aretz, Stefan, and Steinke-Lange, Verena

Subjects
Adult, Male, DNA Copy Number Variations, Genotype, Medizin, High-Throughput Nucleotide Sequencing, Humans, Female, Colorectal Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis, DNA Mismatch Repair, Germ-Line Mutation
Abstract

In many families with suspected Lynch syndrome (LS), no germline mutation in the causative mismatch repair (MMR) genes is detected during routine diagnostics. To identify novel causative genes for LS, the present study investigated 77 unrelated, mutation-negative patients with clinically suspected LS and a loss of MSH2 in tumor tissue. An analysis for genomic copy number variants (CNV) was performed, with subsequent next generation sequencing (NGS) of selected candidate genes in a subgroup of the cohort. Genomic DNA was genotyped using Illumina's HumanOmniExpress Bead Array. After quality control and filtering, 25 deletions and 16 duplications encompassing 73 genes were identified in 28 patients. No recurrent CNV was detected, and none of the CNVs affected the regulatory regions of MSH2. A total of 49 candidate genes from genomic regions implicated by the present CNV analysis and 30 known or assumed risk genes for colorectal cancer (CRC) were then sequenced in a subset of 38 patients using a customized NGS gene panel and Sanger sequencing. Single nucleotide variants were identified in 14 candidate genes from the CNV analysis. The most promising of these candidate genes were: (i) PRKCA, PRKDC, and MCM4, as a functional relation to MSH2 is predicted by network analysis, and (ii) CSMD1, as this is commonly mutated in CRC. Furthermore, six patients harbored POLE variants outside the exonuclease domain, suggesting that these might be implicated in hereditary CRC. Analyses in larger cohorts of suspected LS patients recruited via international collaborations are warranted to verify the present findings.

Published
2017

38. Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

Author

Grolleman, Judith E., primary, de Voer, Richarda M., additional, Elsayed, Fadwa A., additional, Nielsen, Maartje, additional, Weren, Robbert D.A., additional, Palles, Claire, additional, Ligtenberg, Marjolijn J.L., additional, Vos, Janet R., additional, ten Broeke, Sanne W., additional, de Miranda, Noel F.C.C., additional, Kuiper, Renske A., additional, Kamping, Eveline J., additional, Jansen, Erik A.M., additional, Vink-Börger, M. Elisa, additional, Popp, Isabell, additional, Lang, Alois, additional, Spier, Isabel, additional, Hüneburg, Robert, additional, James, Paul A., additional, Li, Na, additional, Staninova, Marija, additional, Lindsay, Helen, additional, Cockburn, David, additional, Spasic-Boskovic, Olivera, additional, Clendenning, Mark, additional, Sweet, Kevin, additional, Capellá, Gabriel, additional, Sjursen, Wenche, additional, Høberg-Vetti, Hildegunn, additional, Jongmans, Marjolijn C., additional, Neveling, Kornelia, additional, Geurts van Kessel, Ad, additional, Morreau, Hans, additional, Hes, Frederik J., additional, Sijmons, Rolf H., additional, Schackert, Hans K., additional, Ruiz-Ponte, Clara, additional, Dymerska, Dagmara, additional, Lubinski, Jan, additional, Rivera, Barbara, additional, Foulkes, William D., additional, Tomlinson, Ian P., additional, Valle, Laura, additional, Buchanan, Daniel. D., additional, Kenwrick, Sue, additional, Adlard, Julian, additional, Dimovski, Aleksandar J., additional, Campbell, Ian G., additional, Aretz, Stefan, additional, Schindler, Detlev, additional, van Wezel, Tom, additional, Hoogerbrugge, Nicoline, additional, and Kuiper, Roland P., additional

Published
2019
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39. Clinical characteristics and EGD surveillance in Lynch-syndrome patients with small bowel/duodenal carcinomas

Author

Vangala, Deepak B., Pox, Christian, Ladigan, Swetlana, Engel, Christoph, Hueneburg, Robert, Perne, Claudia, Steinke-Lange, Verena, Rahner, Nils, Schackert, Hans K., Kloor, Matthias, Holzapfel, Stefanie, Kuhlkamp, Judith, Strassburg, Christian, Morak, Monika, Holinski-Feder, Elke, Buettner, Reinhard, Aretz, Stefan, Loeffler, Markus, Schmiegel, Wolff H., Schulmann, Karsten, Vangala, Deepak B., Pox, Christian, Ladigan, Swetlana, Engel, Christoph, Hueneburg, Robert, Perne, Claudia, Steinke-Lange, Verena, Rahner, Nils, Schackert, Hans K., Kloor, Matthias, Holzapfel, Stefanie, Kuhlkamp, Judith, Strassburg, Christian, Morak, Monika, Holinski-Feder, Elke, Buettner, Reinhard, Aretz, Stefan, Loeffler, Markus, Schmiegel, Wolff H., and Schulmann, Karsten

Published
2018

40. Value of EGD for gastric cancer surveillance in patients with hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome (LS).

Author

Ladigan, Swetlana, Vangala, Deepak B., Kuhlkamp, Judith, Pox, Christian, Engel, Christoph, Hueneburg, Robert, Perne, Claudia, Nattermann, Jacob, Steinke-Lange, Verena, Rahner, Nils, Schackert, Hans K., Kloor, Matthias, Strassburg, Christian, Morak, Monika, Holinski-Feder, Elke, Buttner, Reinhard, Aretz, Stefan, Loeffler, Markus, Schmiegel, Wolff H., Schulmann, Karsten, Ladigan, Swetlana, Vangala, Deepak B., Kuhlkamp, Judith, Pox, Christian, Engel, Christoph, Hueneburg, Robert, Perne, Claudia, Nattermann, Jacob, Steinke-Lange, Verena, Rahner, Nils, Schackert, Hans K., Kloor, Matthias, Strassburg, Christian, Morak, Monika, Holinski-Feder, Elke, Buttner, Reinhard, Aretz, Stefan, Loeffler, Markus, Schmiegel, Wolff H., and Schulmann, Karsten

Published
2018

41. Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes

Author

Kayser, Katrin, Degenhardt, Franziska, Holzapfel, Stefanie, Horpaopan, Sukanya, Peters, Sophia, Spier, Isabel, Morak, Monika, Vangala, Deepak, Rahner, Nils, von Knebel-Doeberitz, Magnus, Schackert, Hans K., Engel, Christoph, Buettner, Reinhard, Wijnen, Juul, Doerks, Tobias, Bork, Peer, Moebus, Susanne, Herms, Stefan, Fischer, Sascha, Hoffmann, Per, Aretz, Stefan, Steinke-Lange, Verena, Kayser, Katrin, Degenhardt, Franziska, Holzapfel, Stefanie, Horpaopan, Sukanya, Peters, Sophia, Spier, Isabel, Morak, Monika, Vangala, Deepak, Rahner, Nils, von Knebel-Doeberitz, Magnus, Schackert, Hans K., Engel, Christoph, Buettner, Reinhard, Wijnen, Juul, Doerks, Tobias, Bork, Peer, Moebus, Susanne, Herms, Stefan, Fischer, Sascha, Hoffmann, Per, Aretz, Stefan, and Steinke-Lange, Verena

Abstract

In many families with suspected Lynch syndrome (LS), no germline mutation in the causative mismatch repair (MMR) genes is detected during routine diagnostics. To identify novel causative genes for LS, the present study investigated 77 unrelated, mutation-negative patients with clinically suspected LS and a loss of MSH2 in tumor tissue. An analysis for genomic copy number variants (CNV) was performed, with subsequent next generation sequencing (NGS) of selected candidate genes in a subgroup of the cohort. Genomic DNA was genotyped using Illumina's HumanOmniExpress Bead Array. After quality control and filtering, 25 deletions and 16 duplications encompassing 73 genes were identified in 28 patients. No recurrent CNV was detected, and none of the CNVs affected the regulatory regions of MSH2. A total of 49 candidate genes from genomic regions implicated by the present CNV analysis and 30 known or assumed risk genes for colorectal cancer (CRC) were then sequenced in a subset of 38 patients using a customized NGS gene panel and Sanger sequencing. Single nucleotide variants were identified in 14 candidate genes from the CNV analysis. The most promising of these candidate genes were: (i) PRKCA, PRKDC, and MCM4, as a functional relation to MSH2 is predicted by network analysis, and (ii) CSMD1, as this is commonly mutated in CRC. Furthermore, six patients harbored POLE variants outside the exonuclease domain, suggesting that these might be implicated in hereditary CRC. Analyses in larger cohorts of suspected LS patients recruited via international collaborations are warranted to verify the present findings.

Published
2018

42. Cancer Risks for PMS2-associated lynch syndrom

Author

Broeke, Sanne W.Ten, Klift, Heleen M.Vander, Tops, Carli M.J., Aretz, Stefan, Bernstein, Inge, Buchanan, Daniel D., Chapelle, Albert Dela, Capella, Gabriel, Clendenning, Mark, Engel, Christoph, Gallinger, Steven, Garcia, Encarna Gomez, Figueiredo, Jane C., Haile, Robert, Hampel, Heather L., Hopper, John L., Hoogerbrugge, Nicoline, Doeberitz, Magnus Von Knebel, Marchand, Loic Le, Letteboer, Tom G.W., Jenkins, Mark A., Lindblom, Annika, Lindor, Noralane M., Mensenkamp, Arjen R., Møller, Pal, Newcomb, Polly A., Van Os, Theo A.M., Pearlman, Rachel, Pineda, Marta, Rahner, Nils, Redeker, Egbert J.W., Olderode-Berends, Maran J.W., Rosty, Christophe, Schackert, Hans K., Scott, Rodney, Senter, Leigha, Spruijt, Liesbeth, Steinke-Lange, Verena, Suerink, Manon, Thibodeau, Stephen, Vos, Yvonne J., Wagner, Anja, Winship, Ingrid, Hes, J. Frederik, Vasen, Hans F.A., Wijnen, Juul T., Nielsen, Maartje, Win, Aung Ko, Broeke, Sanne W.Ten, Klift, Heleen M.Vander, Tops, Carli M.J., Aretz, Stefan, Bernstein, Inge, Buchanan, Daniel D., Chapelle, Albert Dela, Capella, Gabriel, Clendenning, Mark, Engel, Christoph, Gallinger, Steven, Garcia, Encarna Gomez, Figueiredo, Jane C., Haile, Robert, Hampel, Heather L., Hopper, John L., Hoogerbrugge, Nicoline, Doeberitz, Magnus Von Knebel, Marchand, Loic Le, Letteboer, Tom G.W., Jenkins, Mark A., Lindblom, Annika, Lindor, Noralane M., Mensenkamp, Arjen R., Møller, Pal, Newcomb, Polly A., Van Os, Theo A.M., Pearlman, Rachel, Pineda, Marta, Rahner, Nils, Redeker, Egbert J.W., Olderode-Berends, Maran J.W., Rosty, Christophe, Schackert, Hans K., Scott, Rodney, Senter, Leigha, Spruijt, Liesbeth, Steinke-Lange, Verena, Suerink, Manon, Thibodeau, Stephen, Vos, Yvonne J., Wagner, Anja, Winship, Ingrid, Hes, J. Frederik, Vasen, Hans F.A., Wijnen, Juul T., Nielsen, Maartje, and Win, Aung Ko

Published
2018

43. Cancer Risks for PMS2-associated lynch syndrom

Author

Global Public Health & Bioethics, Genetica Klinische Genetica, Child Health, Broeke, Sanne W.Ten, Klift, Heleen M.Vander, Tops, Carli M.J., Aretz, Stefan, Bernstein, Inge, Buchanan, Daniel D., Chapelle, Albert Dela, Capella, Gabriel, Clendenning, Mark, Engel, Christoph, Gallinger, Steven, Garcia, Encarna Gomez, Figueiredo, Jane C., Haile, Robert, Hampel, Heather L., Hopper, John L., Hoogerbrugge, Nicoline, Doeberitz, Magnus Von Knebel, Marchand, Loic Le, Letteboer, Tom G.W., Jenkins, Mark A., Lindblom, Annika, Lindor, Noralane M., Mensenkamp, Arjen R., Møller, Pal, Newcomb, Polly A., Van Os, Theo A.M., Pearlman, Rachel, Pineda, Marta, Rahner, Nils, Redeker, Egbert J.W., Olderode-Berends, Maran J.W., Rosty, Christophe, Schackert, Hans K., Scott, Rodney, Senter, Leigha, Spruijt, Liesbeth, Steinke-Lange, Verena, Suerink, Manon, Thibodeau, Stephen, Vos, Yvonne J., Wagner, Anja, Winship, Ingrid, Hes, J. Frederik, Vasen, Hans F.A., Wijnen, Juul T., Nielsen, Maartje, Win, Aung Ko, Global Public Health & Bioethics, Genetica Klinische Genetica, Child Health, Broeke, Sanne W.Ten, Klift, Heleen M.Vander, Tops, Carli M.J., Aretz, Stefan, Bernstein, Inge, Buchanan, Daniel D., Chapelle, Albert Dela, Capella, Gabriel, Clendenning, Mark, Engel, Christoph, Gallinger, Steven, Garcia, Encarna Gomez, Figueiredo, Jane C., Haile, Robert, Hampel, Heather L., Hopper, John L., Hoogerbrugge, Nicoline, Doeberitz, Magnus Von Knebel, Marchand, Loic Le, Letteboer, Tom G.W., Jenkins, Mark A., Lindblom, Annika, Lindor, Noralane M., Mensenkamp, Arjen R., Møller, Pal, Newcomb, Polly A., Van Os, Theo A.M., Pearlman, Rachel, Pineda, Marta, Rahner, Nils, Redeker, Egbert J.W., Olderode-Berends, Maran J.W., Rosty, Christophe, Schackert, Hans K., Scott, Rodney, Senter, Leigha, Spruijt, Liesbeth, Steinke-Lange, Verena, Suerink, Manon, Thibodeau, Stephen, Vos, Yvonne J., Wagner, Anja, Winship, Ingrid, Hes, J. Frederik, Vasen, Hans F.A., Wijnen, Juul T., Nielsen, Maartje, and Win, Aung Ko

Published
2018

44. Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect

Author

Vogelaar, Ingrid P., Ligtenberg, Marjolijn J. L., van der Post, Rachel S., de Voer, Richarda M., Kets, C. Marleen, Jansen, Trees J. G., Jacobs, Liesbeth, Schreibelt, Gerty, de Vries, I. Jolanda M., Netea, Mihai G., Hoogerbrugge, Nicoline, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Schackert, Hans K., Aalfs, Cora M., Gómez García, Encarna B., Ranzani, Guglielmina N., Molinaro, Valeria, van Hest, Liselotte P., Hes, Frederik J., Holinski Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G. E. M., Sijmons, Rolf H., Wagner, Anja, van der Kolk, Lizet E., Pinheiro, Hugo, Oliveira, Carla, Bjørnevoll, Inga, Høberg Vetti, Hildegunn, Han, J., van Krieken, J. M., Human genetics, CCA - Cancer biology, and Medical Genetics

Subjects
Helicobacter Infections/drug therapy, 0301 basic medicine, Pathology, Cancer Research, Candida albicans/immunology, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], medicine.medical_treatment, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Case Reports, Settore MED/03 - GENETICA MEDICA, Germline, Candida albicans, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Missense mutation, Genetics(clinical), Myeloid Differentiation Factor 88/genetics, Non-U.S. Gov't, Genetics (clinical), Medicine(all), biology, Research Support, Non-U.S. Gov't, Homozygote, Interleukin-17, Candidiasis, Candidiasis/etiology, 3. Good health, Cytokine, Oncology, Original Article, Female, Candidaalbicans, Interleukin 17, Stomach Neoplasms/etiology, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, Th17 response, Research Support, Peripheral blood mononuclear cell, Helicobacter Infections, 03 medical and health sciences, Immune system, Stomach Neoplasms, medicine, Genetics, Journal Article, Humans, cancer, Gastric cancer, MYD88, Myeloid Differentiation Factor 88, business.industry, Cancer, biology.organism_classification, medicine.disease, 030104 developmental biology, Interleukin-17/metabolism, Immunology, business
Abstract

Contains fulltext : 171354.pdf (Publisher’s version ) (Open Access) Gastric cancer is caused by both genetic and environmental factors. A woman who suffered from recurrent candidiasis throughout her life developed diffuse-type gastric cancer at the age of 23 years. Using whole-exome sequencing we identified a germline homozygous missense variant in MYD88. Immunological assays on peripheral blood mononuclear cells revealed an impaired immune response upon stimulation with Candida albicans, characterized by a defective production of the cytokine interleukin-17. Our data suggest that a genetic defect in MYD88 results in an impaired immune response and may increase gastric cancer risk.

Published
2016
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45. Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility

Author

Weren, Robbert D A, primary, van der Post, Rachel S, additional, Vogelaar, Ingrid P, additional, van Krieken, J Han, additional, Spruijt, Liesbeth, additional, Lubinski, Jan, additional, Jakubowska, Anna, additional, Teodorczyk, Urszula, additional, Aalfs, Cora M, additional, van Hest, Liselotte P, additional, Oliveira, Carla, additional, Kamping, Eveline J, additional, Schackert, Hans K, additional, Ranzani, Guglielmina N, additional, Gómez García, Encarna B, additional, Hes, Frederik J, additional, Holinski-Feder, Elke, additional, Genuardi, Maurizio, additional, Ausems, Margreet G E M, additional, Sijmons, Rolf H, additional, Wagner, Anja, additional, van der Kolk, Lizet E, additional, Cats, Annemieke, additional, Bjørnevoll, Inga, additional, Hoogerbrugge, Nicoline, additional, and Ligtenberg, Marjolijn J L, additional

Published
2018
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46. Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Author

Vogelaar, Ingrid P, primary, van der Post, Rachel S, additional, van Krieken, J Han JM, additional, Spruijt, Liesbeth, additional, van Zelst-Stams, Wendy AG, additional, Kets, C Marleen, additional, Lubinski, Jan, additional, Jakubowska, Anna, additional, Teodorczyk, Urszula, additional, Aalfs, Cora M, additional, van Hest, Liselotte P, additional, Pinheiro, Hugo, additional, Oliveira, Carla, additional, Jhangiani, Shalini N, additional, Muzny, Donna M, additional, Gibbs, Richard A, additional, Lupski, James R, additional, de Ligt, Joep, additional, Vissers, Lisenka E L M, additional, Hoischen, Alexander, additional, Gilissen, Christian, additional, van de Vorst, Maartje, additional, Goeman, Jelle J, additional, Schackert, Hans K, additional, Ranzani, Guglielmina N, additional, Molinaro, Valeria, additional, Gómez García, Encarna B, additional, Hes, Frederik J, additional, Holinski-Feder, Elke, additional, Genuardi, Maurizio, additional, Ausems, Margreet G E M, additional, Sijmons, Rolf H, additional, Wagner, Anja, additional, van der Kolk, Lizet E, additional, Bjørnevoll, Inga, additional, Høberg-Vetti, Hildegunn, additional, van Kessel, Ad Geurts, additional, Kuiper, Roland P, additional, Ligtenberg, Marjolijn J L, additional, and Hoogerbrugge, Nicoline, additional

Published
2017
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47. Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Author

Vogelaar, Ingrid P., van der Post, Rachel S., Van Krieken, J. Han J M, Spruijt, Liesbeth, van Zelst-Stams, Wendy A. G., Kets, C. Marleen, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Aalfs, Cora M., Van Hest, Liselotte P., Pinheiro, Hugo, Oliveira, Carla, Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Lupski, James R, De Ligt, Joep, Vissers, Lisenka E L M, Hoischen, Alexander, Gilissen, Christian, Van De Vorst, Maartje, Goeman, Jelle J., Schackert, Hans K, Ranzani, Guglielmina N., Molinaro, Valeria, García, Encarna B.Gómez, Hes, Frederik J., Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G.E.M., Sijmons, Rolf H., Wagner, Anja, Van Der Kolk, Lizet E., Bjørnevoll, Inga, Høberg Vetti, Hildegunn, van Kessel, Ad Geurts, Kuiper, Roland P., Ligtenberg, Marjolijn J. L., Hoogerbrugge, Nicoline, Vogelaar, Ingrid P., van der Post, Rachel S., Van Krieken, J. Han J M, Spruijt, Liesbeth, van Zelst-Stams, Wendy A. G., Kets, C. Marleen, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Aalfs, Cora M., Van Hest, Liselotte P., Pinheiro, Hugo, Oliveira, Carla, Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Lupski, James R, De Ligt, Joep, Vissers, Lisenka E L M, Hoischen, Alexander, Gilissen, Christian, Van De Vorst, Maartje, Goeman, Jelle J., Schackert, Hans K, Ranzani, Guglielmina N., Molinaro, Valeria, García, Encarna B.Gómez, Hes, Frederik J., Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G.E.M., Sijmons, Rolf H., Wagner, Anja, Van Der Kolk, Lizet E., Bjørnevoll, Inga, Høberg Vetti, Hildegunn, van Kessel, Ad Geurts, Kuiper, Roland P., Ligtenberg, Marjolijn J. L., and Hoogerbrugge, Nicoline

Published
2017

48. Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Author

CMM Groep De Ridder, Cancer, Genetica, UMC Utrecht, Genetica Sectie Oncogenetica, Child Health, Vogelaar, Ingrid P., van der Post, Rachel S., Van Krieken, J. Han J M, Spruijt, Liesbeth, van Zelst-Stams, Wendy A. G., Kets, C. Marleen, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Aalfs, Cora M., Van Hest, Liselotte P., Pinheiro, Hugo, Oliveira, Carla, Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Lupski, James R, De Ligt, Joep, Vissers, Lisenka E L M, Hoischen, Alexander, Gilissen, Christian, Van De Vorst, Maartje, Goeman, Jelle J., Schackert, Hans K, Ranzani, Guglielmina N., Molinaro, Valeria, García, Encarna B.Gómez, Hes, Frederik J., Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G.E.M., Sijmons, Rolf H., Wagner, Anja, Van Der Kolk, Lizet E., Bjørnevoll, Inga, Høberg Vetti, Hildegunn, van Kessel, Ad Geurts, Kuiper, Roland P., Ligtenberg, Marjolijn J. L., Hoogerbrugge, Nicoline, CMM Groep De Ridder, Cancer, Genetica, UMC Utrecht, Genetica Sectie Oncogenetica, Child Health, Vogelaar, Ingrid P., van der Post, Rachel S., Van Krieken, J. Han J M, Spruijt, Liesbeth, van Zelst-Stams, Wendy A. G., Kets, C. Marleen, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Aalfs, Cora M., Van Hest, Liselotte P., Pinheiro, Hugo, Oliveira, Carla, Jhangiani, Shalini N., Muzny, Donna M., Gibbs, Richard A., Lupski, James R, De Ligt, Joep, Vissers, Lisenka E L M, Hoischen, Alexander, Gilissen, Christian, Van De Vorst, Maartje, Goeman, Jelle J., Schackert, Hans K, Ranzani, Guglielmina N., Molinaro, Valeria, García, Encarna B.Gómez, Hes, Frederik J., Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G.E.M., Sijmons, Rolf H., Wagner, Anja, Van Der Kolk, Lizet E., Bjørnevoll, Inga, Høberg Vetti, Hildegunn, van Kessel, Ad Geurts, Kuiper, Roland P., Ligtenberg, Marjolijn J. L., and Hoogerbrugge, Nicoline

Published
2017

49. Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect

Author

Genetica Sectie Oncogenetica, Child Health, Cancer, Vogelaar, Ingrid P., Ligtenberg, Marjolijn J L, van der Post, Rachel S., de Voer, Richarda M., Kets, C. Marleen, Jansen, Trees J G, Jacobs, Liesbeth, Schreibelt, Gerty, de Vries, I. Jolanda M, Netea, Mihai G., Hoogerbrugge, Nicoline, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Schackert, Hans K., Aalfs, Cora M., Gómez García, Encarna B., Ranzani, Guglielmina N., Molinaro, Valeria, van Hest, Liselotte P., Hes, Frederik J., Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G E M, Sijmons, Rolf H., Wagner, Anja, van der Kolk, Lizet E., Pinheiro, Hugo, Oliveira, Carla, Bjørnevoll, Inga, Høberg Vetti, Hildegunn, Van Krieken, J. Han J M, Genetica Sectie Oncogenetica, Child Health, Cancer, Vogelaar, Ingrid P., Ligtenberg, Marjolijn J L, van der Post, Rachel S., de Voer, Richarda M., Kets, C. Marleen, Jansen, Trees J G, Jacobs, Liesbeth, Schreibelt, Gerty, de Vries, I. Jolanda M, Netea, Mihai G., Hoogerbrugge, Nicoline, Lubinski, Jan, Jakubowska, Anna, Teodorczyk, Urszula, Schackert, Hans K., Aalfs, Cora M., Gómez García, Encarna B., Ranzani, Guglielmina N., Molinaro, Valeria, van Hest, Liselotte P., Hes, Frederik J., Holinski-Feder, Elke, Genuardi, Maurizio, Ausems, Margreet G E M, Sijmons, Rolf H., Wagner, Anja, van der Kolk, Lizet E., Pinheiro, Hugo, Oliveira, Carla, Bjørnevoll, Inga, Høberg Vetti, Hildegunn, and Van Krieken, J. Han J M

Published
2016

50. High-resolution genomic profiling reveals KIAA1797/miR-491 as a novel candidate colorectal cancer susceptibility locus

Author

Weren, Robbert, Venkatachalam, Ramprasath, Cazier, Jean-Baptiste, Akkers, Robert, Vreede, Lilian, Verwiel, Eugene T. P., Asseldonk, Monique, Kamping, Eveline J., Nagtegaal, Iris D., Kiemeney, Lambertus A. L. M., Aben, Katja K. H., Carvajal-Carmona, Luis, Schackert, Hans K., Tomlinson, Ian, Ligtenberg, Marjolijn J. L., nicoline hoogerbrugge, Kessel, Ad Geurts, and Kuiper, Roland P.

Published
2012

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