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1. Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility

Author

Encarna B. Gomez Garcia, Liesbeth Spruijt, Rolf H. Sijmons, Cora M. Aalfs, Margreet G. E. M. Ausems, Inga Bjørnevoll, Marjolijn J. L. Ligtenberg, Frederik J. Hes, Hans K. Schackert, Anna Jakubowska, Carla Oliveira, Rachel S. van der Post, Guglielmina Nadia Ranzani, Jan Lubinski, Annemieke Cats, Urszula Teodorczyk, Liselotte P. van Hest, Ingrid P. Vogelaar, Eveline J. Kamping, J. Han van Krieken, Maurizio Genuardi, Robbert D.A. Weren, Lizet E. van der Kolk, Elke Holinski-Feder, Anja Wagner, Nicoline Hoogerbrugge, Instituto de Investigação e Inovação em Saúde, Medical Genetics, Human genetics, CCA - Cancer biology and immunology, Clinical Genetics, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, and Human Genetics

Subjects
0301 basic medicine, Male, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], ACCURACY, MAP Kinase Kinase Kinases / genetics, heritability, medicine.disease_cause, GUIDELINES, Germline, Cohort Studies, 0302 clinical medicine, Cadherins / genetics, Genotype, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], ctnna1-map3k6-myd88, genetics, Genetics(clinical), Genetics (clinical), Genetics, Mutation, education.field_of_study, High-Throughput Nucleotide Sequencing, Middle Aged, Cadherins, MAP Kinase Kinase Kinases, Myeloid Differentiation Factor 88 / genetics, Europe, 030220 oncology & carcinogenesis, MOLECULAR INVERSION PROBES, CARCINOMAS, Female, Antigens, CD / genetics, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, Population, Single-nucleotide polymorphism, Biology, cancer: gastric, ctnna1 – map3k6 – myd88, next generation sequencing, 03 medical and health sciences, Young Adult, Germline mutation, SDG 3 - Good Health and Well-being, Antigens, CD, Stomach Neoplasms, Next generation sequencing, medicine, Cancer Genetics, Humans, Genetic Predisposition to Disease, Stomach Neoplasms / genetics, Allele, alpha Catenin / genetics, education, Germ-Line Mutation, Aged, Settore MED/06 - ONCOLOGIA MEDICA, CDH1, MUTATIONS, Cancer, Sequence Analysis, DNA, medicine.disease, 030104 developmental biology, Myeloid Differentiation Factor 88, alpha Catenin
Abstract

BackgroundIn approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; 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 genes CTNNA1, MAP3K6 or MYD88.MethodsWe sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.ResultsPredicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population.ConclusionsBased on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.

Published
2018
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2. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness

Author

Henriette Roed Nielsen, Judith Balmaña, Anne-Marie Gerdes, Ellen Honisch, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Douglas F. Easton, Linda Steele, Ava Kwong, Sung Won Kim, Bjarni A. Agnarsson, Piera Rizzolo, Angela R. Solano, Mads Thomassen, Johannes Lemke, Grazia Artioli, Heli Nevanlinna, Johanna I. Kiiski, Frans B. L. Hogervorst, Jong Won Lee, Diana Eccles, Mark H. Greene, Marc Tischkowitz, David E. Goldgar, Angela R. Bradbury, Javier Benitez, Marie Navratilova, Dominique Stoppa-Lyonnet, Arjen R. Mensenkamp, Alfons Meindl, Zisun Kim, Nadine Tung, Agnes Jager, Matthew L. Freedman, Ana Osorio, Norbert Arnold, Doris Steinemann, Inge Søkilde Pedersen, Patricia Llovet, Rob B. van der Luijt, Vivek L Patel, Munaza Ahmed, Lidia Moserle, Irene Konstantopoulou, Jackie Cook, Jacques Simard, Joan Brunet, Johanna Rantala, Kai-ren Ong, Carole Brewer, Joe Dennis, Sook-Yee Yoon, Hanne Meijers-Heijboer, Roberta Villa, Katie Snape, Louise Izatt, Ana Peixoto, Susan M. Domchek, Nina Ditsch, D. Gareth Evans, Tara M. Friebel, Sue K. Park, Katherine L. Nathanson, Lenka Foretova, Miguel Angel Pujana, Edith Olah, Hélène Schuster, Raymonda Varon-Mateeva, Silvia Tognazzo, Payal D. Shah, Oskar T. Johannsson, Hans Ehrencrona, Paul Gesta, Ian G. Campbell, Drakoulis Yannoukakos, Mirjam Larsen, Anthony V. D'Amico, Liene Nikitina-Zake, Davide Bondavalli, Valérie Bonadona, Paul A. James, Alan Donaldson, Antonis C. Antoniou, Bernd Auber, Andrew K. Godwin, Denise Molina Gomes, Jihyoun Lee, Laurence Faivre, Almuth Caliebe, Pilar Garre, Siddhartha Yadav, Julika Borde, Pedro Pérez-Segura, Birgitte Bertelsen, Paolo Peterlongo, Michael T. Parsons, John L. Hopper, Bruno Buecher, Goska Leslie, Shan Wang-Gohrke, Amanda B. Spurdle, T.M. Mooij, Juliane Ramser, kConFab Investigators, Lídia Feliubadaló, Susanne E. Boonen, Bernard Peissel, Anna von Wachenfeldt, Timothy R. Rebbeck, Christi J. van Asperen, Víctor Lorca, Estela Carrasco, Elisa Alducci, Ulrike Faust, Karin Kast, Gord Glendon, Saundra S. Buys, Fergus J. Couch, Mariarosaria Calvello, Istvan Bodrogi, Kathryn J. Ruddy, Philipp Wagner, Fabienne Lesueur, Evan L. Busch, Hebon Investigators, Laura Cortesi, Christian F. Singer, Ute Hamann, Giuseppe Damante, Stefania Tommasi, Esther M. John, Jacopo Azzollini, Cristina Zanzottera, Angelica M. Gutierrez-Barrera, Emmanuelle Mouret-Fourme, Claire Saule, Rosa B. Barkardottir, Kristin K. Zorn, Kerstin Rhiem, Uffe Birk Jensen, Mark Pomerantz, Yuan Chun Ding, Alison H. Trainer, Marco Montagna, Vijai Joseph, Domenico Palli, Kwang-Pil Ko, Angel M. Cronin, Susan L. Neuhausen, Dieter Niederacher, Laura Ottini, Angela Toss, Rita K. Schmutzler, Muriel Belotti, Jeffrey N. Weitzel, Caroline M. Seynaeve, Ileana Carnevali, Adalgeir Arason, Rosalind A. Eeles, Annie T W Chu, Florentia Fostira, Greet Wieme, Brita Arver, Charlotte Kvist Lautrup, Christoph Engel, Marion Gauthier-Villars, Daniel Barrowdale, Caroline Maria Rossing, Kenneth Offit, Kathleen Claes, Olufunmilayo I. Olopade, Penny Soucy, Alicia Barroso, Manuel R. Teixeira, Wendy K. Chung, Gero Kramer, Tsun Leung Chan, Agostina Stradella, Debra Frost, Noura Mebirouk, Liselotte P. van Hest, Esther Darder, Valentina Silvestri, Annabeth Høgh Petersen, Lesley McGuffog, Andrea Gehrig, Mary Porteous, Matti A. Rookus, Lizet E. van der Kolk, Siranoush Manoukian, Lone Sunde, Conxi Lázaro, Maria A. Caligo, Priyanka Sharma, Anne-Bine Skytte, Claus-Eric Ott, Christian Sutter, Paolo Radice, Veronica Medici, Georgia Chenevix-Trench, Vanesa García-Barberán, Kristiina Aittomäki, Amanda E. Toland, Anna Marie Mulligan, Véronique Mari, Bernd Dworniczak, Lynn Martin, Lara Della Puppa, Phuong L. Mai, George Fountzilas, Yen Y. Tan, Simona Agata, Torben A Kruse, Trinidad Caldés, Rosemarie Davidson, Daniel R. Barnes, Thomas Dyrso Jensen, Åke Borg, Mark E. Robson, Jennifer T. Loud, Vivian Y. Shin, Irene López-Perolio, Leigha Senter, Irene L. Andrulis, Rosa Scarpitta, Angela F. Brady, Annika Lindblom, Diana Torres, Lotte Nylandsted Krogh, Barbara Wappenschmidt, Muhammad Rashid, Jeroen Vierstraete, Mary B. Daly, Annelie Liljegren, Frederieke H. van der Baan, Eunyoung Kang, Alessandra Viel, Santiago Cabezas-Camarero, Eric Hahnen, Laura Matricardi, Marinus J. Blok, Edmond S. K. Ma, Maria Grazia Tibiletti, Catarina Santos, Julian Adlard, Soo Hwang Teo, Giuseppe Giannini, Jan Hauke, Peter J. Hulick, Miguel de la Hoya, Clare Miller, Bernardo Bonanni, Bent Ejlertsen, Lajos Géczi, Liliana Varesco, Orland Diez, N Herold, Christine Lasset, Adrià López-Fernández, Min Hyuk Lee, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, Clinicum, Department of Obstetrics and Gynecology, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Medical Oncology, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Leslie, Goska [0000-0001-5756-6222], Adlard, Julian [0000-0002-1693-0435], Arnold, Norbert [0000-0003-4523-8808], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Barnes, Daniel R [0000-0002-3781-7570], Brunet, Joan [0000-0003-1945-3512], Caligo, Maria A [0000-0003-0589-1829], Campbell, Ian G [0000-0002-7773-4155], Claes, Kathleen BM [0000-0003-0841-7372], Darder, Esther [0000-0002-7764-1397], Dennis, Joe [0000-0003-4591-1214], Dworniczak, Bernd [0000-0003-4981-7903], Eeles, Rosalind A [0000-0002-3698-6241], Ehrencrona, Hans [0000-0002-5589-3622], Ejlertsen, Bent [0000-0001-8761-714X], Evans, D Gareth [0000-0002-8482-5784], Garre, Pilar [0000-0001-8285-4138], Greene, Mark H [0000-0003-1852-9239], Hulick, Peter J [0000-0001-8397-4078], Jager, Agnes [0000-0002-7713-1450], James, Paul [0000-0002-4361-4657], John, Esther M [0000-0003-3259-8003], Joseph, Vijai [0000-0002-7933-151X], Kim, Sung-Won [0000-0002-1413-2800], Kim, Zisun [0000-0002-1413-2800], Konstantopoulou, Irene [0000-0002-0470-0309], Lesueur, Fabienne [0000-0001-7404-4549], Matricardi, Laura [0000-0002-0241-1810], Gomes, Denise Molina [0000-0002-2836-9008], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Palli, Domenico [0000-0002-5558-2437], Park, Sue K [0000-0001-5002-9707], Parsons, Michael T [0000-0003-3242-8477], Peterlongo, Paolo [0000-0001-6951-6855], Petersen, Annabeth Høgh [0000-0002-4503-6942], Pujana, Miguel Angel [0000-0003-3222-4044], Ruddy, Kathryn J [0000-0001-6298-332X], Scarpitta, Rosa [0000-0001-7590-3827], Shah, Payal D [0000-0001-5874-3390], Silvestri, Valentina [0000-0003-0712-9379], Southey, Melissa C [0000-0002-6313-9005], Spurdle, Amanda B [0000-0003-1337-7897], Stoppa-Lyonnet, Dominique [0000-0002-5438-8309], Sunde, Lone [0000-0002-8479-165X], Teixeira, Manuel R [0000-0002-4896-5982], Teo, Soo Hwang [0000-0002-0444-590X], Tommasi, Stefania [0000-0002-2157-2978], Toss, Angela [0000-0002-1854-6701], van der Luijt, Rob B [0000-0002-0018-1089], Vierstraete, Jeroen [0000-0001-7909-6620], Wieme, Greet [0000-0003-2718-5300], Yadav, Siddhartha [0000-0003-4630-9903], Antoniou, Antonis C [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Human genetics, and CCA - Cancer biology and immunology

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, endocrine system diseases, PHENOTYPE, INCREASE, Prostate cancer, 0302 clinical medicine, Risk Factors, Young adult, skin and connective tissue diseases, Aged, 80 and over, Prostate cancer risk, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], MESSENGER-RNA DECAY, BRCA1 Protein, Genomics, GERMLINE MUTATIONS, Middle Aged, Prognosis, OVARIAN, CARRIERS, 3. Good health, 030220 oncology & carcinogenesis, Adult, Heterozygote, medicine.medical_specialty, Adolescent, Tumor suppressor gene, Urology, Association (object-oriented programming), 3122 Cancers, MEDLINE, Article, Young Adult, 03 medical and health sciences, Breast cancer, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, BRCA1, BRCA2, Prostate Cancer, Pathogenic sequence variant location, Risk estimation, Journal Article, Genetic predisposition, medicine, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Risk factor, Genetic Association Studies, Aged, BRCA2 Protein, IDENTIFICATION, business.industry, Prostatic Neoplasms, medicine.disease, GENE, Confidence interval, APC, 030104 developmental biology, Mutation, 3111 Biomedicine, business
Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Published
2020
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3. Association of Genomic Domains in

Author

Vivek L, Patel, Evan L, Busch, Tara M, Friebel, Angel, Cronin, Goska, Leslie, Lesley, McGuffog, Julian, Adlard, Simona, Agata, Bjarni A, Agnarsson, Munaza, Ahmed, Kristiina, Aittomäki, Elisa, Alducci, Irene L, Andrulis, Adalgeir, Arason, Norbert, Arnold, Grazia, Artioli, Brita, Arver, Bernd, Auber, Jacopo, Azzollini, Judith, Balmaña, Rosa B, Barkardottir, Daniel R, Barnes, Alicia, Barroso, Daniel, Barrowdale, Muriel, Belotti, Javier, Benitez, Birgitte, Bertelsen, Marinus J, Blok, Istvan, Bodrogi, Valérie, Bonadona, Bernardo, Bonanni, Davide, Bondavalli, Susanne E, Boonen, Julika, Borde, Ake, Borg, Angela R, Bradbury, Angela, Brady, Carole, Brewer, Joan, Brunet, Bruno, Buecher, Saundra S, Buys, Santiago, Cabezas-Camarero, Trinidad, Caldés, Almuth, Caliebe, Maria A, Caligo, Mariarosaria, Calvello, Ian G, Campbell, Ileana, Carnevali, Estela, Carrasco, Tsun L, Chan, Annie T W, Chu, Wendy K, Chung, Kathleen B M, Claes, Gemo Study, Collaborators, Embrace, Collaborators, Jackie, Cook, Laura, Cortesi, Fergus J, Couch, Mary B, Daly, Giuseppe, Damante, Esther, Darder, Rosemarie, Davidson, Miguel, de la Hoya, Lara Della, Puppa, Joe, Dennis, Orland, Díez, Yuan Chun, Ding, Nina, Ditsch, Susan M, Domchek, Alan, Donaldson, Bernd, Dworniczak, Douglas F, Easton, Diana M, Eccles, Rosalind A, Eeles, Hans, Ehrencrona, Bent, Ejlertsen, Christoph, Engel, D Gareth, Evans, Laurence, Faivre, Ulrike, Faust, Lídia, Feliubadaló, Lenka, Foretova, Florentia, Fostira, George, Fountzilas, Debra, Frost, Vanesa, García-Barberán, Pilar, Garre, Marion, Gauthier-Villars, Lajos, Géczi, Andrea, Gehrig, Anne-Marie, Gerdes, Paul, Gesta, Giuseppe, Giannini, Gord, Glendon, Andrew K, Godwin, David E, Goldgar, Mark H, Greene, Angelica M, Gutierrez-Barrera, Eric, Hahnen, Ute, Hamann, Jan, Hauke, Natalie, Herold, Frans B L, Hogervorst, Ellen, Honisch, John L, Hopper, Peter J, Hulick, KConFab, Investigators, Hebon, Investigators, Louise, Izatt, Agnes, Jager, Paul, James, Ramunas, Janavicius, Uffe Birk, Jensen, Thomas Dyrso, Jensen, Oskar Th, Johannsson, Esther M, John, Vijai, Joseph, Eunyoung, Kang, Karin, Kast, Johanna I, Kiiski, Sung-Won, Kim, Zisun, Kim, Kwang-Pil, Ko, Irene, Konstantopoulou, Gero, Kramer, Lotte, Krogh, Torben A, Kruse, Ava, Kwong, Mirjam, Larsen, Christine, Lasset, Charlotte, Lautrup, Conxi, Lazaro, Jihyoun, Lee, Jong Won, Lee, Min Hyuk, Lee, Johannes, Lemke, Fabienne, Lesueur, Annelie, Liljegren, Annika, Lindblom, Patricia, Llovet, Adria, Lopez-Fernández, Irene, Lopez-Perolio, Victor, Lorca, Jennifer T, Loud, Edmond S K, Ma, Phuong L, Mai, Siranoush, Manoukian, Veronique, Mari, Lynn, Martin, Laura, Matricardi, Noura, Mebirouk, Veronica, Medici, Hanne E J, Meijers-Heijboer, Alfons, Meindl, Arjen R, Mensenkamp, Clare, Miller, Denise Molina, Gomes, Marco, Montagna, Thea M, Mooij, Lidia, Moserle, Emmanuelle, Mouret-Fourme, Anna Marie, Mulligan, Katherine L, Nathanson, Marie, Navratilova, Heli, Nevanlinna, Dieter, Niederacher, Finn C Cilius, Nielsen, Liene, Nikitina-Zake, Kenneth, Offit, Edith, Olah, Olufunmilayo I, Olopade, Kai-Ren, Ong, Ana, Osorio, Claus-Eric, Ott, Domenico, Palli, Sue K, Park, Michael T, Parsons, Inge Sokilde, Pedersen, Bernard, Peissel, Ana, Peixoto, Pedro, Pérez-Segura, Paolo, Peterlongo, Annabeth Høgh, Petersen, Mary E, Porteous, Miguel Angel, Pujana, Paolo, Radice, Juliane, Ramser, Johanna, Rantala, Muhammad U, Rashid, Kerstin, Rhiem, Piera, Rizzolo, Mark E, Robson, Matti A, Rookus, Caroline M, Rossing, Kathryn J, Ruddy, Catarina, Santos, Claire, Saule, Rosa, Scarpitta, Rita K, Schmutzler, Hélène, Schuster, Leigha, Senter, Caroline M, Seynaeve, Payal D, Shah, Priyanka, Sharma, Vivian Y, Shin, Valentina, Silvestri, Jacques, Simard, Christian F, Singer, Anne-Bine, Skytte, Katie, Snape, Angela R, Solano, Penny, Soucy, Melissa C, Southey, Amanda B, Spurdle, Linda, Steele, Doris, Steinemann, Dominique, Stoppa-Lyonnet, Agostina, Stradella, Lone, Sunde, Christian, Sutter, Yen Y, Tan, Manuel R, Teixeira, Soo Hwang, Teo, Mads, Thomassen, Maria Grazia, Tibiletti, Marc, Tischkowitz, Silvia, Tognazzo, Amanda E, Toland, Stefania, Tommasi, Diana, Torres, Angela, Toss, Alison H, Trainer, Nadine, Tung, Christi J, van Asperen, Frederieke H, van der Baan, Lizet E, van der Kolk, Rob B, van der Luijt, Liselotte P, van Hest, Liliana, Varesco, Raymonda, Varon-Mateeva, Alessandra, Viel, Jeroen, Vierstraete, Roberta, Villa, Anna, von Wachenfeldt, Philipp, Wagner, Shan, Wang-Gohrke, Barbara, Wappenschmidt, Jeffrey N, Weitzel, Greet, Wieme, Siddhartha, Yadav, Drakoulis, Yannoukakos, Sook-Yee, Yoon, Cristina, Zanzottera, Kristin K, Zorn, Anthony V, D'Amico, Matthew L, Freedman, Mark M, Pomerantz, Georgia, Chenevix-Trench, Antonis C, Antoniou, Susan L, Neuhausen, Laura, Ottini, Henriette Roed, Nielsen, and Timothy R, Rebbeck

Subjects
Adult, Aged, 80 and over, BRCA2 Protein, Male, Heterozygote, Adolescent, BRCA1 Protein, Prostatic Neoplasms, Genomics, Middle Aged, Prognosis, Young Adult, Risk Factors, Mutation, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged
Abstract

Pathogenic sequence variants (PSV) in

Published
2019

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

Author

Carla Oliveira, Roland P. Kuiper, Hildegunn Høberg-Vetti, James R. Lupski, Encarna B. Gomez Garcia, Margreet G. E. M. Ausems, Christian Gilissen, Liesbeth Spruijt, Elke Holinski-Feder, C. Marleen Kets, Urszula Teodorczyk, Jelle J. Goeman, Rachel S. van der Post, Ad Geurts van Kessel, Anja Wagner, Alexander Hoischen, Anna Jakubowska, Wendy A. G. van Zelst-Stams, Rolf H. Sijmons, Cora M. Aalfs, Nicoline Hoogerbrugge, Maartje van de Vorst, Marjolijn J. L. Ligtenberg, Maurizio Genuardi, Shalini N. Jhangiani, Jan Lubinski, Lisenka E.L.M. Vissers, Frederik J. Hes, Inga Bjørnevoll, J. Han van Krieken, Hugo Pinheiro, Hans K. Schackert, Joep de Ligt, Ingrid P. Vogelaar, Guglielmina Nadia Ranzani, Donna M. Muzny, Liselotte P. van Hest, Richard A. Gibbs, Lizet E. van der Kolk, Valeria Molinaro, CCA - Cancer biology and immunology, Human genetics, Medical Genetics, Human Genetics, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, Clinical Genetics, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
0301 basic medicine, Male, Candidate gene, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], VARIANTS, Gene mutation, Bioinformatics, Germline, COLORECTAL-CANCER, 0302 clinical medicine, CDH1 MUTATIONS, Stomach Neoplasms/diagnosis, HISTORY, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Genetics(clinical), Exome, Early Detection of Cancer, DIFFUSE, Genetics (clinical), Exome sequencing, RISK, Genetics, Medicine(all), Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Middle Aged, Cadherins, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Sequence Analysis, DNA/methods, 030220 oncology & carcinogenesis, Female, Genetic Testing/methods, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, MUTATION CARRIERS, Biology, Article, CLASSIFICATION, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Stomach Neoplasms, HELICOBACTER-PYLORI, Antigens, CD, RESOURCE, Molecular genetics, Genetic predisposition, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Aged, Settore MED/06 - ONCOLOGIA MEDICA, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], gastric cancer, Cadherins/genetics, Sequence Analysis, DNA, 030104 developmental biology, Early Detection of Cancer/methods, exome
Abstract

Contains fulltext : 182216.pdf (Publisher’s version ) (Open Access) Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

Published
2017
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5. Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1

Author

Margreet G. E. M. Ausems, Neeltje Arts, J. Han van Krieken, Marjolijn J. L. Ligtenberg, Encarna B. Gomez Garcia, Arjen R. Mensenkamp, Annemieke Cats, Rachel S. van der Post, Frederik J. Hes, Ingrid P. Vogelaar, Peggy Manders, Rolf H. Sijmons, Cora M. Aalfs, Liselotte P. van Hest, Lizet E. van der Kolk, Nicoline Hoogerbrugge, Anja Wagner, RS: GROW - Oncology, Clinical Genetics, Clinical sciences, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Human Genetics, Human genetics, and CCA - Disease profiling

Subjects
Oncology, Male, MISSENSE MUTATIONS, LBC, Pathology, Heredity, Time Factors, Colorectal cancer, Carcinogenesis, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], DNA Mutational Analysis, Kaplan-Meier Estimate, Stomach Neoplasms/genetics, FAMILY-HISTORY, COLORECTAL-CANCER, ENDOSCOPIC SURVEILLANCE, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], risk factors, Family history, Non-U.S. Gov't, Netherlands, Medicine(all), Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Research Support, Non-U.S. Gov't, Stomach, Gastroenterology, E-CADHERIN MUTATIONS, Neoplastic Syndromes, Hereditary/genetics, Middle Aged, Cadherins, Prognosis, Pedigree, Survival Rate, Phenotype, young adult, LOBULAR BREAST-CANCER, Female, Hereditary diffuse gastric cancer, Adult, medicine.medical_specialty, TOTAL GASTRECTOMY, EARLY-ONSET, Breast Neoplasms, Genetic Risk Factor, Breast Neoplasms/genetics, Research Support, Germline mutation, Breast cancer, SDG 3 - Good Health and Well-being, Neoplastic Syndromes, Hereditary, Stomach Neoplasms, Antigens, CD, Predictive Value of Tests, Internal medicine, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Comparative Study, Survival rate, Survival analysis, Germ-Line Mutation, Aged, Proportional Hazards Models, Retrospective Studies, Hepatology, business.industry, Cadherins/genetics, Cancer, Carcinoma, Lobular/genetics, medicine.disease, SPLICING SIGNALS, Carcinoma, Lobular, CLINICAL MANAGEMENT, business
Abstract

Contains fulltext : 153344.pdf (Publisher’s version ) (Closed access) BACKGROUND & AIMS: Germline mutations in the cadherin 1, type 1, E-cadherin gene (CDH1) cause a predisposition to gastric cancer. We evaluated the ability of the internationally accepted hereditary diffuse gastric cancer (HDGC) criteria to identify individuals with pathogenic mutations in CDH1, and assessed their outcomes. The criteria were as follows: families with 2 or more cases of gastric cancer, with at least 1 patient diagnosed with diffuse gastric cancer (DGC) before age 50; families with 3 or more cases of DGC; families with 1 DGC before the age of 40; and families with a history of DGC and lobular breast cancer, with 1 diagnosis before the age of 50. METHODS: We collected results of a CDH1 mutation analysis of 578 individuals from 499 families tested in The Netherlands between 1999 and 2014 (118 families met the HDGC criteria for testing and 236 did not; there were 145 families with incomplete data and/or availability of only first-degree relatives). Data were linked with family histories and findings from clinical and pathology analyses. The Kaplan-Meier method and Cox regression analysis were used to evaluate the overall survival of patients with and without CDH1 mutations. RESULTS: In a cohort study in The Netherlands, the HDGC criteria identified individuals with a germline CDH1 mutation with a positive predictive value of 14% and 89% sensitivity. There were 18 pathogenic CDH1 mutations in 499 families (4%); 16 of these mutations were detected in the 118 families who met the HDGC criteria for testing. One pathogenic CDH1 mutation was detected in the 236 families who did not meet HDGC criteria and 1 in the 145 families with incomplete data and/or availability of only first-degree relatives. No CDH1 mutations were found in the 67 families whose members developed intestinal-type gastric cancer, or in the 22 families whose families developed lobular breast cancer. Among patients who fulfilled the HDGC criteria and had pathogenic CDH1 mutations, 36% survived for 1 year and 4% survived for 5 years; among patients who fulfilled the HDGC criteria but did not carry pathogenic CDH1 mutations, 48% survived for 1 year and 13% survived for 5 years (P = .014 for comparative survival analysis between patients with and without a CDH1 mutation). CONCLUSIONS: All individuals with a CDH1 mutation had a personal or family history of diffuse gastric cancer. Patients with gastric cancer and germline CDH1 mutations had shorter survival times than patients who met the HDGC criteria but did not have CDH1 mutations.

Published
2015
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6. Functional analysis of MSH2 unclassified variants found in suspected Lynch syndrome patients reveals pathogenicity due to attenuated mismatch repair

Author

Anja Wagner, Judith Prins, Arjen R. Mensenkamp, Ans M.W. van den Ouweland, Frans B. L. Hogervorst, Winand N.M. Dinjens, Liselotte P. van Hest, Marjolijn J. L. Ligtenberg, C. Marleen Kets, Rob J. Dekker, Hein te Riele, Eva A. L. Wielders, Jan Hettinger, Senno Verhoef, Fred H. Menko, Hendrikus J. Dubbink, Human genetics, CCA - Oncogenesis, Erasmus MC other, Clinical Genetics, and Pathology

Subjects
Adult, Male, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, DNA Mutational Analysis, Molecular Sequence Data, Biology, medicine.disease_cause, DNA Mismatch Repair, Cell Line, Mice, SDG 3 - Good Health and Well-being, Molecular genetics, Genetics, medicine, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Animals, Humans, Missense mutation, Computer Simulation, Allele, Codon, neoplasms, Embryonic Stem Cells, Genetics (clinical), Aged, Aged, 80 and over, Mutation, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Base Sequence, nutritional and metabolic diseases, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Immunohistochemistry, Penetrance, Lynch syndrome, digestive system diseases, Pedigree, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], MutS Homolog 2 Protein, Amino Acid Substitution, MSH2, Female, DNA mismatch repair
Abstract

Item does not contain fulltext BACKGROUND: Lynch syndrome, an autosomal-dominant disorder characterised by high colorectal and endometrial cancer risks, is caused by inherited mutations in DNA mismatch repair (MMR) genes. Mutations fully abrogating gene function are unambiguously disease causing. However, missense mutations often have unknown functional implications, hampering genetic counselling. We have applied a novel approach to study three MSH2 unclassified variants (UVs) found in Dutch families with suspected Lynch syndrome. METHODS: The three mutations were recreated in the endogenous Msh2 gene in mouse embryonic stem cells by oligonucleotide-directed gene modification. The effect of the UVs on MMR activity was then tested using a set of functional assays interrogating the main MMR functions. RESULTS: We recreated and functionally tested three MSH2 UVs: MSH2-Y165D (c.493T>G), MSH2-Q690E (c.2068C>G) and MSH2-M813V (c.2437A>G). We observed reduced levels of MSH2-Y165D and MSH2-Q690E but not MSH2-M813V proteins. MSH2-M813V was able to support all MMR functions similar to wild-type MSH2, whereas MSH2-Y165D and MSH2-Q690E showed partial defects. CONCLUSIONS: Based on the results from our functional assays, we conclude that the MSH2-M813V variant is not disease causing. The MSH2-Y165D and MSH2-Q690E variants affect MMR function and are therefore likely the underlying cause of familial cancer predisposition. Since the MMR defect is partial, these variants may represent low penetrance alleles.

Published
2014
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7. OBSL1 Mutations in 3-M Syndrome are Associated With a Modulation of IGFBP2 and IGFBP5 Expression Levels

Author

Mélanie Fradin, Helen Stewart, Valérie Cormier-Daire, Céline Huber, Anna Rajab, Hanan Hamamy, David Skidmore, Arnold Munnich, Yasemin Alanay, Thomas Edouard, Allan M. Lund, Jacques L. Michaud, Liselotte P. van Hest, Maité Tauber, Daniela Bezerra Da Silva, Martine Le Merrer, Christine Oley, Albert David, Chirag Patel, Human genetics, and Other Research

Subjects
Adult, Male, Candidate gene, Mutation, Missense, Locus (genetics), Biology, Genetics, medicine, Humans, Missense mutation, Family, RNA, Messenger, Child, Gene, Cells, Cultured, Growth Disorders, Genetics (clinical), Microarray analysis techniques, Genetic heterogeneity, Syndrome, Fibroblasts, Cullin Proteins, Disease gene identification, medicine.disease, Insulin-Like Growth Factor Binding Proteins, Cytoskeletal Proteins, Gene Expression Regulation, Codon, Nonsense, 3-M syndrome, Female
Abstract

3-M syndrome is an autosomal recessive disorder characterized by severe pre- and postnatal growth retardation and minor skeletal changes. We have previously identified CUL7 as a disease-causing gene but we have also provided evidence of genetic heterogeneity in the 3-M syndrome. By homozygosity mapping in two inbred families, we found a second disease locus on chromosome 2q35-36.1 in a 5.2-Mb interval that encompasses 60 genes. To select candidate genes, we performed microarray analysis of cultured skin fibroblast RNA from one patient, looking for genes with altered expression; we found decreased expression of IGFBP2 and increased expression of IGFBP5. However, direct sequencing of these two genes failed to detect any anomaly. We then considered other candidate genes by their function/location and found nine distinct mutations in the OBSL1 gene in 13 families including eight nonsense and one missense mutations. To further understand the links between OBSL1, CUL7, and insulin-like growth factor binding proteins (IGFBPs), we performed real-time quantitative PCR (RT-PCR) analysis for OBSL1, CUL7, IGFBP2, and IGFBP5, using cultured fibroblast RNAs from two patients with distinct OBSL1 mutations (p.F697G; p.H814RfsX15). We found normal CUL7 mRNA levels but abnormal IGFBP2 and IGFBP5 mRNA levels in the two patients, suggesting that OBSL1 modulates the expression of IGFBP proteins.

Published
2010
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8. Increased colorectal cancer risk during follow-up in patients with hyperplastic polyposis syndrome: a multicentre cohort study

Author

Elisabeth M. H. Mathus-Vliegen, Carel J. M. van Noesel, Monique E. van Leerdam, Jan J. Koornstra, Liselotte P. van Hest, Karam S. Boparai, Paul Fockens, Martin Houben, Evelien Dekker, Annemieke Cats, Fokko M. Nagengast, Faculteit der Geneeskunde, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Gastroenterology & Hepatology, Neurosciences, Clinical Genetics, Human genetics, CCA - Innovative therapy, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, and Pathology

Subjects
Adult, Male, medicine.medical_specialty, Colorectal cancer, Colon Adenoma, COLONIC POLYPS, Colonoscopy, NEOPLASIA, SESSILE SERRATED ADENOMAS, Gastroenterology, CLASSIFICATION, Chromoendoscopy, SDG 3 - Good Health and Well-being, Internal medicine, medicine, CHROMOENDOSCOPY, Humans, Cumulative incidence, Risk factor, TANDEM COLONOSCOPY, DNA METHYLATION, neoplasms, Aged, Netherlands, Hyperplasia, medicine.diagnostic_test, Hereditary cancer and cancer-related syndromes [ONCOL 1], Intestinal Polyposis, business.industry, PATHWAYS, Syndrome, Middle Aged, Prognosis, medicine.disease, digestive system diseases, PREVALENCE, Hyperplastic Polyp, INDIGOCARMINE, Disease Progression, Female, Colorectal Neoplasms, Epidemiologic Methods, business, Cohort study
Abstract

Contains fulltext : 88068.pdf (Publisher’s version ) (Closed access) BACKGROUND AND AIMS: Patients with hyperplastic polyposis syndrome (HPS) receive endoscopic surveillance to prevent malignant progression of polyps. However, the optimal treatment and surveillance protocol for these patients is unknown. The aim of this study was to describe the clinical and pathological features of a large HPS cohort during multiple years of endoscopic surveillance. METHODS: Databases were searched for patients with HPS, who were analysed retrospectively. Endoscopy reports and histopathology reports were collected to evaluate frequency of endoscopic surveillance and to obtain information regarding polyp and the presence of colorectal cancer (CRC). RESULTS: In 77 patients with HPS, 1984 polyps were identified during a mean follow-up period of 5.6 years (range: 0.5-26.6). In 27 (35%) patients CRC was detected of which 22 (28.5%) at initial endoscopy. CRC was detected during surveillance in five patients (cumulative incidence: 6.5%) after a median follow-up time of 1.3 years and a median interval of 11 months. Of these interval CRCs, 4/5 were detected in diminutive serrated polyps (range: 4-16 mm). The cumulative risk of CRC under surveillance was 7% at 5 years. At multivariate logistic regression, an increasing number of hyperplastic polyps (OR 1.05, p=0.013) and serrated adenomas (OR 1.09, p=0.048) was significantly associated with CRC presence. CONCLUSIONS: HPS patients undergoing endoscopic surveillance have an increased CRC risk. The number of serrated polyps is positively correlated with the presence of CRC in HPS, thus supporting a 'serrated pathway' to CRC. To prevent malignant progression, adequate detection and removal of all polyps seems advisable. If this is not feasible, surgical resection should be considered. 01 augustus 2010

Published
2010
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9. Two TP53 germline mutations in a classical Li-Fraumeni syndrome family

Author

Senno Verhoef, Hanne Meijers-Heijboer, Anja Wagner, Liselotte P. van Hest, Conny A. van der Meer, Mariëlle W. G. Ruijs, Laura J. van't Veer, Human Genetics, Human genetics, and Clinical Genetics

Subjects
Adult, Male, Cancer Research, Tumor suppressor gene, Adolescent, Biology, Germline, Li-Fraumeni Syndrome, Exon, Germline mutation, medicine, Genetics, Adrenocortical carcinoma, Humans, Genetics(clinical), Age of Onset, Child, Genetics (clinical), Germ-Line Mutation, Aged, Netherlands, Aged, 80 and over, Splice site mutation, Middle Aged, medicine.disease, Pedigree, Oncology, Li–Fraumeni syndrome, Child, Preschool, Mutation (genetic algorithm), Female, Tumor Suppressor Protein p53
Abstract

Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited cancer predisposition syndrome characterized by a combination of tumors including sarcoma, breast cancer, brain tumors, adrenocortical carcinoma and leukemia. Germline mutations in the tumor suppressor gene TP53 are associated with LFS. We present a family with LFS in which initially a novel germline TP53 intron 5 splice site mutation was found. A second germline TP53 mutation, the exon 7 Asn235Ser (704A→G) mutation, was detected in this family through pre-symptomatic DNA testing. This latter mutation has been reported repeatedly in the literature as a pathogenic mutation involved in LFS. We provide evidence for pathogenicity of the novel intron 5 splice site mutation, whereas this evidence is lacking for the exon 7 Asn235Ser (704A→G) mutation. Our findings emphasize the importance of performing additional tests in case of germline sequence variants with uncertain functional effects.

Published
2007
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