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

BACKGROUND: In 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. METHODS: We 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. RESULTS: Predicted 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. CONCLUSIONS: Based 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

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

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

β-Defensin genomic copy number does not influence the age of onset in Huntington's Disease

none498siHuntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a CAG triplet repeat tract in the huntingtin gene. While the length of this CAG expansion is the major determinant of the age of onset (AO), other genetic factors have also been shown to play a modulatory role. Recent evidence suggests that neuroinflammations is a pivotal factor in the pathogenesis of HD, and that targeting this process may have important therapeutic ramifications. The human β-defensin 2 (hBD2)- encoded by DEFB4- is an antimicrobial peptide that exhibits inducible expression in astrocytes during inflammation and is an important regulator of innate and adaptive immune response. Therefore, DEFB4 may contribute to the neuroinflammatory processes observed in HD.openVittori A, Orth M, Roos RA, Outeiro TF, Giorgini F, Hollox EJ, Bachoud-Levi AC, Bentivoglio AR, Biunno I, Bonelli RM, Burgunder JM, Dunnett SB, Ferreira JJ, Handley OJ, Heiberg A, Illmann T, Landwehrmeyer GB, Levey J, Martinez-Jaurrieta MD, Nielsen JE, Pro Koivisto S, Piiiviirinta M, Roos RA, Sebastian AR, Tabrizi SJ, Vandenberghe W, Verellen-Dumoulin C, Zaremba J, Uhrova T, Wahlstrom J, Barth K, Correia-Guedes L, Finisterra AM, Bascuiiana Garde M, Betz S, Bos R, Ecker D, Handley OJ, Held C, Koppers K, Laura M, Descals AM, Mestre T, Monza D, Townhill J, Padieu H, Paterski L, Peppa N, Rialland A, Røren N, Sasinkova P, Trigo Cubillo P, van Walsem M, Witjes-Ane MN, Yudina E, Zielonka D, Zielonka E, Zinzi P, Bonelli RM, Herranhof B, HOd A, Kapfhammer HP, Koppitz M, Magnet M, Otti D, Painold A, Reisinge K, Scheib M, Hecht K, Lilek S, Muller N, Schoggl H, Ullah J, Ribal P, Verellen-Dumoulin C, Klempff J, Majerova V, Roth J, Hjermind LE, Jakobsen O, Vinthev-Jensen T, Larsen IU, Nielsen JE, Stokholm J, Hiivola H, Martikainen K, Tuuha K, Santala M, Milkereit E, Kosinski CM, Probst D, Reetz K, Sass C, Schiefer J, Schlangen C, Werner CJ, Andrich J, Ellrichmann G, Hoffmann R, Kaminski B, Saft C, Stamm C, Lange H, Lohle M, Schmidt S, Storch A, Wolz A, Wolz M, Capetian P, Lambeck J, Zucker B, Boelmans K, Ganos C, Hidding U, Lewerenz J, Miinchau A, Orth M, Schmalfeld J, Stubbe L, Zittel S, Heinicke W, Ribbat M, Longinus B, Miihlau M, Peinemann A, Stiidtler M, Weindl A, Winkelmann J, Ziegler C, Bechtel N, Beckmann H, Bohlen S, Holzner E, Lange H, Reilmann R, Rohm S, Rumpf S, Schepers S, Dose M, Leythaeuser G, Marquard R, Raab T, Schrenk C, Schuierer M, Barth K, Buck A, Ecker D, Eschenbach C, Held C, Landwehrmeyer B, Lezius F, Nepper S, Niess A, Orth M, Schwenk D, Siissmuth S, Trautmann S, Weydt P, Cormio C, de Tommaso M, Sciruicchio V, Serpino C, Ghelli E, Ginestroni A, Bertini E, Massaro F, Mechi C, Paganini M, Piacentini S, Pradella S, Romoli AM, Sorbi S, Abbruzzese G, Ferrandes MB, Di Maria E, Ferrandes G, Mandich P, Marchese R, Di Donato S, Gellera C, Genitrini S, Mariotti C, Nanetti L, Monza D, Soliveri P, Tomasello C, De Michele G, DiMaio L, Massarelli M, Rinaldi C, Roca A, Rossi F, Russo CV, Salvatore E, Sorrentino P, Tucci T, De Nicola A, Elifani F, Petrollini M, Martino T, Lovo F, Squitieri F, Bentivoglio AR, Catalli C, Di Giacopo R, Fasano A, Frontali M, Guidubaldi A, Ialongo T, Jacopini G, Loria G, Piano C, Piccininni C, Quaranta D, Romano S, Soleti F, Spadaro M, Zinzi P, van Hout MS, van Vugt JP, de Weert A, Bolwijn JJ, Neurologie P, Dekker M, Neurologie P, Leenders KL, van Oostrom JC, Bos R, Dumas EM, Jurgens CK, van den Bogaard SJ, Roos RA, 't Hart EP, Kremer B, Verstappen CC, Heiberg A, van Walsem MR, Frich J, Aaserud O, Wehus R, Bjørgo K, Fannemel M, Gørvell P, Lorentzen E, Koivisto SP, Retterstøl L, Stokke B, Bjørnevoll I, Sando SB, Dziadkiewicz A, Nowak M, Robowski P, Sitek E, Slawek J, Soltan W, Szinwelski M, Blaszczyk M, Boczarska-Jedynak M, Ciach-Wysocka E, Gorzkowska A, Jasinska-Myga B, Opala G, Klodowska G, Stompel D, Ciach-Wysocka E, Banaszkiewicz K, Boewiriska D, Bojakowska-Jaremek K, Neurologii A, Dec M, Krawczyk M, Rudziriska M, Szczudlik A, Szczygiel E, Wasielewska A, Wojcik M, Wojcik M, Bryl A, Ciesielska A, Klimberg A, Marcinkowski J, Samara H, Sempolowicz J, Zielonka D, Janik P, Kalbarczyk A, Kwiecinski H, Jamrozik Z, Antczak J, Jachinska K, Krysa W, Rakowicz M, Richter P, Rola R, Ryglewicz D, Sienkiewicz-Jarosz H, Sulek A, Witkowski G, Zdzienicka E, Zaremba J, Zieora-Jakutowicz K, Coelho M, Correia-Guedes L, Ferreira JJ, Mestre T, Mendes T, Valadas A, Andrade C, Joao PS, Gago M, Garrett C, Joao PS, Guerra MR, Joao PS, Solis P, Herrera CD, Garcia PM, Cubo E, Mariscal N, Sanchez J, Barrero FJ, Alonso-Frech F, Perez MR, Fenollar M, Garda R, Rivera SV, Villanueva C, Alegre J, Bascuiiana M, Ventura MF, Ribas GG, Moreno JL, Cubillo PT, Rufz PJ, Frech FA, Dfaz J, Guerrero R, Dfaz J, Artiga MJ, Dfaz J, Sanchez V, Alcaraz LF, de Ia Arrixaca V, Manzanares S, de Ia Arrixaca V, Perea MF, Reinante G, Arrixaca Ia, Torres MM, Moreau LV, de Ia Arrixaca V, Barbera MA, Guia DB, Hernanz LC, Catena JL, Sebastian R, Ferrer PQ, Carruesco GT, Bas J, Busquets N, Calopa M, Buongiorno MT, Munoz E, Elorza MD, Lopez CD, Terol DS, Robert MF, Rufz BG, Casado AG, Martinez IH, Viladrich CM, Pons R, Roca E, Llesoy JR, Idiago JM, Vergara MR, Garcia SS, Riballo AV, Hoglund A, Palhagen SE, Paucar M, Sandstrom B, Svenningsson P, Reza-Soltani TW, Burgunder JM, Kaelin A, Romero I, Schupbach M, Stebler Y, Zaugg SW, Akhtar S, Crooks J, Curtis A, de Souza J, Rickards H, Wright J, Barker RA, Di Pietro A, Fisher K, Goodman AO, Hill S, Kershaw A, Mason S, O'Keefe D, Swain R, Guzman NV, Busse M, Butcher C, Clenaghan C, Dunnett S, Fullam R, Jones L, Jones U, Khalil H, Minster S, Owen M, Hunt S, Price K, Rosser A, Townhill J, Edwards M, Ho C, McGill M, Pearson P, Porteous M, Brockie P, Foster J, Johns N, McKenzie S, Rothery J, Thomas G, Yates S, Burrows L, Chu C, Fletcher A, Gallantrae D, Harding A, Hamer S, Kraus A, Laver F, Longthorpe M, Markova I, Raman A, Silva M, Thomson A, Wild S, Yardumian P, Hobson E, Jamieson S, Musgrave H, Rowett L, Toscano J, Wild S, Yardumian P, Clayton C, Dipple H, Middleton J, Patino D, Andrews T, Dougherty A, Kavalier F, Golding C, Laing H, Lashwood A, Robertson D, Ruddy D, Whaite A, Santhouse A, Andrews T, Bruno S, Doherty K, Lahiri N, Novak M, Patel A, Rosser E, Tabrizi S, Taylor R, Warner T, Wild E, Arran N, Bek J, Callaghan J, Craufurd D, Fullam R, Howard L, Hare M, Huson S, Johnson L, Jones M, Murphy H, Oughton E, Partington-Janes L, Rogers D, Snowden J, Sollom A, Stopford C, Thompson J, Trender-Gerhard I.Vittori, A; Orth, M; Roos, Ra; Outeiro, Tf; Giorgini, F; Hollox, Ej; Bachoud-Levi, Ac; Bentivoglio, Ar; Biunno, I; Bonelli, Rm; Burgunder, Jm; Dunnett, Sb; Ferreira, Jj; Handley, Oj; Heiberg, A; Illmann, T; Landwehrmeyer, Gb; Levey, J; Martinez-Jaurrieta, Md; Nielsen, Je; Pro Koivisto, S; Piiiviirinta, M; Roos, Ra; Sebastian, Ar; Tabrizi, Sj; Vandenberghe, W; Verellen-Dumoulin, C; Zaremba, J; Uhrova, T; Wahlstrom, J; Barth, K; Correia-Guedes, L; Finisterra, Am; Bascuiiana Garde, M; Betz, S; Bos, R; Ecker, D; Handley, Oj; Held, C; Koppers, K; Laura, M; Descals, Am; Mestre, T; Monza, D; Townhill, J; Padieu, H; Paterski, L; Peppa, N; Rialland, A; Røren, N; Sasinkova, P; Trigo Cubillo, P; van Walsem, M; Witjes-Ane, Mn; Yudina, E; Zielonka, D; Zielonka, E; Zinzi, P; Bonelli, Rm; Herranhof, B; Hod, A; Kapfhammer, Hp; Koppitz, M; Magnet, M; Otti, D; Painold, A; Reisinge, K; Scheib, M; Hecht, K; Lilek, S; Muller, N; Schoggl, H; Ullah, J; Ribal, P; Verellen-Dumoulin, C; Klempff, J; Majerova, V; Roth, J; Hjermind, Le; Jakobsen, O; Vinthev-Jensen, T; Larsen, Iu; Nielsen, Je; Stokholm, J; Hiivola, H; Martikainen, K; Tuuha, K; Santala, M; Milkereit, E; Kosinski, Cm; Probst, D; Reetz, K; Sass, C; Schiefer, J; Schlangen, C; Werner, Cj; Andrich, J; Ellrichmann, G; Hoffmann, R; Kaminski, B; Saft, C; Stamm, C; Lange, H; Lohle, M; Schmidt, S; Storch, A; Wolz, A; Wolz, M; Capetian, P; Lambeck, J; Zucker, B; Boelmans, K; Ganos, C; Hidding, U; Lewerenz, J; Miinchau, A; Orth, M; Schmalfeld, J; Stubbe, L; Zittel, S; Heinicke, W; Ribbat, M; Longinus, B; Miihlau, M; Peinemann, A; Stiidtler, M; Weindl, A; Winkelmann, J; Ziegler, C; Bechtel, N; Beckmann, H; Bohlen, S; Holzner, E; Lange, H; Reilmann, R; Rohm, S; Rumpf, S; Schepers, S; Dose, M; Leythaeuser, G; Marquard, R; Raab, T; Schrenk, C; Schuierer, M; Barth, K; Buck, A; Ecker, D; Eschenbach, C; Held, C; Landwehrmeyer, B; Lezius, F; Nepper, S; Niess, A; Orth, M; Schwenk, D; Siissmuth, S; Trautmann, S; Weydt, P; Cormio, C; de Tommaso, M; Sciruicchio, V; Serpino, C; Ghelli, E; Ginestroni, A; Bertini, E; Massaro, F; Mechi, C; Paganini, M; Piacentini, S; Pradella, S; Romoli, Am; Sorbi, S; Abbruzzese, G; Ferrandes, Mb; Di Maria, E; Ferrandes, G; Mandich, P; Marchese, R; Di Donato, S; Gellera, C; Genitrini, S; Mariotti, C; Nanetti, L; Monza, D; Soliveri, P; Tomasello, C; De Michele, G; Dimaio, L; Massarelli, M; Rinaldi, C; Roca, A; Rossi, F; Russo, Cv; Salvatore, E; Sorrentino, P; Tucci, T; De Nicola, A; Elifani, F; Petrollini, M; Martino, T; Lovo, F; Squitieri, F; Bentivoglio, Ar; Catalli, C; Di Giacopo, R; Fasano, A; Frontali, M; Guidubaldi, A; Ialongo, T; Jacopini, G; Loria, G; Piano, C; Piccininni, C; Quaranta, D; Romano, S; Soleti, F; Spadaro, M; Zinzi, P; van Hout, Ms; van Vugt, Jp; de Weert, A; Bolwijn, Jj; Neurologie, P; Dekker, M; Neurologie, P; Leenders, Kl; van Oostrom, Jc; Bos, R; Dumas, Em; Jurgens, Ck; van den Bogaard, Sj; Roos, Ra; 't Hart, Ep; Kremer, B; Verstappen, Cc; Heiberg, A; van Walsem, Mr; Frich, J; Aaserud, O; Wehus, R; Bjørgo, K; Fannemel, M; Gørvell, P; Lorentzen, E; Koivisto, Sp; Retterstøl, L; Stokke, B; Bjørnevoll, I; Sando, Sb; Dziadkiewicz, A; Nowak, M; Robowski, P; Sitek, E; Slawek, J; Soltan, W; Szinwelski, M; Blaszczyk, M; Boczarska-Jedynak, M; Ciach-Wysocka, E; Gorzkowska, A; Jasinska-Myga, B; Opala, G; Klodowska, G; Stompel, D; Ciach-Wysocka, E; Banaszkiewicz, K; Boewiriska, D; Bojakowska-Jaremek, K; Neurologii, A; Dec, M; Krawczyk, M; Rudziriska, M; Szczudlik, A; Szczygiel, E; Wasielewska, A; Wojcik, M; Wojcik, M; Bryl, A; Ciesielska, A; Klimberg, A; Marcinkowski, J; Samara, H; Sempolowicz, J; Zielonka, D; Janik, P; Kalbarczyk, A; Kwiecinski, H; Jamrozik, Z; Antczak, J; Jachinska, K; Krysa, W; Rakowicz, M; Richter, P; Rola, R; Ryglewicz, D; Sienkiewicz-Jarosz, H; Sulek, A; Witkowski, G; Zdzienicka, E; Zaremba, J; Zieora-Jakutowicz, K; Coelho, M; Correia-Guedes, L; Ferreira, Jj; Mestre, T; Mendes, T; Valadas, A; Andrade, C; Joao, Ps; Gago, M; Garrett, C; Joao, Ps; Guerra, Mr; Joao, Ps; Solis, P; Herrera, Cd; Garcia, Pm; Cubo, E; Mariscal, N; Sanchez, J; Barrero, Fj; Alonso-Frech, F; Perez, Mr; Fenollar, M; Garda, R; Rivera, Sv; Villanueva, C; Alegre, J; Bascuiiana, M; Ventura, Mf; Ribas, Gg; Moreno, Jl; Cubillo, Pt; Rufz, Pj; Frech, Fa; Dfaz, J; Guerrero, R; Dfaz, J; Artiga, Mj; Dfaz, J; Sanchez, V; Alcaraz, Lf; de Ia Arrixaca, V; Manzanares, S; de Ia Arrixaca, V; Perea, Mf; Reinante, G; Arrixaca, Ia; Torres, Mm; Moreau, Lv; de Ia Arrixaca, V; Barbera, Ma; Guia, Db; Hernanz, Lc; Catena, Jl; Sebastian, R; Ferrer, Pq; Carruesco, Gt; Bas, J; Busquets, N; Calopa, M; Buongiorno, Mt; Munoz, E; Elorza, Md; Lopez, Cd; Terol, Ds; Robert, Mf; Rufz, Bg; Casado, Ag; Martinez, Ih; Viladrich, Cm; Pons, R; Roca, E; Llesoy, Jr; Idiago, Jm; Vergara, Mr; Garcia, Ss; Riballo, Av; Hoglund, A; Palhagen, Se; Paucar, M; Sandstrom, B; Svenningsson, P; Reza-Soltani, Tw; Burgunder, Jm; Kaelin, A; Romero, I; Schupbach, M; Stebler, Y; Zaugg, Sw; Akhtar, S; Crooks, J; Curtis, A; de Souza, J; Rickards, H; Wright, J; Barker, Ra; Di Pietro, A; Fisher, K; Goodman, Ao; Hill, S; Kershaw, A; Mason, S; O'Keefe, D; Swain, R; Guzman, Nv; Busse, M; Butcher, C; Clenaghan, C; Dunnett, S; Fullam, R; Jones, L; Jones, U; Khalil, H; Minster, S; Owen, M; Hunt, S; Price, K; Rosser, A; Townhill, J; Edwards, M; Ho, C; Mcgill, M; Pearson, P; Porteous, M; Brockie, P; Foster, J; Johns, N; Mckenzie, S; Rothery, J; Thomas, G; Yates, S; Burrows, L; Chu, C; Fletcher, A; Gallantrae, D; Harding, A; Hamer, S; Kraus, A; Laver, F; Longthorpe, M; Markova, I; Raman, A; Silva, M; Thomson, A; Wild, S; Yardumian, P; Hobson, E; Jamieson, S; Musgrave, H; Rowett, L; Toscano, J; Wild, S; Yardumian, P; Clayton, C; Dipple, H; Middleton, J; Patino, D; Andrews, T; Dougherty, A; Kavalier, F; Golding, C; Laing, H; Lashwood, A; Robertson, D; Ruddy, D; Whaite, A; Santhouse, A; Andrews, T; Bruno, S; Doherty, K; Lahiri, N; Novak, M; Patel, A; Rosser, E; Tabrizi, S; Taylor, R; Warner, T; Wild, E; Arran, N; Bek, J; Callaghan, J; Craufurd, D; Fullam, R; Howard, L; Hare, M; Huson, S; Johnson, L; Jones, M; Murphy, H; Oughton, E; Partington-Janes, L; Rogers, D; Snowden, J; Sollom, A; Stopford, C; Thompson, J; Trender-Gerhard, I