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6. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Author

Lecarpentier, J., Silvestri, V., Kuchenbaecker, K.B., Barrowdale, D., Dennis, J., McGuffog, L., Soucy, P., Leslie, G., Rizzolo, P., Navazio, A.S., Valentini, V., Zelli, V., Lee, A., Olama, A.A. al, Tyrer, J.P., Southey, M., John, E.M., Conner, T.A., Goldgar, D.E., Buys, S.S., Janavicius, R., Steele, L., Ding, Y.C., Neuhausen, S.L., Hansen, T.V.O., Osorio, A., Weitzel, J.N., Toss, A., Medici, V., Cortesi, L., Zanna, I., Palli, D., Radice, P., Manoukian, S., Peissel, B., Azzollini, J., Viel, A., Cini, G., Damante, G., Tommasi, S., Peterlongo, P., Fostira, F., Hamann, U., Evans, D.G., Henderson, A., Brewer, C., Eccles, D., Cook, J., Ong, K.R., Walker, L., Side, L.E., Porteous, M.E., Davidson, R., Hodgson, S., Frost, D., Adlard, J., Izatt, L., Eeles, R., Ellis, S., Tischkowitz, M., Godwin, A.K., Meindl, A., Gehrig, A., Dworniczak, B., Sutter, C., Engel, C., Niederacher, D., Steinemann, D., Hahnen, E., Hauke, J., Rhiem, K., Kast, K., Arnold, N., Ditsch, N., Wang-Gohrke, S., Wappenschmidt, B., Wand, D., Lasset, C., Stoppa-Lyonnet, D., Belotti, M., Damiola, F., Barjhoux, L., Mazoyer, S., Heetvelde, M. van, Poppe, B., Leeneer, K. de, Claes, K.B.M., Hoya, M. de la, Garcia-Barberan, V., Caldes, T., Perez Segura, P., Kiiski, J.I., Aittomaki, K., Khan, S., Nevanlinna, H., Asperen, C.J. van, Vaszko, T., Kasler, M., Olah, E., Balmana, J., Gutierrez-Enriquez, S., Diez, O., Teule, A., Izquierdo, A., Darder, E., Brunet, J., Valle, J. del, Feliubadalo, L., Pujana, M.A., Lazaro, C., Arason, A., Agnarsson, B.A., Johannsson, O.T., Barkardottir, R.B., Alducci, E., Tognazzo, S., Montagna, M., Teixeira, M.R., Pinto, P., Spurdle, A.B., Holland, H., Lee, J.W., Lee, M.H., Lee, J., Kim, S.W., Kang, E., Kim, Z., Sharma, P., Rebbeck, T.R., Vijai, J., Robson, M., Lincoln, A., Musinsky, J., Gaddam, P., Tan, Y.Y., Berger, A., Singer, C.F., Loud, J.T., Greene, M.H., Mulligan, A.M., Glendon, G., Andrulis, I.L., Toland, A.E., Senter, L., Bojesen, A., Nielsen, H.R., Skytte, A.B., Sunde, L., Jensen, U.B., Pedersen, I.S., Krogh, L., Kruse, T.A., Caligo, M.A., Yoon, S.Y., Teo, S.H., Wachenfeldt, A. von, Huo, D., Nielsen, S.M., Olopade, O.I., Nathanson, K.L., Domchek, S.M., Lorenchick, C., Jankowitz, R.C., Campbell, I., James, P., Mitchell, G., Orr, N., Park, S.K., Thomassen, M., Offit, K., Couch, F.J., Simard, J., Easton, D.F., Chenevix-Trench, G., Schmutzler, R.K., Antoniou, A.C., Ottini, L., EMBRACE, GEMO Study Collaborators, HEBON, KConFab Investigators, Dennis, Joe [0000-0003-4591-1214], Leslie, Goska [0000-0001-5756-6222], Lee, Andrew [0000-0003-0677-0252], Amin Al Olama, Ali [0000-0002-7178-3431], Tyrer, Jonathan [0000-0003-3724-4757], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository

Subjects
Adult, Aged, 80 and over, Male, Heterozygote, Multifactorial Inheritance, Genes, BRCA2, Age Factors, Genes, BRCA1, Prostatic Neoplasms, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Breast Neoplasms, Male, Case-Control Studies, Mutation, Humans, Genetic Predisposition to Disease, Genetic Testing, skin and connective tissue diseases, Aged, Genome-Wide Association Study
Abstract

$\textbf{Purpose}$ $\textit{BRCA1/2}$ mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of $\textit{BRCA1/2}$ mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of $\textit{BRCA1/2}$ mutations and implications for cancer risk prediction. $\textbf{Materials and Methods}$ We genotyped 1,802 male carriers of $\textit{BRCA1/2}$ mutations from the Consortium of Investigators of Modifiers of $\textit{BRCA1/2}$ by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of $\textit{BRCA1/2}$ mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. $\textbf{Results}$ In male carriers of $\textit{BRCA1/2}$ mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; $P$ = 8.6 × 10$^{-6}$)). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; $P$ = 3.2 × 10$^{-9}$)). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of $\textit{BRCA1}$ mutations and from 19% to 61% for carriers of $\textit{BRCA2}$ mutations, respectively. $\textbf{Conclusion}$ PRSs may provide informative cancer risk stratification for male carriers of $\textit{BRCA1/2}$ mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

Published
2017

7. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author

Phelan, C. (Catherine), Kuchenbaecker, K.B. (Karoline), Tyrer, J.P. (Jonathan P.), Kar, S.P. (Siddhartha P.), Lawrenson, K. (Kate), Winham, S.J. (Stacey J.), Dennis, J. (Joe), Pirie, A. (Ailith), Riggan, M.J. (Marjorie J.), Chornokur, G. (Ganna), Earp, M.A. (Madalene A.), Lyra, P.C. (Paulo C.), Lee, J.M. (Janet M.), Coetzee, S. (Simon), Beesley, J. (Jonathan), McGuffog, L. (Lesley), Soucy, P. (Penny), Dicks, E. (Ed), Lee, A. (Andrew), Barrowdale, D. (Daniel), Lecarpentier, J. (Julie), Leslie, G. (Goska), Aalfs, C.M. (Cora), Aben, K.K.H. (Katja), Adams, M. (Marcia), Adlard, J.W. (Julian), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N. (Natalia), Aravantinos, G. (Gerasimos), Arnold, N. (Norbert), Arun, B.K. (Banu), Arver, B. (Brita), Azzollini, J., Balmana, J. (Judith), Banerjee, S. (Susana), Barjhoux, L. (Laure), Barkardottir, R.B. (Rosa B.), Bean, Y. (Yukie), Beckmann, M.W. (Matthias), Beeghly-Fadiel, A. (Alicia), Benítez, J. (Javier), Bermisheva, M. (Marina), Bernardini, M.Q. (Marcus Q.), Birrer, M.J. (Michael J.), Bjorge, L. (Line), Black, A., Blankstein, K. (Kenneth), Blok, M.J. (Marinus), Bodelon, C. (Clara), Bogdanova, N. (Natalia), Bojesen, A. (Anders), Bonanni, B. (Bernardo), Borg, Å. (Åke), Bradbury, A.R. (Angela R.), Brenton, J.D. (James D.), Brewer, C. (Carole), Brinton, L.A. (Louise), Broberg, P. (Per), Brooks-Wilson, A. (Angela), Bruinsma, F. (Fiona), Brunet, J. (Joan), Buecher, B. (Bruno), Butzow, R. (Ralf), Buys, S.S. (Saundra), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Cannioto, R. (Rikki), Carney, M.E. (Michael), Cescon, T. (Terence), Chan, S. (Salina), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Chen, X.Q. (Xiao Qing), Chiew, Y.-E. (Yoke-Eng), Chiquette, J. (Jocelyne), Chung, W. (Wendy), Claes, K. (Kathleen), Conner, T. (Thomas), Cook, L.S. (Linda S.), Cook, J. (Jackie), Cramer, D.W. (Daniel), Cunningham, J.M. (Julie), D'Aloisio, A.A. (Aimee A.), Daly, M.B. (Mary), Damiola, F. (Francesca), Damirovna, S.D. (Sakaeva Dina), Dansonka-Mieszkowska, A. (Agnieszka), Dao, F. (Fanny), Davidson, R. (Rosemarie), DeFazio, A. (Anna), Delnatte, C.D. (Capucine), Doheny, K.F. (Kimberly), Díez, O. (Orland), Ding, Y.C. (Yuan Chun), Doherty, J.A. (Jennifer), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Dossus, L. (Laure), Duran, M. (Mercedes), Dürst, M. (Matthias), Dworniczak, B. (Bernd), Eccles, D. (Diana), Edwards, T. (Todd), Eeles, R. (Rosalind), Eilber, U. (Ursula), Ejlertsen, B. (Bent), Ekici, A.B. (Arif), Ellis, S. (Steve), Elvira, M. (Mingajeva), Eng, K.H. (Kevin H.), Engel, C. (Christoph), Evans, D.G. (Gareth), Fasching, P.A. (Peter), Ferguson, S. (Sarah), Ferrer, S.F., Flanagan, J.M. (James), Fogarty, Z.C. (Zachary C.), Fortner, R.T. (Renée T.), Fostira, F. (Florentia), Foulkes, W.D. (William D.), Fountzilas, G. (George), Fridley, B.L. (Brooke), Friebel, M.O.W. (Mark ), Friedman, E. (Eitan), Frost, D. (Debra), Ganz, P.A. (Patricia), Garber, J. (Judy), García, M.J. (María J.), Garcia-Barberan, V. (Vanesa), Gehrig, P.A. (Paola A.), Gentry-Maharaj, A. (Aleksandra), Gerdes, A-M. (Anne-Marie), Giles, G.G. (Graham G.), Glasspool, R. (Rosalind), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Radice, P. (Paolo), Goranova, T. (Teodora), Gore, M. (Martin), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Gruber, S.B. (Stephen), Hahnen, E. (Eric), Haiman, C.A. (Christopher), Håkansson, N. (Niclas), Hamann, U. (Ute), Hansen, T.V.O. (Thomas V.O.), Harrington, P.A. (Patricia A.), Harris, H.R. (Holly), Hauke, J. (Jan), Hein, A. (Alexander), Henderson, A. (Alex), Hildebrandt, M.A.T. (Michelle A.T.), Hillemanns, P. (Peter), Hodgson, S. (Shirley), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Hogervorst, F.B.L. (Frans B. L.), Holland, H. (Helene), Hooning, M.J. (Maartje J.), Hosking, K. (Karen), Huang, R.-Y. (Ruea-Yea), Hulick, P.J. (Peter), Hung, J. (Jillian), Hunter, D.J. (David J.), Huntsman, D.G. (David G.), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Iversen, E. (Erik), Izatt, L. (Louise), Izquierdo, A. (A.), Jakubowska, A. (Anna), James, P. (Paul), Janavicius, R. (Ramunas), Jernetz, M. (Mats), Jensen, A. (Allan), Jensen, U.B., John, E.M. (Esther), Johnatty, S.E. (Sharon), Jones, M.E. (Michael E.), Kannisto, P. (Päivi), Karlan, B.Y. (Beth), Karnezis, A. (Anthony), Kast, K. (Karin), Kennedy, C.J. (Catherine J.), Khusnutdinova, E.K. (Elza), Kiemeney, L.A.L.M. (Bart), Kiiski, J.I. (Johanna I.), Kim, S.-W. (Sung-Won), Kjaer, M. (Michael), Köbel, M. (Martin), Kopperud, R.K. (Reidun K.), Kruse, T.A. (Torben), Kupryjanczyk, J. (Jolanta), Kwong, A. (Ava), Laitman, Y. (Yael), Lambrechts, D. (Diether), Larrañaga, N. (Nerea), Larson, M.C. (Melissa), Lazaro, C. (Conxi), Le, N.D. (Nhu D.), Le Marchand, L. (Loic), Lee, J.W. (Jong Won), Lele, S.B. (Shashikant B.), Leminen, A. (Arto), Leroux, D. (Dominique), Lester, J. (Jenny), Lesueur, F. (Fabienne), Levine, D.A. (Douglas), Liang, D. (Dong), Liebrich, C. (Clemens), Lilyquist, J. (Jenna), Lipworth, L. (Loren), Lissowska, J. (Jolanta), Lu, K.H. (Karen), Lubinski, J. (Jan), Luccarini, C. (Craig), Lundvall, L. (Lene), Mai, P.L. (Phuong), Mendoza-Fandiño, G. (Gustavo), Manoukian, S. (Siranoush), Massuger, L.F. (Leon), May, T. (Taymaa), Mazoyer, S. (Sylvie), McAlpine, J.N. (Jessica N.), McGuire, V. (Valerie), McLaughlin, J. (John), McNeish, I. (Iain), Meijers-Heijboer, E.J. (Hanne), Meindl, A. (Alfons), Menon, U. (Usha), Mensenkamp, A.R. (Arjen R.), Merritt, M.A. (Melissa A.), Milne, R.L. (Roger), Mitchell, G. (Gillian), Modugno, F. (Francesmary), Moes-Sosnowska, J. (Joanna), Moffitt, M. (Melissa), Montagna, M. (Marco), Moysich, K.B. (Kirsten), Mulligan, A.M. (Anna Marie), Musinsky, J. (Jacob), Nathanson, K.L. (Katherine), Nedergaard, L. (Lotte), Ness, R.B. (Roberta), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Niederacher, D. (Dieter), Nussbaum, R. (Robert), Odunsi, K. (Kunle), Olah, E. (Edith), Olopade, O.I. (Olofunmilayo), Olsson, H. (Håkan), Olswold, C. (Curtis), O'Malley, D.M. (David M.), Ong, K.-R. (Kai-Ren), Onland-Moret, N.C. (Charlotte), Orr, N. (Nick), Orsulic, S. (Sandra), Osorio, A. (Ana), Palli, D. (Domenico), Papi, L. (Laura), Park-Simon, T.-W., Paul, J. (James), Pearce, C.L. (Celeste), Pedersen, I.S. (Inge Søkilde), Peeters, P.H.M., Peissel, B. (Bernard), Peixoto, A. (Ana), Pejovic, T. (Tanja), Pelttari, L.M. (Liisa M.), Permuth, J.B. (Jennifer B.), Peterlongo, P. (Paolo), Pezzani, L. (Lidia), Pfeiler, G. (Georg), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Pike, M.C. (Malcolm), Piskorz, A.M. (Anna M.), Poblete, S.R. (Samantha R.), Pócza, T. (Tímea), Poole, E.M. (Elizabeth M.), Poppe, B. (Bruce), Porteous, M.E. (Mary), Prieur, F. (Fabienne), Prokofyeva, D. (Darya), Pugh, E. (Elizabeth), Pujana, M.A. (Miquel Angel), Pujol, P. (Pascal), Rantala, J. (Johanna), Rappaport-Fuerhauser, C. (Christine), Rennert, G. (Gad), Rhiem, K. (Kerstin), Rice, P. (Patricia), Richardson, A.L. (Andrea), Robson, M. (Mark), Rodriguez, G.C. (Gustavo), Rodríguez-Antona, C. (Cristina), Romm, J. (Jane), Rookus, M.A. (Matti), Rossing, M.A. (Mary Anne), Rothstein, J.H. (Joseph H.), Rudolph, A. (Anja), Runnebaum, I.B. (Ingo), Salvesen, H.B. (Helga), Sandler, D.P. (Dale P.), Schoemaker, M.J. (Minouk J.), Senter, L. (Leigha), Setiawan, V.W. (V. Wendy), Severi, G. (Gianluca), Sharma, P. (Priyanka), Shelford, T. (Tameka), Siddiqui, N. (Nadeem), Side, L. (Lucy), Sieh, W. (Weiva), Singer, C.F. (Christian), Sobol, H. (Hagay), Song, H. (Honglin), Southey, M.C. (Melissa), Spurdle, A.B. (Amanda), Stadler, Z. (Zsofia), Steinemann, D. (Doris), Stoppa-Lyonnet, D. (Dominique), Sucheston-Campbell, L.E. (Lara E.), Sukiennicki, G. (Grzegorz), Sutphen, R. (Rebecca), Sutter, C. (Christian), Swerdlow, A.J. (Anthony ), Szabo, C. (Csilla), Szafron, L. (Lukasz), Tan, Y.Y. (Yen Y.), Taylor, J.A. (Jack A.), Tea, M.-K., Teixeira, P.J., Teo, S.-H. (Soo-Hwang), Terry, K.L. (Kathryn L.), Thompson, P.J. (Pamela J.), Thomsen, L.C.V. (Liv Cecilie Vestrheim), Thull, D.L. (Darcy L.), Tihomirova, L. (Laima), Tinker, A.V. (Anna V.), Tischkowitz, M. (Marc), Tognazzo, S. (Silvia), Toland, A.E. (Amanda Ewart), Tone, A. (Alicia), Trabert, B. (Britton), Travis, S.P.L. (Simon), Trichopoulou, A. (Antonia), Tung, N. (Nadine), Tworoger, S. (Shelley), Van Altena, A.M. (Anne M.), Van Den Berg, D. (David), Van Der Hout, A.H. (Annemarie H.), Luijt, R.B. (Rob) van der, Van Heetvelde, M. (Mattias), Van Nieuwenhuysen, E. (Els), Rensburg, E.J. (Elizabeth) van, Vanderstichele, A. (Adriaan), Varon-Mateeva, R. (Raymonda), Vega, A. (Ana), Edwards, D.V. (Digna Velez), Vergote, I., Vierkant, R.A. (Robert), Vijai, J. (Joseph), Vratimos, A. (Athanassios), Walker, L.J. (Lisa), Walsh, C. (Christine), Wand, D. (Dorothea), Wang-Gohrke, S. (Shan), Wappenschmidt, B. (Barbara), Webb, P.M. (Penelope M.), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wentzensen, N. (N.), Whittemore, A.S. (Alice), Wijnen, J.T. (Juul), Wilkens, L.R. (Lynne), Wolk, K. (Kerstin), Woo, M. (Michelle), Wu, X. (Xifeng), Wu, A.H. (Anna), Yang, H.P. (Hannah), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Zorn, K.K. (Kristin K.), Narod, S.A. (Steven A.), Easton, D.F. (Douglas), Amos, W., Schildkraut, J.M. (Joellen), Ramus, S.J. (Susan), Ottini, L. (Laura), Goodman, M.T. (Marc), Park, S.K. (Sue K.), Kelemen, L.E. (Linda), Risch, H. (Harvey), Thomassen, M. (Mads), Offit, K. (Kenneth), Simard, J. (Jacques), Schmutzler, R.K. (Rita), Hazelett, D. (Dennis), Monteiro, A.N.A. (Alvaro N.), Couch, F.J. (Fergus), Berchuck, A. (Andrew), Chenevix-Trench, G. (Georgia), Goode, E.L. (Ellen), Sellers, T.F., Gayther, S.A. (Simon), Antoniou, A.C. (Antonis), Pharoah, P.D.P. (Paul), Phelan, C. (Catherine), Kuchenbaecker, K.B. (Karoline), Tyrer, J.P. (Jonathan P.), Kar, S.P. (Siddhartha P.), Lawrenson, K. (Kate), Winham, S.J. (Stacey J.), Dennis, J. (Joe), Pirie, A. (Ailith), Riggan, M.J. (Marjorie J.), Chornokur, G. (Ganna), Earp, M.A. (Madalene A.), Lyra, P.C. (Paulo C.), Lee, J.M. (Janet M.), Coetzee, S. (Simon), Beesley, J. (Jonathan), McGuffog, L. (Lesley), Soucy, P. (Penny), Dicks, E. (Ed), Lee, A. (Andrew), Barrowdale, D. (Daniel), Lecarpentier, J. (Julie), Leslie, G. (Goska), Aalfs, C.M. (Cora), Aben, K.K.H. (Katja), Adams, M. (Marcia), Adlard, J.W. (Julian), Andrulis, I.L. (Irene), Anton-Culver, H. (Hoda), Antonenkova, N. (Natalia), Aravantinos, G. (Gerasimos), Arnold, N. (Norbert), Arun, B.K. (Banu), Arver, B. (Brita), Azzollini, J., Balmana, J. (Judith), Banerjee, S. (Susana), Barjhoux, L. (Laure), Barkardottir, R.B. (Rosa B.), Bean, Y. (Yukie), Beckmann, M.W. (Matthias), Beeghly-Fadiel, A. (Alicia), Benítez, J. (Javier), Bermisheva, M. (Marina), Bernardini, M.Q. (Marcus Q.), Birrer, M.J. (Michael J.), Bjorge, L. (Line), Black, A., Blankstein, K. (Kenneth), Blok, M.J. (Marinus), Bodelon, C. (Clara), Bogdanova, N. (Natalia), Bojesen, A. (Anders), Bonanni, B. (Bernardo), Borg, Å. (Åke), Bradbury, A.R. (Angela R.), Brenton, J.D. (James D.), Brewer, C. (Carole), Brinton, L.A. (Louise), Broberg, P. (Per), Brooks-Wilson, A. (Angela), Bruinsma, F. (Fiona), Brunet, J. (Joan), Buecher, B. (Bruno), Butzow, R. (Ralf), Buys, S.S. (Saundra), Caldes, T. (Trinidad), Caligo, M.A. (Maria A.), Campbell, I. (Ian), Cannioto, R. (Rikki), Carney, M.E. (Michael), Cescon, T. (Terence), Chan, S. (Salina), Chang-Claude, J. (Jenny), Chanock, S.J. (Stephen), Chen, X.Q. (Xiao Qing), Chiew, Y.-E. (Yoke-Eng), Chiquette, J. (Jocelyne), Chung, W. (Wendy), Claes, K. (Kathleen), Conner, T. (Thomas), Cook, L.S. (Linda S.), Cook, J. (Jackie), Cramer, D.W. (Daniel), Cunningham, J.M. (Julie), D'Aloisio, A.A. (Aimee A.), Daly, M.B. (Mary), Damiola, F. (Francesca), Damirovna, S.D. (Sakaeva Dina), Dansonka-Mieszkowska, A. (Agnieszka), Dao, F. (Fanny), Davidson, R. (Rosemarie), DeFazio, A. (Anna), Delnatte, C.D. (Capucine), Doheny, K.F. (Kimberly), Díez, O. (Orland), Ding, Y.C. (Yuan Chun), Doherty, J.A. (Jennifer), Domchek, S.M. (Susan), Dorfling, C.M. (Cecilia), Dörk, T. (Thilo), Dossus, L. (Laure), Duran, M. (Mercedes), Dürst, M. (Matthias), Dworniczak, B. (Bernd), Eccles, D. (Diana), Edwards, T. (Todd), Eeles, R. (Rosalind), Eilber, U. (Ursula), Ejlertsen, B. (Bent), Ekici, A.B. (Arif), Ellis, S. (Steve), Elvira, M. (Mingajeva), Eng, K.H. (Kevin H.), Engel, C. (Christoph), Evans, D.G. (Gareth), Fasching, P.A. (Peter), Ferguson, S. (Sarah), Ferrer, S.F., Flanagan, J.M. (James), Fogarty, Z.C. (Zachary C.), Fortner, R.T. (Renée T.), Fostira, F. (Florentia), Foulkes, W.D. (William D.), Fountzilas, G. (George), Fridley, B.L. (Brooke), Friebel, M.O.W. (Mark ), Friedman, E. (Eitan), Frost, D. (Debra), Ganz, P.A. (Patricia), Garber, J. (Judy), García, M.J. (María J.), Garcia-Barberan, V. (Vanesa), Gehrig, P.A. (Paola A.), Gentry-Maharaj, A. (Aleksandra), Gerdes, A-M. (Anne-Marie), Giles, G.G. (Graham G.), Glasspool, R. (Rosalind), Glendon, G. (Gord), Godwin, A.K. (Andrew K.), Radice, P. (Paolo), Goranova, T. (Teodora), Gore, M. (Martin), Greene, M.H. (Mark H.), Gronwald, J. (Jacek), Gruber, S.B. (Stephen), Hahnen, E. (Eric), Haiman, C.A. (Christopher), Håkansson, N. (Niclas), Hamann, U. (Ute), Hansen, T.V.O. (Thomas V.O.), Harrington, P.A. (Patricia A.), Harris, H.R. (Holly), Hauke, J. (Jan), Hein, A. (Alexander), Henderson, A. (Alex), Hildebrandt, M.A.T. (Michelle A.T.), Hillemanns, P. (Peter), Hodgson, S. (Shirley), Høgdall, C.K. (Claus), Høgdall, E. (Estrid), Hogervorst, F.B.L. (Frans B. L.), Holland, H. (Helene), Hooning, M.J. (Maartje J.), Hosking, K. (Karen), Huang, R.-Y. (Ruea-Yea), Hulick, P.J. (Peter), Hung, J. (Jillian), Hunter, D.J. (David J.), Huntsman, D.G. (David G.), Huzarski, T. (Tomasz), Imyanitov, E.N. (Evgeny), Isaacs, C. (Claudine), Iversen, E. (Erik), Izatt, L. (Louise), Izquierdo, A. (A.), Jakubowska, A. (Anna), James, P. (Paul), Janavicius, R. (Ramunas), Jernetz, M. (Mats), Jensen, A. (Allan), Jensen, U.B., John, E.M. (Esther), Johnatty, S.E. (Sharon), Jones, M.E. (Michael E.), Kannisto, P. (Päivi), Karlan, B.Y. (Beth), Karnezis, A. (Anthony), Kast, K. (Karin), Kennedy, C.J. (Catherine J.), Khusnutdinova, E.K. (Elza), Kiemeney, L.A.L.M. (Bart), Kiiski, J.I. (Johanna I.), Kim, S.-W. (Sung-Won), Kjaer, M. (Michael), Köbel, M. (Martin), Kopperud, R.K. (Reidun K.), Kruse, T.A. (Torben), Kupryjanczyk, J. (Jolanta), Kwong, A. (Ava), Laitman, Y. (Yael), Lambrechts, D. (Diether), Larrañaga, N. (Nerea), Larson, M.C. (Melissa), Lazaro, C. (Conxi), Le, N.D. (Nhu D.), Le Marchand, L. (Loic), Lee, J.W. (Jong Won), Lele, S.B. (Shashikant B.), Leminen, A. (Arto), Leroux, D. (Dominique), Lester, J. (Jenny), Lesueur, F. (Fabienne), Levine, D.A. (Douglas), Liang, D. (Dong), Liebrich, C. (Clemens), Lilyquist, J. (Jenna), Lipworth, L. (Loren), Lissowska, J. (Jolanta), Lu, K.H. (Karen), Lubinski, J. (Jan), Luccarini, C. (Craig), Lundvall, L. (Lene), Mai, P.L. (Phuong), Mendoza-Fandiño, G. (Gustavo), Manoukian, S. (Siranoush), Massuger, L.F. (Leon), May, T. (Taymaa), Mazoyer, S. (Sylvie), McAlpine, J.N. (Jessica N.), McGuire, V. (Valerie), McLaughlin, J. (John), McNeish, I. (Iain), Meijers-Heijboer, E.J. (Hanne), Meindl, A. (Alfons), Menon, U. (Usha), Mensenkamp, A.R. (Arjen R.), Merritt, M.A. (Melissa A.), Milne, R.L. (Roger), Mitchell, G. (Gillian), Modugno, F. (Francesmary), Moes-Sosnowska, J. (Joanna), Moffitt, M. (Melissa), Montagna, M. (Marco), Moysich, K.B. (Kirsten), Mulligan, A.M. (Anna Marie), Musinsky, J. (Jacob), Nathanson, K.L. (Katherine), Nedergaard, L. (Lotte), Ness, R.B. (Roberta), Neuhausen, S.L. (Susan), Nevanlinna, H. (Heli), Niederacher, D. (Dieter), Nussbaum, R. (Robert), Odunsi, K. (Kunle), Olah, E. (Edith), Olopade, O.I. (Olofunmilayo), Olsson, H. (Håkan), Olswold, C. (Curtis), O'Malley, D.M. (David M.), Ong, K.-R. (Kai-Ren), Onland-Moret, N.C. (Charlotte), Orr, N. (Nick), Orsulic, S. (Sandra), Osorio, A. (Ana), Palli, D. (Domenico), Papi, L. (Laura), Park-Simon, T.-W., Paul, J. (James), Pearce, C.L. (Celeste), Pedersen, I.S. (Inge Søkilde), Peeters, P.H.M., Peissel, B. (Bernard), Peixoto, A. (Ana), Pejovic, T. (Tanja), Pelttari, L.M. (Liisa M.), Permuth, J.B. (Jennifer B.), Peterlongo, P. (Paolo), Pezzani, L. (Lidia), Pfeiler, G. (Georg), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Pike, M.C. (Malcolm), Piskorz, A.M. (Anna M.), Poblete, S.R. (Samantha R.), Pócza, T. (Tímea), Poole, E.M. (Elizabeth M.), Poppe, B. (Bruce), Porteous, M.E. (Mary), Prieur, F. (Fabienne), Prokofyeva, D. (Darya), Pugh, E. (Elizabeth), Pujana, M.A. (Miquel Angel), Pujol, P. (Pascal), Rantala, J. (Johanna), Rappaport-Fuerhauser, C. (Christine), Rennert, G. (Gad), Rhiem, K. (Kerstin), Rice, P. (Patricia), Richardson, A.L. (Andrea), Robson, M. (Mark), Rodriguez, G.C. (Gustavo), Rodríguez-Antona, C. (Cristina), Romm, J. (Jane), Rookus, M.A. (Matti), Rossing, M.A. (Mary Anne), Rothstein, J.H. (Joseph H.), Rudolph, A. (Anja), Runnebaum, I.B. (Ingo), Salvesen, H.B. (Helga), Sandler, D.P. (Dale P.), Schoemaker, M.J. (Minouk J.), Senter, L. (Leigha), Setiawan, V.W. (V. Wendy), Severi, G. (Gianluca), Sharma, P. (Priyanka), Shelford, T. (Tameka), Siddiqui, N. (Nadeem), Side, L. (Lucy), Sieh, W. (Weiva), Singer, C.F. (Christian), Sobol, H. (Hagay), Song, H. (Honglin), Southey, M.C. (Melissa), Spurdle, A.B. (Amanda), Stadler, Z. (Zsofia), Steinemann, D. (Doris), Stoppa-Lyonnet, D. (Dominique), Sucheston-Campbell, L.E. (Lara E.), Sukiennicki, G. (Grzegorz), Sutphen, R. (Rebecca), Sutter, C. (Christian), Swerdlow, A.J. (Anthony ), Szabo, C. (Csilla), Szafron, L. (Lukasz), Tan, Y.Y. (Yen Y.), Taylor, J.A. (Jack A.), Tea, M.-K., Teixeira, P.J., Teo, S.-H. (Soo-Hwang), Terry, K.L. (Kathryn L.), Thompson, P.J. (Pamela J.), Thomsen, L.C.V. (Liv Cecilie Vestrheim), Thull, D.L. (Darcy L.), Tihomirova, L. (Laima), Tinker, A.V. (Anna V.), Tischkowitz, M. (Marc), Tognazzo, S. (Silvia), Toland, A.E. (Amanda Ewart), Tone, A. (Alicia), Trabert, B. (Britton), Travis, S.P.L. (Simon), Trichopoulou, A. (Antonia), Tung, N. (Nadine), Tworoger, S. (Shelley), Van Altena, A.M. (Anne M.), Van Den Berg, D. (David), Van Der Hout, A.H. (Annemarie H.), Luijt, R.B. (Rob) van der, Van Heetvelde, M. (Mattias), Van Nieuwenhuysen, E. (Els), Rensburg, E.J. (Elizabeth) van, Vanderstichele, A. (Adriaan), Varon-Mateeva, R. (Raymonda), Vega, A. (Ana), Edwards, D.V. (Digna Velez), Vergote, I., Vierkant, R.A. (Robert), Vijai, J. (Joseph), Vratimos, A. (Athanassios), Walker, L.J. (Lisa), Walsh, C. (Christine), Wand, D. (Dorothea), Wang-Gohrke, S. (Shan), Wappenschmidt, B. (Barbara), Webb, P.M. (Penelope M.), Weinberg, C.R. (Clarice R.), Weitzel, J.N. (Jeffrey), Wentzensen, N. (N.), Whittemore, A.S. (Alice), Wijnen, J.T. (Juul), Wilkens, L.R. (Lynne), Wolk, K. (Kerstin), Woo, M. (Michelle), Wu, X. (Xifeng), Wu, A.H. (Anna), Yang, H.P. (Hannah), Yannoukakos, D. (Drakoulis), Ziogas, A. (Argyrios), Zorn, K.K. (Kristin K.), Narod, S.A. (Steven A.), Easton, D.F. (Douglas), Amos, W., Schildkraut, J.M. (Joellen), Ramus, S.J. (Susan), Ottini, L. (Laura), Goodman, M.T. (Marc), Park, S.K. (Sue K.), Kelemen, L.E. (Linda), Risch, H. (Harvey), Thomassen, M. (Mads), Offit, K. (Kenneth), Simard, J. (Jacques), Schmutzler, R.K. (Rita), Hazelett, D. (Dennis), Monteiro, A.N.A. (Alvaro N.), Couch, F.J. (Fergus), Berchuck, A. (Andrew), Chenevix-Trench, G. (Georgia), Goode, E.L. (Ellen), Sellers, T.F., Gayther, S.A. (Simon), Antoniou, A.C. (Antonis), and Pharoah, P.D.P. (Paul)

Abstract

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Published
2017
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8. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Author

Lecarpentier, J, Silvestri, V, Kuchenbaecker, KB, Barrowdale, D, Dennis, J, McGuffog, L, Soucy, P, Leslie, G, Rizzolo, P, Navazio, AS, Valentini, V, Zelli, V, Lee, A, Al Olama, AA, Tyrer, JP, Southey, M, John, EM, Conner, TA, Goldgar, DE, Buys, SS, Janavicius, R, Steele, L, Ding, YC, Neuhausen, SL, Hansen, TVO, Osorio, A, Weitzel, JN, Toss, A, Medici, V, Cortesi, L, Zanna, I, Palli, D, Radice, P, Manoukian, S, Peissel, B, Azzollini, J, Viel, A, Cini, G, Damante, G, Tommasi, S, Peterlongo, P, Fostira, F, Hamann, U, Evans, DG, Henderson, A, Brewer, C, Eccles, D, Cook, J, Ong, K-R, Walker, L, Side, LE, Porteous, ME, Davidson, R, Hodgson, S, Frost, D, Adlard, J, Izatt, L, Eeles, R, Ellis, S, Tischkowitz, M, Godwin, AK, Meindl, A, Gehrig, A, Dworniczak, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Hahnen, E, Hauke, J, Rhiem, K, Kast, K, Arnold, N, Ditsch, N, Wang-Gohrke, S, Wappenschmidt, B, Wand, D, Lasset, C, Stoppa-Lyonnet, D, Belotti, M, Damiola, F, Barjhoux, L, Mazoyer, S, Van Heetvelde, M, Poppe, B, De Leeneer, K, Claes, KBM, de la Hoya, M, Garcia-Barberan, V, Caldes, T, Perez Segura, P, Kiiski, JI, Aittomaeki, K, Khan, S, Nevanlinna, H, van Asperen, CJ, Vaszko, T, Kasler, M, Olah, E, Balmana, J, Gutierrez-Enriquez, S, Diez, O, Teule, A, Izquierdo, A, Darder, E, Brunet, J, Del Valle, J, Feliubadalo, L, Pujana, MA, Lazaro, C, Arason, A, Agnarsson, BA, Johannsson, OT, Barkardottir, RB, Alducci, E, Tognazzo, S, Montagna, M, Teixeira, MR, Pinto, P, Spurdle, AB, Holland, H, Lee, JW, Lee, MH, Lee, J, Kim, S-W, Kang, E, Kim, Z, Sharma, P, Rebbeck, TR, Vijai, J, Robson, M, Lincoln, A, Musinsky, J, Gaddam, P, Tan, YY, Berger, A, Singer, CF, Loud, JT, Greene, MH, Mulligan, AM, Glendon, G, Andrulis, IL, Toland, AE, Senter, L, Bojesen, A, Nielsen, HR, Skytte, A-B, Sunde, L, Jensen, UB, Pedersen, IS, Krogh, L, Kruse, TA, Caligo, MA, Yoon, S-Y, Teo, S-H, von Wachenfeldt, A, Huo, D, Nielsen, SM, Olopade, OI, Nathanson, KL, Domchek, SM, Lorenchick, C, Jankowitz, RC, Campbell, I, James, P, Mitchell, G, Orr, N, Park, SK, Thomassen, M, Offit, K, Couch, FJ, Simard, J, Easton, DF, Chenevix-Trench, G, Schmutzler, RK, Antoniou, AC, Ottini, L, Lecarpentier, J, Silvestri, V, Kuchenbaecker, KB, Barrowdale, D, Dennis, J, McGuffog, L, Soucy, P, Leslie, G, Rizzolo, P, Navazio, AS, Valentini, V, Zelli, V, Lee, A, Al Olama, AA, Tyrer, JP, Southey, M, John, EM, Conner, TA, Goldgar, DE, Buys, SS, Janavicius, R, Steele, L, Ding, YC, Neuhausen, SL, Hansen, TVO, Osorio, A, Weitzel, JN, Toss, A, Medici, V, Cortesi, L, Zanna, I, Palli, D, Radice, P, Manoukian, S, Peissel, B, Azzollini, J, Viel, A, Cini, G, Damante, G, Tommasi, S, Peterlongo, P, Fostira, F, Hamann, U, Evans, DG, Henderson, A, Brewer, C, Eccles, D, Cook, J, Ong, K-R, Walker, L, Side, LE, Porteous, ME, Davidson, R, Hodgson, S, Frost, D, Adlard, J, Izatt, L, Eeles, R, Ellis, S, Tischkowitz, M, Godwin, AK, Meindl, A, Gehrig, A, Dworniczak, B, Sutter, C, Engel, C, Niederacher, D, Steinemann, D, Hahnen, E, Hauke, J, Rhiem, K, Kast, K, Arnold, N, Ditsch, N, Wang-Gohrke, S, Wappenschmidt, B, Wand, D, Lasset, C, Stoppa-Lyonnet, D, Belotti, M, Damiola, F, Barjhoux, L, Mazoyer, S, Van Heetvelde, M, Poppe, B, De Leeneer, K, Claes, KBM, de la Hoya, M, Garcia-Barberan, V, Caldes, T, Perez Segura, P, Kiiski, JI, Aittomaeki, K, Khan, S, Nevanlinna, H, van Asperen, CJ, Vaszko, T, Kasler, M, Olah, E, Balmana, J, Gutierrez-Enriquez, S, Diez, O, Teule, A, Izquierdo, A, Darder, E, Brunet, J, Del Valle, J, Feliubadalo, L, Pujana, MA, Lazaro, C, Arason, A, Agnarsson, BA, Johannsson, OT, Barkardottir, RB, Alducci, E, Tognazzo, S, Montagna, M, Teixeira, MR, Pinto, P, Spurdle, AB, Holland, H, Lee, JW, Lee, MH, Lee, J, Kim, S-W, Kang, E, Kim, Z, Sharma, P, Rebbeck, TR, Vijai, J, Robson, M, Lincoln, A, Musinsky, J, Gaddam, P, Tan, YY, Berger, A, Singer, CF, Loud, JT, Greene, MH, Mulligan, AM, Glendon, G, Andrulis, IL, Toland, AE, Senter, L, Bojesen, A, Nielsen, HR, Skytte, A-B, Sunde, L, Jensen, UB, Pedersen, IS, Krogh, L, Kruse, TA, Caligo, MA, Yoon, S-Y, Teo, S-H, von Wachenfeldt, A, Huo, D, Nielsen, SM, Olopade, OI, Nathanson, KL, Domchek, SM, Lorenchick, C, Jankowitz, RC, Campbell, I, James, P, Mitchell, G, Orr, N, Park, SK, Thomassen, M, Offit, K, Couch, FJ, Simard, J, Easton, DF, Chenevix-Trench, G, Schmutzler, RK, Antoniou, AC, and Ottini, L

Abstract

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

Published
2017

9. Phenotype-genotype correlations in patients with Marinesco-Sjogren syndrome

Author

Ezgu, FATİH SÜHEYL, Wilcox, W. R., Schneider, A., Wertelecki, W., Wand, D., Porpora, K., He, W., Hansmann, I., Graham, J. M., Li, S., Krejci, P., and de Sousa, C.

Abstract

Marinesco-Sjogren syndrome (MSS; MIM 248800) is an autosomal recessive disorder characterized by congenital cerebellar ataxia, early cataracts, developmental delay, myopathy and short stature. Alterations in the gene SIL1 cause MSS in some patients with typical findings. In this study, molecular investigations including sequencing of the SIL1 gene, western blotting and microscopic investigations in fibroblast cultures were carried out in a cohort of 15 patients from 14 unrelated families, including the large, inbred family reported by Superneau et al., having the clinical features of MSS to provide insights into the pathophysiology of the disorder. A total of seven different mutations were found in eight of the patients from seven families. The mutations caused loss of the BIP-associated protein (BAP) protein in four patients by western blot. Novel clinical features such as dental abnormalities, iris coloboma, eczema and hormonal abnormalities were noticed in some patients, but there was no clear way to distinguish those with and without SIL1 mutations. Cultured fibroblasts contained numerous cytoplasmic inclusion bodies, similar to those identified in the brain of the whoozy mouse in five unrelated patients, three with and two without SIL1 mutations, suggesting some SIL1 negative patients share a common cellular pathogenesis with those who are SIL1 positive.

Published
2014

10. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, V, Barrowdale, D, Mulligan, AM, Neuhausen, SL, Fox, S, Karlan, BY, Mitchell, G, James, P, Thull, DL, Zorn, KK, Carter, NJ, Nathanson, KL, Dornchek, SM, Rebbeck, TR, Ramus, SJ, Nussbaum, RL, Olopade, OI, Rantala, J, Yoon, S-Y, Caligo, MA, Spugnesi, L, Bojesen, A, Pedersen, IS, Thomassen, M, Jensen, UB, Toland, AE, Senter, L, Andrulis, IL, Glendon, G, Hulick, PJ, Irnyanitov, EN, Greene, MH, Mai, PL, Singer, CF, Rappaport-Fuerhauser, C, Kramer, G, Vijai, J, Offit, K, Robson, M, Lincoln, A, Jacobs, L, Machackova, E, Foretova, L, Navratilova, M, Vasickova, P, Couch, FJ, Hallberg, E, Ruddy, KJ, Sharma, P, Kim, S-W, Teixeira, MR, Pinte, P, Montagna, M, Matricardi, L, Arason, A, Johannsson, OT, Barkardottir, RB, Jakubowska, A, Lubinski, J, Izquierdo, A, Angel Pujana, M, Balmana, J, Diez, O, Ivady, G, Papp, J, Olah, E, Kwong, A, Nevanlinna, H, Aittomaki, K, Perez Segura, P, Caldes, T, Van Maerken, T, Poppe, B, Claes, KBM, Isaacs, C, Elan, C, Lasset, C, Stoppa-Lyonnet, D, Barjhoux, L, Belotti, M, Meindl, A, Gehrig, A, Sutter, C, Enger, C, Niederacher, D, Steinemann, D, Hahnen, E, Kast, K, Arnold, N, Varon-Mateeva, R, Wand, D, Godwin, AK, Evans, DG, Frost, D, Perkins, J, Adlard, J, Izatt, L, Platte, R, Eeles, R, Ellis, S, Hamann, U, Garber, J, Fostira, F, Fountzilas, G, Pasini, B, Giannini, G, Rizzolo, P, Russo, A, Cortesi, L, Papi, L, Varesco, L, Palli, D, Zanna, I, Savarese, A, Radice, P, Manoukian, S, Peissel, B, Barile, M, Bonanni, B, Viel, A, Pensotti, V, Tommasi, S, Peterlongo, P, Weitzel, JN, Osorio, A, Benitez, J, McGuffog, L, Healey, S, Gerdes, A-M, Ejlertsen, B, Hansen, TVO, Steele, L, Ding, YC, Tung, N, Janavicius, R, Goldgar, DE, Buys, SS, Daly, MB, Bane, A, Terry, MB, John, EM, Southey, M, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Ottini, L, Silvestri, V, Barrowdale, D, Mulligan, AM, Neuhausen, SL, Fox, S, Karlan, BY, Mitchell, G, James, P, Thull, DL, Zorn, KK, Carter, NJ, Nathanson, KL, Dornchek, SM, Rebbeck, TR, Ramus, SJ, Nussbaum, RL, Olopade, OI, Rantala, J, Yoon, S-Y, Caligo, MA, Spugnesi, L, Bojesen, A, Pedersen, IS, Thomassen, M, Jensen, UB, Toland, AE, Senter, L, Andrulis, IL, Glendon, G, Hulick, PJ, Irnyanitov, EN, Greene, MH, Mai, PL, Singer, CF, Rappaport-Fuerhauser, C, Kramer, G, Vijai, J, Offit, K, Robson, M, Lincoln, A, Jacobs, L, Machackova, E, Foretova, L, Navratilova, M, Vasickova, P, Couch, FJ, Hallberg, E, Ruddy, KJ, Sharma, P, Kim, S-W, Teixeira, MR, Pinte, P, Montagna, M, Matricardi, L, Arason, A, Johannsson, OT, Barkardottir, RB, Jakubowska, A, Lubinski, J, Izquierdo, A, Angel Pujana, M, Balmana, J, Diez, O, Ivady, G, Papp, J, Olah, E, Kwong, A, Nevanlinna, H, Aittomaki, K, Perez Segura, P, Caldes, T, Van Maerken, T, Poppe, B, Claes, KBM, Isaacs, C, Elan, C, Lasset, C, Stoppa-Lyonnet, D, Barjhoux, L, Belotti, M, Meindl, A, Gehrig, A, Sutter, C, Enger, C, Niederacher, D, Steinemann, D, Hahnen, E, Kast, K, Arnold, N, Varon-Mateeva, R, Wand, D, Godwin, AK, Evans, DG, Frost, D, Perkins, J, Adlard, J, Izatt, L, Platte, R, Eeles, R, Ellis, S, Hamann, U, Garber, J, Fostira, F, Fountzilas, G, Pasini, B, Giannini, G, Rizzolo, P, Russo, A, Cortesi, L, Papi, L, Varesco, L, Palli, D, Zanna, I, Savarese, A, Radice, P, Manoukian, S, Peissel, B, Barile, M, Bonanni, B, Viel, A, Pensotti, V, Tommasi, S, Peterlongo, P, Weitzel, JN, Osorio, A, Benitez, J, McGuffog, L, Healey, S, Gerdes, A-M, Ejlertsen, B, Hansen, TVO, Steele, L, Ding, YC, Tung, N, Janavicius, R, Goldgar, DE, Buys, SS, Daly, MB, Bane, A, Terry, MB, John, EM, Southey, M, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Ottini, L

Abstract

BACKGROUND: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). METHODS: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)). CONCLUSIONS: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.

Published
2016

11. changes in Schimke immuno-osseous dysplasia?

Author

Morimoto, M, Yu, ZX, Stenzel, P, Clewing, JM, Najafian, B, Mayfield, C, Hendson, G, Weinkauf, JG, Gormley, AK, Parham, DM, Ponniah, U, Andre, JL, Asakura, Y, Basiratnia, M, Bogdanovic, R, Bokenkamp, A, Bonneau, D, Buck, A, Charrow, J, Cochat, P, Cordeiro, I, Deschenes, G, Fenkci, MS, Frange, P, Frund, S, Fryssira, H, Guillen-Navarro, E, Keller, K, Kirmani, S, Kobelka, C, Lamfers, P, Levtchenko, E, Lewis, DB, Massella, L, McLeod, DR, Milford, DV, Nobili, F, Saraiva, JM, Semerci, CN, Shoemaker, L, Stajic, N, Stein, A, Taha, D, Wand, D, Zonana, J, Lucke, T, and Boerkoel, CF

Subjects
Pulmonary emphysema, Schimke immuno-osseous dysplasia, SMARCAL1, Elastin, Vascular disease
Abstract

Background: Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown. Methods: We reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients. Results: Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression. Conclusions: This first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.

Published
2012

18. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author

Phelan, CM, Kuchenbaecker, KB, Tyrer, JP, Kar, SP, Lawrenson, K, Winham, SJ, Dennis, J, Pirie, A, Riggan, MJ, Chornokur, G, Earp, MA, Lyra, PC, Lee, JM, Coetzee, S, Beesley, J, McGuffog, L, Soucy, P, Dicks, E, Lee, A, Barrowdale, D, Lecarpentier, J, Leslie, G, Aalfs, CM, Aben, KKH, Adams, M, Adlard, J, Andrulis, IL, Anton-Culver, H, Antonenkova, N, AOCS Study Group, Aravantinos, G, Arnold, N, Arun, BK, Arver, B, Azzollini, J, Balmaña, J, Banerjee, SN, Barjhoux, L, Barkardottir, RB, Bean, Y, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Birrer, MJ, Bjorge, L, Black, A, Blankstein, K, Blok, MJ, Bodelon, C, Bogdanova, N, Bojesen, A, Bonanni, B, Borg, Å, Bradbury, AR, Brenton, JD, Brewer, C, Brinton, L, Broberg, P, Brooks-Wilson, A, Bruinsma, F, Brunet, J, Buecher, B, Butzow, R, Buys, SS, Caldes, T, Caligo, MA, Campbell, I, Cannioto, R, Carney, ME, Cescon, T, Chan, SB, Chang-Claude, J, Chanock, S, Chen, XQ, Chiew, Y-E, Chiquette, J, Chung, WK, Claes, KBM, Conner, T, Cook, LS, Cook, J, Cramer, DW, Cunningham, JM, D'Aloisio, AA, Daly, MB, Damiola, F, Damirovna, SD, Dansonka-Mieszkowska, A, Dao, F, Davidson, R, DeFazio, A, Delnatte, C, Doheny, KF, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dorfling, CM, Dörk, T, Dossus, L, Duran, M, Dürst, M, Dworniczak, B, Eccles, D, Edwards, T, Eeles, R, Eilber, U, Ejlertsen, B, Ekici, AB, Ellis, S, Elvira, M, EMBRACE Study, Eng, KH, Engel, C, Evans, DG, Fasching, PA, Ferguson, S, Ferrer, SF, Flanagan, JM, Fogarty, ZC, Fortner, RT, Fostira, F, Foulkes, WD, Fountzilas, G, Fridley, BL, Friebel, TM, Friedman, E, Frost, D, Ganz, PA, Garber, J, García, MJ, Garcia-Barberan, V, Gehrig, A, GEMO Study Collaborators, Gentry-Maharaj, A, Gerdes, A-M, Giles, GG, Glasspool, R, Glendon, G, Godwin, AK, Goldgar, DE, Goranova, T, Gore, M, Greene, MH, Gronwald, J, Gruber, S, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hansen, TVO, Harrington, PA, Harris, HR, Hauke, J, HEBON Study, Hein, A, Henderson, A, Hildebrandt, MAT, Hillemanns, P, Hodgson, S, Høgdall, CK, Høgdall, E, Hogervorst, FBL, Holland, H, Hooning, MJ, Hosking, K, Huang, R-Y, Hulick, PJ, Hung, J, Hunter, DJ, Huntsman, DG, Huzarski, T, Imyanitov, EN, Isaacs, C, Iversen, ES, Izatt, L, Izquierdo, A, Jakubowska, A, James, P, Janavicius, R, Jernetz, M, Jensen, A, Jensen, UB, John, EM, Johnatty, S, Jones, ME, Kannisto, P, Karlan, BY, Karnezis, A, Kast, K, KConFab Investigators, Kennedy, CJ, Khusnutdinova, E, Kiemeney, LA, Kiiski, JI, Kim, S-W, Kjaer, SK, Köbel, M, Kopperud, RK, Kruse, TA, Kupryjanczyk, J, Kwong, A, Laitman, Y, Lambrechts, D, Larrañaga, N, Larson, MC, Lazaro, C, Le, ND, Le Marchand, L, Lee, JW, Lele, SB, Leminen, A, Leroux, D, Lester, J, Lesueur, F, Levine, DA, Liang, D, Liebrich, C, Lilyquist, J, Lipworth, L, Lissowska, J, Lu, KH, Lubinński, J, Luccarini, C, Lundvall, L, Mai, PL, Mendoza-Fandiño, G, Manoukian, S, Massuger, LFAG, May, T, Mazoyer, S, McAlpine, JN, McGuire, V, McLaughlin, McNeish, I, Meijers-Heijboer, H, Meindl, A, Menon, U, Mensenkamp, AR, Merritt, MA, Milne, RL, Mitchell, G, Modugno, F, Moes-Sosnowska, J, Moffitt, M, Montagna, M, Moysich, KB, Mulligan, AM, Musinsky, J, Nathanson, KL, Nedergaard, L, Ness, RB, Neuhausen, SL, Nevanlinna, H, Niederacher, D, Nussbaum, RL, Odunsi, K, Olah, E, Olopade, OI, Olsson, H, Olswold, C, O'Malley, DM, Ong, K-R, Onland-Moret, NC, OPAL Study Group, Orr, N, Orsulic, S, Osorio, A, Palli, D, Papi, L, Park-Simon, T-W, Paul, J, Pearce, CL, Pedersen, IS, Peeters, PHM, Peissel, B, Peixoto, A, Pejovic, T, Pelttari, LM, Permuth, JB, Peterlongo, P, Pezzani, L, Pfeiler, G, Phillips, K-A, Piedmonte, M, Pike, MC, Piskorz, AM, Poblete, Pocza, T, Poole, EM, Poppe, B, Porteous, ME, Prieur, F, Prokofyeva, D, Pugh, E, Pujana, MA, Pujol, P, Radice, P, Rantala, J, Rappaport-Fuerhauser, C, Rennert, G, Rhiem, K, Rice, P, Richardson, A, Robson, M, Rodriguez, GC, Rodríguez-Antona, C, Romm, J, Rookus, MA, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Salvesen, HB, Sandler, DP, Schoemaker, MJ, Senter, L, Setiawan, VW, Severi, G, Sharma, P, Shelford, T, Siddiqui, N, Side, LE, Sieh, W, Singer, CF, Sobol, H, Song, H, Southey, MC, Spurdle, AB, Stadler, Z, Steinemann, D, Stoppa-Lyonnet, D, Sucheston-Campbell, LE, Sukiennicki, G, Sutphen, R, Sutter, C, Swerdlow, AJ, Szabo, CI, Szafron, L, Tan, YY, Taylor, JA, Tea, M-K, Teixeira, MR, Teo, S-H, Terry, KL, Thompson, PJ, Thomsen, LCV, Thull, DL, Tihomirova, L, Tinker, AV, Tischkowitz, M, Tognazzo, S, Toland, AE, Tone, A, Trabert, B, Travis, RC, Trichopoulou, A, Tung, N, Tworoger, SS, Van Altena, AM, Van Den Berg, D, Van Der Hout, AH, Van Der Luijt, RB, Van Heetvelde, M, Van Nieuwenhuysen, E, Van Rensburg, EJ, Vanderstichele, A, Varon-Mateeva, R, Vega, A, Edwards, DV, Vergote, I, Vierkant, RA, Vijai, J, Vratimos, A, Walker, L, Walsh, C, Wand, D, Wang-Gohrke, S, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, Whittemore, AS, Wijnen, JT, Wilkens, LR, Wolk, A, Woo, M, Wu, X, Wu, AH, Yang, H, Yannoukakos, D, Ziogas, A, Zorn, KK, Narod, SA, Easton, DF, Amos, CI, Schildkraut, JM, Ramus, SJ, Ottini, L, Goodman, MT, Park, SK, Kelemen, LE, Risch, HA, Thomassen, M, Offit, K, Simard, J, Schmutzler, RK, Hazelett, D, Monteiro, AN, Couch, FJ, Berchuck, A, Chenevix-Trench, G, Goode, EL, Sellers, TA, Gayther, SA, Antoniou, AC, and Pharoah, PDP

Subjects
ovarian cancer, endocrine system diseases, genome-wide association studies, epidemiology, female genital diseases and pregnancy complications, 3. Good health
Abstract

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 $\textit{BRCA1}$ and $\textit{BRCA2}$ mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

19. Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?

Author

Morimoto Marie, Yu Zhongxin, Stenzel Peter, Clewing J, Najafian Behzad, Mayfield Christy, Hendson Glenda, Weinkauf Justin G, Gormley Andrew K, Parham David M, Ponniah Umakumaran, André Jean-Luc, Asakura Yumi, Basiratnia Mitra, Bogdanović Radovan, Bokenkamp Arend, Bonneau Dominique, Buck Anna, Charrow Joel, Cochat Pierre, Cordeiro Isabel, Deschenes Georges, Fenkçi M, Frange Pierre, Fründ Stefan, Fryssira Helen, Guillen-Navarro Encarna, Keller Kory, Kirmani Salman, Kobelka Christine, Lamfers Petra, Levtchenko Elena, Lewis David B, Massella Laura, McLeod D, Milford David V, Nobili François, Saraiva Jorge M, Semerci C, Shoemaker Lawrence, Stajić Nataša, Stein Anja, Taha Doris, Wand Dorothea, Zonana Jonathan, Lücke Thomas, and Boerkoel Cornelius F

Subjects
Schimke immuno-osseous dysplasia, SMARCAL1, Elastin, Vascular disease, Pulmonary emphysema, Medicine
Abstract

Abstract Background Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown. Methods We reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients. Results Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression. Conclusions This first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.

Published
2012
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20. Gelsolin-Amyloidosis - An Exceptional Cause of Blepharochalasis.

Author

Yahya F, Kesenheimer E, Decard BF, Sinnreich M, Wand D, and Goldblum D

Subjects
Gelsolin genetics, Gelsolin metabolism, Humans, Mutation, Amyloidosis complications, Amyloidosis diagnosis, Corneal Dystrophies, Hereditary
Abstract

Competing Interests: The authors declare that they have no conflict of interest.

Published
2021
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21. Fragile-X-Associated Tremor/Ataxia Syndrome or Alcohol-Induced Cerebellar Degeneration? A Case Report.

Author

Grigioni G, Saleh C, Jaszczuk P, Wand D, Wilmes S, and Hund-Georgiadis M

Abstract

Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that manifests with intention tremor, progressive gait ataxia, and cognitive impairment. The disease is genetically characterized by a premutation of the FMR1 gene on the X-chromosome manifesting with a CGG triplet expansion between 55 and 200. Given the phenotypical variety of this disease, diagnosis is frequently delayed. We present and discuss a male patient whose diagnosis of FXTAS was delayed due to his concomitant alcohol abuse., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2020 by S. Karger AG, Basel.)

Published
2020
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22. Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.

Author

Besnard T, Sloboda N, Goldenberg A, Küry S, Cogné B, Breheret F, Trochu E, Conrad S, Vincent M, Deb W, Balguerie X, Barbarot S, Baujat G, Ben-Omran T, Bursztejn AC, Carmignac V, Datta AN, Delignières A, Faivre L, Gardie B, Guéant JL, Kuentz P, Lenglet M, Nassogne MC, Ramaekers V, Schnur RE, Si Y, Torti E, Thevenon J, Vabres P, Van Maldergem L, Wand D, Wiedemann A, Cariou B, Redon R, Lamazière A, Bézieau S, Feillet F, and Isidor B

Subjects
Age of Onset, Alopecia complications, Alopecia pathology, Child, Child, Preschool, Cholesterol genetics, Developmental Disabilities complications, Developmental Disabilities pathology, Epilepsy complications, Epilepsy genetics, Epilepsy pathology, Female, Humans, Infant, Intellectual Disability complications, Intellectual Disability pathology, Lanosterol genetics, Lanosterol metabolism, Male, Mutation, Pedigree, Phenotype, Squalene analogs & derivatives, Squalene metabolism, Exome Sequencing, Alopecia genetics, Cholesterol metabolism, Developmental Disabilities genetics, Intellectual Disability genetics, Intramolecular Transferases genetics
Abstract

Purpose: Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features., Methods: Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay., Results: We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance., Conclusion: In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.

Published
2019
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23. [The Thyroid Hormone Receptor Mediated Luciferase Reporter Gene Assays Screening for EDCs].

Author

Wand D, Lu KQ, Bao QL, Hu JQ, Song J, Zhou MM, Zhou LH, Shan JY, Zeng X, and Li Y

Abstract

Objective: This study in order to use report gene assay based on the thyroid hormone receptor (TR) α/β from human origin for screening endocrine disruptors chemicals (EDCs), evaluating the thyroid hormone activity of Bisphenol (BPA), 1-Naphthaleny methyl carbamate and 1-naphthol (1-NAP)., Methods: Using Rhesus monkey kidney cells (LLC-MK2) as transfection cell to establish the gene report assay system based on pGL-3-promega and pGL4.27 of TRα/β through the method of transient transfection. Using T3 and T4 as positive subjects to evaluation the effectiveness of two detection systems and detect the thyroid hormone activity of BPA, 1-Naphthaleny methyl carbamate, 1-NAP., Results: The TRβ LLC-MK2 report gene assay based on pGL3-promega, the minimum detectable limit of T3 is 1.216×10 -11 mol/L, the largest induction multiple was shown at 7.482×10 -6 mol/L, the expression multiple of induced Lucifrerase was 5.98-fold that of the vehicle control, the EC 50 was 3.327×10 -8 mol/L; The minimum detectable limit of T4 was 1.622×10 -8 mol/L, the largest induction Luc expression was 3.4-fold of vehicle control, the EC 50 was 2.213×10 -7 mol/L. The TRβ LLC-MK2 report gene assay based on pGL4.27, the minimum detectable limit of T3 was 9.863×10 -12 mol/L, the largest induction Luc expression as shown at 1.671×10 -6 mol/L, resulting in 8.57-fold of vehicle control, the EC 50 is 3.327×10 -8 mol/L. The minimum detectable limit of T4 was 1.349×10 -9 mol/L, the largest induction Luc expression was 4.6-fold of vehicle control, the EC 50 is 4.074×10 -7 mol/L. There was no thyroid hormone activity by using TRβ report gene assay to evaluate BPA, 1-Naphthaleny methyl carbamate or 1-NAP, but 1-Naphthaleny methyl carbamate and 1-NAP have some degree receptor antagonism., Conclusions: The TRβ LLC-MK2 report gene assay based on pGL3- promega and pGL4.27 show highly sensitive (pGL4.27 relatively higher), can be used to screen for EDCS and test chemical thyroid hormone activity effectively., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)

Published
2018

24. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Author

Phelan CM, Kuchenbaecker KB, Tyrer JP, Kar SP, Lawrenson K, Winham SJ, Dennis J, Pirie A, Riggan MJ, Chornokur G, Earp MA, Lyra PC Jr, Lee JM, Coetzee S, Beesley J, McGuffog L, Soucy P, Dicks E, Lee A, Barrowdale D, Lecarpentier J, Leslie G, Aalfs CM, Aben KKH, Adams M, Adlard J, Andrulis IL, Anton-Culver H, Antonenkova N, Aravantinos G, Arnold N, Arun BK, Arver B, Azzollini J, Balmaña J, Banerjee SN, Barjhoux L, Barkardottir RB, Bean Y, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bermisheva M, Bernardini MQ, Birrer MJ, Bjorge L, Black A, Blankstein K, Blok MJ, Bodelon C, Bogdanova N, Bojesen A, Bonanni B, Borg Å, Bradbury AR, Brenton JD, Brewer C, Brinton L, Broberg P, Brooks-Wilson A, Bruinsma F, Brunet J, Buecher B, Butzow R, Buys SS, Caldes T, Caligo MA, Campbell I, Cannioto R, Carney ME, Cescon T, Chan SB, Chang-Claude J, Chanock S, Chen XQ, Chiew YE, Chiquette J, Chung WK, Claes KBM, Conner T, Cook LS, Cook J, Cramer DW, Cunningham JM, D'Aloisio AA, Daly MB, Damiola F, Damirovna SD, Dansonka-Mieszkowska A, Dao F, Davidson R, DeFazio A, Delnatte C, Doheny KF, Diez O, Ding YC, Doherty JA, Domchek SM, Dorfling CM, Dörk T, Dossus L, Duran M, Dürst M, Dworniczak B, Eccles D, Edwards T, Eeles R, Eilber U, Ejlertsen B, Ekici AB, Ellis S, Elvira M, Eng KH, Engel C, Evans DG, Fasching PA, Ferguson S, Ferrer SF, Flanagan JM, Fogarty ZC, Fortner RT, Fostira F, Foulkes WD, Fountzilas G, Fridley BL, Friebel TM, Friedman E, Frost D, Ganz PA, Garber J, García MJ, Garcia-Barberan V, Gehrig A, Gentry-Maharaj A, Gerdes AM, Giles GG, Glasspool R, Glendon G, Godwin AK, Goldgar DE, Goranova T, Gore M, Greene MH, Gronwald J, Gruber S, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hansen TVO, Harrington PA, Harris HR, Hauke J, Hein A, Henderson A, Hildebrandt MAT, Hillemanns P, Hodgson S, Høgdall CK, Høgdall E, Hogervorst FBL, Holland H, Hooning MJ, Hosking K, Huang RY, Hulick PJ, Hung J, Hunter DJ, Huntsman DG, Huzarski T, Imyanitov EN, Isaacs C, Iversen ES, Izatt L, Izquierdo A, Jakubowska A, James P, Janavicius R, Jernetz M, Jensen A, Jensen UB, John EM, Johnatty S, Jones ME, Kannisto P, Karlan BY, Karnezis A, Kast K, Kennedy CJ, Khusnutdinova E, Kiemeney LA, Kiiski JI, Kim SW, Kjaer SK, Köbel M, Kopperud RK, Kruse TA, Kupryjanczyk J, Kwong A, Laitman Y, Lambrechts D, Larrañaga N, Larson MC, Lazaro C, Le ND, Le Marchand L, Lee JW, Lele SB, Leminen A, Leroux D, Lester J, Lesueur F, Levine DA, Liang D, Liebrich C, Lilyquist J, Lipworth L, Lissowska J, Lu KH, Lubinński J, Luccarini C, Lundvall L, Mai PL, Mendoza-Fandiño G, Manoukian S, Massuger LFAG, May T, Mazoyer S, McAlpine JN, McGuire V, McLaughlin JR, McNeish I, Meijers-Heijboer H, Meindl A, Menon U, Mensenkamp AR, Merritt MA, Milne RL, Mitchell G, Modugno F, Moes-Sosnowska J, Moffitt M, Montagna M, Moysich KB, Mulligan AM, Musinsky J, Nathanson KL, Nedergaard L, Ness RB, Neuhausen SL, Nevanlinna H, Niederacher D, Nussbaum RL, Odunsi K, Olah E, Olopade OI, Olsson H, Olswold C, O'Malley DM, Ong KR, Onland-Moret NC, Orr N, Orsulic S, Osorio A, Palli D, Papi L, Park-Simon TW, Paul J, Pearce CL, Pedersen IS, Peeters PHM, Peissel B, Peixoto A, Pejovic T, Pelttari LM, Permuth JB, Peterlongo P, Pezzani L, Pfeiler G, Phillips KA, Piedmonte M, Pike MC, Piskorz AM, Poblete SR, Pocza T, Poole EM, Poppe B, Porteous ME, Prieur F, Prokofyeva D, Pugh E, Pujana MA, Pujol P, Radice P, Rantala J, Rappaport-Fuerhauser C, Rennert G, Rhiem K, Rice P, Richardson A, Robson M, Rodriguez GC, Rodríguez-Antona C, Romm J, Rookus MA, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Salvesen HB, Sandler DP, Schoemaker MJ, Senter L, Setiawan VW, Severi G, Sharma P, Shelford T, Siddiqui N, Side LE, Sieh W, Singer CF, Sobol H, Song H, Southey MC, Spurdle AB, Stadler Z, Steinemann D, Stoppa-Lyonnet D, Sucheston-Campbell LE, Sukiennicki G, Sutphen R, Sutter C, Swerdlow AJ, Szabo CI, Szafron L, Tan YY, Taylor JA, Tea MK, Teixeira MR, Teo SH, Terry KL, Thompson PJ, Thomsen LCV, Thull DL, Tihomirova L, Tinker AV, Tischkowitz M, Tognazzo S, Toland AE, Tone A, Trabert B, Travis RC, Trichopoulou A, Tung N, Tworoger SS, van Altena AM, Van Den Berg D, van der Hout AH, van der Luijt RB, Van Heetvelde M, Van Nieuwenhuysen E, van Rensburg EJ, Vanderstichele A, Varon-Mateeva R, Vega A, Edwards DV, Vergote I, Vierkant RA, Vijai J, Vratimos A, Walker L, Walsh C, Wand D, Wang-Gohrke S, Wappenschmidt B, Webb PM, Weinberg CR, Weitzel JN, Wentzensen N, Whittemore AS, Wijnen JT, Wilkens LR, Wolk A, Woo M, Wu X, Wu AH, Yang H, Yannoukakos D, Ziogas A, Zorn KK, Narod SA, Easton DF, Amos CI, Schildkraut JM, Ramus SJ, Ottini L, Goodman MT, Park SK, Kelemen LE, Risch HA, Thomassen M, Offit K, Simard J, Schmutzler RK, Hazelett D, Monteiro AN, Couch FJ, Berchuck A, Chenevix-Trench G, Goode EL, Sellers TA, Gayther SA, Antoniou AC, and Pharoah PDP

Subjects
Alleles, BRCA1 Protein genetics, BRCA2 Protein genetics, Carcinoma, Ovarian Epithelial, Female, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Mutation, Neoplasms, Glandular and Epithelial pathology, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Risk Factors, Telomere-Binding Proteins genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics
Abstract

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

Published
2017
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25. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2.

Author

Silvestri V, Barrowdale D, Mulligan AM, Neuhausen SL, Fox S, Karlan BY, Mitchell G, James P, Thull DL, Zorn KK, Carter NJ, Nathanson KL, Domchek SM, Rebbeck TR, Ramus SJ, Nussbaum RL, Olopade OI, Rantala J, Yoon SY, Caligo MA, Spugnesi L, Bojesen A, Pedersen IS, Thomassen M, Jensen UB, Toland AE, Senter L, Andrulis IL, Glendon G, Hulick PJ, Imyanitov EN, Greene MH, Mai PL, Singer CF, Rappaport-Fuerhauser C, Kramer G, Vijai J, Offit K, Robson M, Lincoln A, Jacobs L, Machackova E, Foretova L, Navratilova M, Vasickova P, Couch FJ, Hallberg E, Ruddy KJ, Sharma P, Kim SW, Teixeira MR, Pinto P, Montagna M, Matricardi L, Arason A, Johannsson OT, Barkardottir RB, Jakubowska A, Lubinski J, Izquierdo A, Pujana MA, Balmaña J, Diez O, Ivady G, Papp J, Olah E, Kwong A, Nevanlinna H, Aittomäki K, Perez Segura P, Caldes T, Van Maerken T, Poppe B, Claes KB, Isaacs C, Elan C, Lasset C, Stoppa-Lyonnet D, Barjhoux L, Belotti M, Meindl A, Gehrig A, Sutter C, Engel C, Niederacher D, Steinemann D, Hahnen E, Kast K, Arnold N, Varon-Mateeva R, Wand D, Godwin AK, Evans DG, Frost D, Perkins J, Adlard J, Izatt L, Platte R, Eeles R, Ellis S, Hamann U, Garber J, Fostira F, Fountzilas G, Pasini B, Giannini G, Rizzolo P, Russo A, Cortesi L, Papi L, Varesco L, Palli D, Zanna I, Savarese A, Radice P, Manoukian S, Peissel B, Barile M, Bonanni B, Viel A, Pensotti V, Tommasi S, Peterlongo P, Weitzel JN, Osorio A, Benitez J, McGuffog L, Healey S, Gerdes AM, Ejlertsen B, Hansen TV, Steele L, Ding YC, Tung N, Janavicius R, Goldgar DE, Buys SS, Daly MB, Bane A, Terry MB, John EM, Southey M, Easton DF, Chenevix-Trench G, Antoniou AC, and Ottini L

Subjects
Adult, Aged, Breast Neoplasms pathology, Breast Neoplasms, Male pathology, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Neoplasm Staging, Polymorphism, Single Nucleotide, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms genetics, Breast Neoplasms, Male genetics
Abstract

Background: BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs)., Methods: We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database., Results: Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12))., Conclusions: On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.

Published
2016
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26. Low-level hyperinsulinism with hypoglycemic spells in an infant with mosaic Turner syndrome and mild Kabuki-like phenotype: a case report and review of the literature.

Author

Pietzner V, Weigel JF, Wand D, Merkenschlager A, and Bernhard MK

Subjects
Abnormalities, Multiple, Female, Humans, In Situ Hybridization, Fluorescence, Infant, Karyotyping, Phenotype, Turner Syndrome genetics, Face abnormalities, Hematologic Diseases complications, Hyperinsulinism complications, Hypoglycemia complications, Mosaicism, Turner Syndrome complications, Vestibular Diseases complications
Abstract

Background: Impaired glucose tolerance and type 2 diabetes are well-known features in patients with Turner syndrome. To the best of our knowledge, there is only one reported case of hyperinsulinemic hypoglycemia associated with a complex mosaic Turner syndrome available in the current literature., Patient: We report on the case of a 13-month-old girl with a complex mosaic Turner genotype and mild hyperinsulinemic hypoglycemia responsive to diazoxide therapy., Results: Cytogenetic analyses showed two or possibly three cell lines. Sixty percent of the cell lines had a 45,X genotype and the rest had 46,XX with a marker ring chromosome. Diagnosis of a mosaic Turner syndrome and mild Kabuki-like phenotype was confirmed., Conclusions: Despite the rareness of this case, clinicians should be aware of the possibility of hyperinsulinemic hypoglycemia in patients with Turner syndrome to prevent further brain damage caused by hypoglycemic episodes and seizures. Although the mechanism leading to hyperinsulinism in this condition is still unknown, the present report discusses this rare presentation and gives an overview on the current literature regarding this case.

Published
2014
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27. SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome.

Author

Krieger M, Roos A, Stendel C, Claeys KG, Sonmez FM, Baudis M, Bauer P, Bornemann A, de Goede C, Dufke A, Finkel RS, Goebel HH, Häussler M, Kingston H, Kirschner J, Medne L, Muschke P, Rivier F, Rudnik-Schöneborn S, Spengler S, Inzana F, Stanzial F, Benedicenti F, Synofzik M, Lia Taratuto A, Pirra L, Tay SK, Topaloglu H, Uyanik G, Wand D, Williams D, Zerres K, Weis J, and Senderek J

Subjects
Adolescent, B-Lymphocytes, Brain pathology, Brain ultrastructure, Cells, Cultured, DNA Mutational Analysis, Family Health, Female, Humans, Magnetic Resonance Imaging, Male, Muscle, Skeletal pathology, Muscle, Skeletal ultrastructure, Retrospective Studies, Spinocerebellar Degenerations pathology, Spinocerebellar Degenerations physiopathology, Guanine Nucleotide Exchange Factors genetics, Mutation genetics, Spinocerebellar Degenerations genetics
Abstract

Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjögren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjögren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjögren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be missing in young children. As cognitive impairment is not obligatory, patients without intellectual disability but a Marinesco-Sjögren syndrome-compatible phenotype should receive SIL1 mutation analysis. Despite allelic heterogeneity and many families with private mutations, the phenotype related to SIL1 mutations is relatively homogenous. Based on SIL1 expression studies we speculate that this may arise from a uniform effect of different mutations on protein expression.

Published
2013
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28. SOX10 mutation with peripheral amyelination and developmental disturbance of axons.

Author

Parthey K, Kornhuber M, Kunze C, Wand D, Nolte KW, Nikolin S, Weis J, and Schröder JM

Subjects
Axons ultrastructure, Humans, Infant, Newborn, Male, Microscopy, Electron, Transmission, Muscle, Skeletal pathology, Muscle, Skeletal ultrastructure, Sural Nerve pathology, Sural Nerve ultrastructure, Axons pathology, Demyelinating Diseases complications, Demyelinating Diseases genetics, Demyelinating Diseases pathology, Mutation genetics, Peripheral Nervous System Diseases complications, Peripheral Nervous System Diseases genetics, Peripheral Nervous System Diseases pathology, SOXE Transcription Factors genetics
Abstract

In this study we describe a case of a term infant with the neurological variant of Waardenburg syndrome type 4 (i.e., PCWH = peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease, as defined in OMIM #609136) due to a novel heterozygous base exchange (c.671C>G) in exon 4 of SOX10. Magnetic resonance imaging suggested central myelin deficiency with cerebral and cerebellar hypoplasia. Hirschsprung disease was confirmed by rectal biopsy. Sural nerve biopsy revealed hypoplasia due to amyelination (with the exception of a single, small myelinated fiber) and severe reduction in the number of axons., (Copyright © 2011 Wiley Periodicals, Inc.)

Published
2012
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29. Combined partial trisomy 11q and partial monosomy 10p in a 19-year-old female patient: phenotypic and genotypic findings.

Author

Hagen A, Bigl A, Wand D, Klopocki E, Heller R, Siekmeyer M, Siekmeyer W, Kiess W, and Merkenschlager A

Subjects
Abnormal Karyotype, Adult, Chromosome Deletion, Chromosome Disorders diagnosis, Chromosomes, Human, Pair 10 genetics, Chromosomes, Human, Pair 11 genetics, Comparative Genomic Hybridization, Facies, Female, Humans, Trisomy diagnosis, Young Adult, Chromosome Disorders complications, Chromosome Disorders genetics, Genotype, Phenotype, Trisomy genetics
Abstract

Constitutional partial trisomy 11q in man mostly occurs in combination with partial trisomy 22 due to a balanced parental translocation t(11;22). Occasionally a chromosome other than 22 is involved in the parental translocation with chromosome 11, resulting in partial monosomy for the other participating chromosome. We report of a patient with partial trisomy 11q and partial monosomy 10p [46,XX,der(10)t(10;11)(p15;q22)] due to a paternal balanced translocation [46,XY,t(10;11)(p15;q22)]. Array CGH showed heterozygosity for a deletion of ∼3.46 Mb at 10p15.3p15.2 and gain of ∼32.21 Mb at 11q22.2q25. The patient, a 19-year-old woman, has a multiple congenital anomaly syndrome with severe developmental and growth delay, muscular hypotonia, iris coloboma, abnormal external ears, widely spaced nipples, atrial septum defect, clubfoot, and arthrogryposis multiplex congenita. Despite multiple health problems and numerous hospitalizations due to massive seizures, pulmonary insufficiency and recurrent infections the patient reached adulthood. The clinical features in our patient are compared to other cases reported in the literature of either partial monosomy 10p or partial trisomy 11q. To the best of our knowledge, this is the first report of the combination of partial trisomy 11q and partial monosomy 10p. Comparing the molecular karyotype and the phenotype of our patient to other patients, the clinical features of our patient are more likely due to partial trisomy 11q than to partial monosomy 10p., (Copyright © 2011 Wiley Periodicals, Inc.)

Published
2011
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30. Quinestrol treatment induced testicular damage via oxidative stress in male Mongolian gerbils (Meriones unguiculatus).

Author

Shen W, Shi D, Wand D, Guo Y, Hai S, and Yue Z

Subjects
Animals, Antioxidants metabolism, Body Weight drug effects, Dose-Response Relationship, Drug, Gerbillinae, Glutathione Peroxidase metabolism, Male, Malondialdehyde blood, Malondialdehyde metabolism, Organ Size drug effects, Superoxide Dismutase metabolism, Testis enzymology, Testis metabolism, Testis pathology, Time Factors, Estrogens administration & dosage, Estrogens adverse effects, Oxidative Stress drug effects, Quinestrol administration & dosage, Quinestrol adverse effects, Rodenticides administration & dosage, Rodenticides adverse effects, Testis drug effects
Abstract

The hypothesis that quinestrol exerts testicular damage via oxidative stress was investigated in male gerbils using a daily oral gavage of 3.5 mg/kg body weight for 2 weeks (the multidose-treated group) or 35 mg/kg body weight (the single-dose-treated group). The testicular histological morphology, antioxidant capacity and malondialdehyde (MDA) concentration in testicular tissue and plasma were assessed at 15, 30, and 60 days following treatment. The results showed that the activity of the antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxide (GSH-Px), and total antioxidant capacity (T-AOC), at 15 days after treatment in testicular tissue decreased, which led to the MDA concentration increasing while at the same time germ cells were rarefied and showed an irregular distribution in seminiferous tubules of quinestrol-treated gerbils. At 30 days, the testicular weight and antioxidant capacity continued to decrease, while the MDA concentration continued to increase, and testicular histopathological changes were more pronounced. Single-dose and multidose drug treatment had a similar effect on the antioxidant enzymes and MDA, but testicular damage was relatively severe at 15 and 30 days after multidose treatment. By 60 days of treatment withdrawal, however, the above parameters recovered to control levels. The results show that quinestrol causes reversible damage to gerbil testes that might be caused by the oxidative stress and that multidose treatment has more effects on testicular damage compared with one-dose treatment.

Published
2011
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31. Expanding the spectrum of TBX5 mutations in Holt-Oram syndrome: detection of two intragenic deletions by quantitative real time PCR, and report of eight novel point mutations.

Author

Borozdin W, Bravo Ferrer Acosta AM, Bamshad MJ, Botzenhart EM, Froster UG, Lemke J, Schinzel A, Spranger S, McGaughran J, Wand D, Chrzanowska KH, and Kohlhase J

Subjects
Arrhythmias, Cardiac diagnosis, Arrhythmias, Cardiac genetics, Codon, Nonsense, Cohort Studies, DNA Mutational Analysis methods, Female, Heart Defects, Congenital diagnosis, Humans, Male, Pedigree, Phenotype, Polymerase Chain Reaction, RNA Splice Sites, Syndrome, Upper Extremity Deformities, Congenital diagnosis, Gene Deletion, Heart Defects, Congenital genetics, Point Mutation, T-Box Domain Proteins genetics, Upper Extremity Deformities, Congenital genetics
Abstract

Mutations in the gene TBX5 cause Holt-Oram syndrome (HOS), an autosomal dominant disorder characterized by anterior (i.e., radial ray) upper limb malformations and congenital heart defects and/or cardiac conduction anomalies. The detection rate for TBX5 mutations in HOS patients has been given as 30-35% in most reports. However, a detection rate of 74% was reported when strict clinical inclusion criteria for HOS were applied prior to TBX5 analysis. Still, in a significant proportion of typical HOS cases no mutation can be found within the TBX5 coding region and flanking intronic sequences. One explanation could be that large but submicroscopic deletions of TBX5 could cause HOS, yet only one such TBX5 deletion has been reported to date. We developed a quantitative Real Time PCR strategy to detect large, submicroscopic deletions in TBX5. Using this assay, we screened a total of 102 TBX5 mutation negative patients and discovered two novel intragenic deletions. One deletion of 7756 bp removes exon 6 and a considerable part of the neighboring intronic sequences, and the other of 3695 bp removes exon 9 with the stop codon and the 3'UTR completely as well as a part of the preceding intron 8. We conclude that quantitative Real Time PCR is a reliable method to detect submicroscopic deletions within TBX5. However, such deletions explain only approximately 2% of the TBX5 mutational spectrum in HOS cases. In addition, we also present eight novel TBX5 mutations (three nonsense, one splice mutation, four short deletions) as detected by direct sequencing in 21 families not previously analyzed for mutations., ((c) 2006 Wiley-Liss, Inc.)

Published
2006
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32. [Significance of the identification of hereditary cancer for routine oncological diagnosis].

Author

Weissflog G, Wand D, and Schwarz R

Subjects
Humans, Mutation, Neoplastic Syndromes, Hereditary epidemiology, Risk Factors, Genetic Predisposition to Disease, Neoplastic Syndromes, Hereditary diagnosis, Neoplastic Syndromes, Hereditary genetics
Abstract

Genetic factors are likely to be the primary determinants of the cancer seen in around 5 - 10 % of all cancer patients. More than 20 inherited cancer syndromes are now known. For many of these cases molecular genetic diagnostic may be accomplished. Within the scope of genetic counselling and testing, which can validate the genetic background of cancer, the interdisciplinary cooperation of Primary Care Physicians (PCP) and human geneticists is necessary. The results of our empirical study on risk identification in familial cancer suggest that PCP in the acute care inform cancer patients only to a little extent about the possible genetic background of their disease. PCP also very rarely initiate genetic counselling and testing, which would be desirable for preventive reasons.

Published
2006
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33. Acrofacial dysostosis (AFD) with preaxial limb hypoplasia (Nager AFD) and club foot diagnosed in a fetus from 1812 in the anatomical collections at the University of Halle, Germany.

Author

Göbbel L, Schultka R, Klunker R, Stock K, Wand D, Olsson L, Gerlach A, and Tönnies H

Subjects
Abnormalities, Multiple genetics, Abnormalities, Multiple history, Genome, Human, Germany, History, 19th Century, Humans, Magnetic Resonance Imaging, Nucleic Acid Hybridization methods, Syndrome, Tomography, Spiral Computed, Universities, Abnormalities, Multiple pathology, Clubfoot pathology, Fetus abnormalities, Limb Deformities, Congenital pathology, Mandibulofacial Dysostosis pathology
Abstract

The Anatomical Collections of the Department of Anatomy and Cell Biology at the University of Halle, Germany, comprise more than 8,000 specimens, about 600 of them congenital anomalies. The collection of abnormal human and animal specimens began with the private collections of Johann Friedrich Meckel the Elder (1724-1774), his son Philipp Friedrich Theodor Meckel (1755-1803), and his grandson Johann Friedrich Meckel the Younger (1781-1833). Meckel the Younger founded the science of developmental pathology in Germany. Radiographical techniques, computer tomographic methods (CT), magnetic resonance imaging (MRI), and molecular cytogenetic techniques, for example, comparative genomic hybridization (CGH) were used to diagnose abnormal human fetuses in the Meckel Collection. On examination of one of the human fetuses, originally described by JF Meckel the Younger in 1812 or earlier, we found striking clinical manifestations including mandibulofacial defects and preaxially malformed limbs. With respect to external findings, we propose that the condition is acrofacial dysostosis (AFD) with preaxial limb hypoplasia (Nager AFD) in combination with club foot, tibial torsion, and single umbilical artery. We used genetic analyses to test whether the observed limb malformations could be caused by aneuploidy. CGH-ratio profiles of all chromosomes were apparently normal. It is likely that Meckel's specimen is the earliest known fetus with Nager AFD., ((c) 2005 Wiley-Liss, Inc.)

Published
2005
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34. Association of migraine-like headaches with Schimke immuno-osseous dysplasia.

Author

Kilic SS, Donmez O, Sloan EA, Elizondo LI, Huang C, André JL, Bogdanovic R, Cockfield S, Cordeiro I, Deschenes G, Fründ S, Kaitila I, Lama G, Lamfers P, Lücke T, Milford DV, Najera L, Rodrigo F, Saraiva JM, Schmidt B, Smith GC, Stajic N, Stein A, Taha D, Wand D, Armstrong D, and Boerkoel CF

Subjects
Bone Diseases, Developmental metabolism, Bone Diseases, Developmental pathology, Child, DNA Helicases analysis, DNA Helicases genetics, Headache pathology, Humans, Immune System Diseases pathology, Immunohistochemistry, Male, Migraine Disorders complications, Migraine Disorders pathology, Mutation, Retrospective Studies, Surveys and Questionnaires, Bone Diseases, Developmental complications, Headache complications
Abstract

Schimke immuno-osseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia, nephropathy, and T-cell deficiency. SIOD is caused by mutations in the putative chromatin remodeling protein SMARCAL1. We report an 8-year-old boy with SIOD and recurrent, severe, refractory migraine-like headaches. Through a retrospective questionnaire-based study, we found that refractory and severely disabling migraine-like headaches occur in nearly half of SIOD patients. We have also found that the vasodilator minoxidil provided symptomatic relief for one patient. We hypothesize that these headaches may arise from an intrinsic vascular, neuroimmune, or neurovascular defect resulting from loss of SMARCAL1 function., (Copyright (c) 2005 Wiley-Liss, Inc.)

Published
2005
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