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1.  Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer 
Bojesen, Stig E | Pooley, Karen A | Johnatty, Sharon E | Beesley, Jonathan | Michailidou, Kyriaki | Tyrer, Jonathan P | Edwards, Stacey L | Pickett, Hilda A | Shen, Howard C | Smart, Chanel E | Hillman, Kristine M | Mai, Phuong L | Lawrenson, Kate | Stutz, Michael D | Lu, Yi | Karevan, Rod | Woods, Nicholas | Johnston, Rebecca L | French, Juliet D | Chen, Xiaoqing | Weischer, Maren | Nielsen, Sune F | Maranian, Melanie J | Ghoussaini, Maya | Ahmed, Shahana | Baynes, Caroline | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | Healey, Sue | Lush, Michael | Tessier, Daniel C | Vincent, Daniel | Bacot, Françis | Vergote, Ignace | Lambrechts, Sandrina | Despierre, Evelyn | Risch, Harvey A | González-Neira, Anna | Rossing, Mary Anne | Pita, Guillermo | Doherty, Jennifer A | Álvarez, Nuria | Larson, Melissa C | Fridley, Brooke L | Schoof, Nils | Chang-Claude, Jenny | Cicek, Mine S | Peto, Julian | Kalli, Kimberly R | Broeks, Annegien | Armasu, Sebastian M | Schmidt, Marjanka K | Braaf, Linde M | Winterhoff, Boris | Nevanlinna, Heli | Konecny, Gottfried E | Lambrechts, Diether | Rogmann, Lisa | Guénel, Pascal | Teoman, Attila | Milne, Roger L | Garcia, Joaquin J | Cox, Angela | Shridhar, Vijayalakshmi | Burwinkel, Barbara | Marme, Frederik | Hein, Rebecca | Sawyer, Elinor J | Haiman, Christopher A | Wang-Gohrke, Shan | Andrulis, Irene L | Moysich, Kirsten B | Hopper, John L | Odunsi, Kunle | Lindblom, Annika | Giles, Graham G | Brenner, Hermann | Simard, Jacques | Lurie, Galina | Fasching, Peter A | Carney, Michael E | Radice, Paolo | Wilkens, Lynne R | Swerdlow, Anthony | Goodman, Marc T | Brauch, Hiltrud | García-Closas, Montserrat | Hillemanns, Peter | Winqvist, Robert | Dürst, Matthias | Devilee, Peter | Runnebaum, Ingo | Jakubowska, Anna | Lubinski, Jan | Mannermaa, Arto | Butzow, Ralf | Bogdanova, Natalia V | Dörk, Thilo | Pelttari, Liisa M | Zheng, Wei | Leminen, Arto | Anton-Culver, Hoda | Bunker, Clareann H | Kristensen, Vessela | Ness, Roberta B | Muir, Kenneth | Edwards, Robert | Meindl, Alfons | Heitz, Florian | Matsuo, Keitaro | du Bois, Andreas | Wu, Anna H | Harter, Philipp | Teo, Soo-Hwang | Schwaab, Ira | Shu, Xiao-Ou | Blot, William | Hosono, Satoyo | Kang, Daehee | Nakanishi, Toru | Hartman, Mikael | Yatabe, Yasushi | Hamann, Ute | Karlan, Beth Y | Sangrajrang, Suleeporn | Kjaer, Susanne Krüger | Gaborieau, Valerie | Jensen, Allan | Eccles, Diana | Høgdall, Estrid | Shen, Chen-Yang | Brown, Judith | Woo, Yin Ling | Shah, Mitul | Azmi, Mat Adenan Noor | Luben, Robert | Omar, Siti Zawiah | Czene, Kamila | Vierkant, Robert A | Nordestgaard, Børge G | Flyger, Henrik | Vachon, Celine | Olson, Janet E | Wang, Xianshu | Levine, Douglas A | Rudolph, Anja | Weber, Rachel Palmieri | Flesch-Janys, Dieter | Iversen, Edwin | Nickels, Stefan | Schildkraut, Joellen M | Silva, Isabel Dos Santos | Cramer, Daniel W | Gibson, Lorna | Terry, Kathryn L | Fletcher, Olivia | Vitonis, Allison F | van der Schoot, C Ellen | Poole, Elizabeth M | Hogervorst, Frans B L | Tworoger, Shelley S | Liu, Jianjun | Bandera, Elisa V | Li, Jingmei | Olson, Sara H | Humphreys, Keith | Orlow, Irene | Blomqvist, Carl | Rodriguez-Rodriguez, Lorna | Aittomäki, Kristiina | Salvesen, Helga B | Muranen, Taru A | Wik, Elisabeth | Brouwers, Barbara | Krakstad, Camilla | Wauters, Els | Halle, Mari K | Wildiers, Hans | Kiemeney, Lambertus A | Mulot, Claire | Aben, Katja K | Laurent-Puig, Pierre | van Altena, Anne M | Truong, Thérèse | Massuger, Leon F A G | Benitez, Javier | Pejovic, Tanja | Perez, Jose Ignacio Arias | Hoatlin, Maureen | Zamora, M Pilar | Cook, Linda S | Balasubramanian, Sabapathy P | Kelemen, Linda E | Schneeweiss, Andreas | Le, Nhu D | Sohn, Christof | Brooks-Wilson, Angela | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Cybulski, Cezary | Henderson, Brian E | Menkiszak, Janusz | Schumacher, Fredrick | Wentzensen, Nicolas | Marchand, Loic Le | Yang, Hannah P | Mulligan, Anna Marie | Glendon, Gord | Engelholm, Svend Aage | Knight, Julia A | Høgdall, Claus K | Apicella, Carmel | Gore, Martin | Tsimiklis, Helen | Song, Honglin | Southey, Melissa C | Jager, Agnes | van den Ouweland, Ans M W | Brown, Robert | Martens, John W M | Flanagan, James M | Kriege, Mieke | Paul, James | Margolin, Sara | Siddiqui, Nadeem | Severi, Gianluca | Whittemore, Alice S | Baglietto, Laura | McGuire, Valerie | Stegmaier, Christa | Sieh, Weiva | Müller, Heiko | Arndt, Volker | Labrèche, France | Gao, Yu-Tang | Goldberg, Mark S | Yang, Gong | Dumont, Martine | McLaughlin, John R | Hartmann, Arndt | Ekici, Arif B | Beckmann, Matthias W | Phelan, Catherine M | Lux, Michael P | Permuth-Wey, Jenny | Peissel, Bernard | Sellers, Thomas A | Ficarazzi, Filomena | Barile, Monica | Ziogas, Argyrios | Ashworth, Alan | Gentry-Maharaj, Aleksandra | Jones, Michael | Ramus, Susan J | Orr, Nick | Menon, Usha | Pearce, Celeste L | Brüning, Thomas | Pike, Malcolm C | Ko, Yon-Dschun | Lissowska, Jolanta | Figueroa, Jonine | Kupryjanczyk, Jolanta | Chanock, Stephen J | Dansonka-Mieszkowska, Agnieszka | Jukkola-Vuorinen, Arja | Rzepecka, Iwona K | Pylkäs, Katri | Bidzinski, Mariusz | Kauppila, Saila | Hollestelle, Antoinette | Seynaeve, Caroline | Tollenaar, Rob A E M | Durda, Katarzyna | Jaworska, Katarzyna | Hartikainen, Jaana M | Kosma, Veli-Matti | Kataja, Vesa | Antonenkova, Natalia N | Long, Jirong | Shrubsole, Martha | Deming-Halverson, Sandra | Lophatananon, Artitaya | Siriwanarangsan, Pornthep | Stewart-Brown, Sarah | Ditsch, Nina | Lichtner, Peter | Schmutzler, Rita K | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Tseng, Chiu-Chen | Stram, Daniel O | van den Berg, David | Yip, Cheng Har | Ikram, M Kamran | Teh, Yew-Ching | Cai, Hui | Lu, Wei | Signorello, Lisa B | Cai, Qiuyin | Noh, Dong-Young | Yoo, Keun-Young | Miao, Hui | Iau, Philip Tsau-Choong | Teo, Yik Ying | McKay, James | Shapiro, Charles | Ademuyiwa, Foluso | Fountzilas, George | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Healey, Catherine S | Luccarini, Craig | Peock, Susan | Stoppa-Lyonnet, Dominique | Peterlongo, Paolo | Rebbeck, Timothy R | Piedmonte, Marion | Singer, Christian F | Friedman, Eitan | Thomassen, Mads | Offit, Kenneth | Hansen, Thomas V O | Neuhausen, Susan L | Szabo, Csilla I | Blanco, Ignacio | Garber, Judy | Narod, Steven A | Weitzel, Jeffrey N | Montagna, Marco | Olah, Edith | Godwin, Andrew K | Yannoukakos, Drakoulis | Goldgar, David E | Caldes, Trinidad | Imyanitov, Evgeny N | Tihomirova, Laima | Arun, Banu K | Campbell, Ian | Mensenkamp, Arjen R | van Asperen, Christi J | van Roozendaal, Kees E P | Meijers-Heijboer, Hanne | Collée, J Margriet | Oosterwijk, Jan C | Hooning, Maartje J | Rookus, Matti A | van der Luijt, Rob B | van Os, Theo A M | Evans, D Gareth | Frost, Debra | Fineberg, Elena | Barwell, Julian | Walker, Lisa | Kennedy, M John | Platte, Radka | Davidson, Rosemarie | Ellis, Steve D | Cole, Trevor | Paillerets, Brigitte Bressac-de | Buecher, Bruno | Damiola, Francesca | Faivre, Laurence | Frenay, Marc | Sinilnikova, Olga M | Caron, Olivier | Giraud, Sophie | Mazoyer, Sylvie | Bonadona, Valérie | Caux-Moncoutier, Virginie | Toloczko-Grabarek, Aleksandra | Gronwald, Jacek | Byrski, Tomasz | Spurdle, Amanda B | Bonanni, Bernardo | Zaffaroni, Daniela | Giannini, Giuseppe | Bernard, Loris | Dolcetti, Riccardo | Manoukian, Siranoush | Arnold, Norbert | Engel, Christoph | Deissler, Helmut | Rhiem, Kerstin | Niederacher, Dieter | Plendl, Hansjoerg | Sutter, Christian | Wappenschmidt, Barbara | Borg, Åke | Melin, Beatrice | Rantala, Johanna | Soller, Maria | Nathanson, Katherine L | Domchek, Susan M | Rodriguez, Gustavo C | Salani, Ritu | Kaulich, Daphne Gschwantler | Tea, Muy-Kheng | Paluch, Shani Shimon | Laitman, Yael | Skytte, Anne-Bine | Kruse, Torben A | Jensen, Uffe Birk | Robson, Mark | Gerdes, Anne-Marie | Ejlertsen, Bent | Foretova, Lenka | Savage, Sharon A | Lester, Jenny | Soucy, Penny | Kuchenbaecker, Karoline B | Olswold, Curtis | Cunningham, Julie M | Slager, Susan | Pankratz, Vernon S | Dicks, Ed | Lakhani, Sunil R | Couch, Fergus J | Hall, Per | Monteiro, Alvaro N A | Gayther, Simon A | Pharoah, Paul D P | Reddel, Roger R | Goode, Ellen L | Greene, Mark H | Easton, Douglas F | Berchuck, Andrew | Antoniou, Antonis C | Chenevix-Trench, Georgia | Dunning, Alison M
Nature genetics  2013;45(4):371-384e2.
TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10−7), reduced estrogen receptor negative (ER-negative) (P=1.0×10−8) and BRCA1 mutation carrier (P=1.1×10−5) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10−14), increased low malignant potential ovarian cancer risk (P=1.3×10−15) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10−12) and BRCA1 mutation carrier (P=1.6×10−14) breast and invasive ovarian (P=1.3×10−11) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splice-variant.
doi:10.1038/ng.2566
PMCID: PMC3670748  PMID: 23535731
2.  Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 
Couch, Fergus J. | Gaudet, Mia M. | Antoniou, Antonis C. | Ramus, Susan J. | Kuchenbaecker, Karoline B. | Soucy, Penny | Beesley, Jonathan | Chen, Xiaoqing | Wang, Xianshu | Kirchhoff, Tomas | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | Healey, Sue | Sinilnikova, Olga M. | Andrulis, Irene L. | Ozcelik, Hilmi | Mulligan, Anna Marie | Thomassen, Mads | Gerdes, Anne-Marie | Jensen, Uffe Birk | Skytte, Anne-Bine | Kruse, Torben A. | Caligo, Maria A. | von Wachenfeldt, Anna | Barbany-Bustinza, Gisela | Loman, Niklas | Soller, Maria | Ehrencrona, Hans | Karlsson, Per | Nathanson, Katherine L. | Rebbeck, Timothy R. | Domchek, Susan M. | Jakubowska, Ania | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Złowocka, Elżbieta | Huzarski, Tomasz | Byrski, Tomasz | Gronwald, Jacek | Cybulski, Cezary | Górski, Bohdan | Osorio, Ana | Durán, Mercedes | Tejada, María Isabel | Benitez, Javier | Hamann, Ute | Hogervorst, Frans B.L. | van Os, Theo A. | van Leeuwen, Flora E. | Meijers-Heijboer, Hanne E.J. | Wijnen, Juul | Blok, Marinus J. | Kets, Marleen | Hooning, Maartje J. | Oldenburg, Rogier A. | Ausems, Margreet G.E.M. | Peock, Susan | Frost, Debra | Ellis, Steve D. | Platte, Radka | Fineberg, Elena | Evans, D. Gareth | Jacobs, Chris | Eeles, Rosalind A. | Adlard, Julian | Davidson, Rosemarie | Eccles, Diana M. | Cole, Trevor | Cook, Jackie | Paterson, Joan | Brewer, Carole | Douglas, Fiona | Hodgson, Shirley V. | Morrison, Patrick J. | Walker, Lisa | Porteous, Mary E. | Kennedy, M. John | Side, Lucy E. | Bove, Betsy | Godwin, Andrew K. | Stoppa-Lyonnet, Dominique | Fassy-Colcombet, Marion | Castera, Laurent | Cornelis, François | Mazoyer, Sylvie | Léoné, Mélanie | Boutry-Kryza, Nadia | Bressac-de Paillerets, Brigitte | Caron, Olivier | Pujol, Pascal | Coupier, Isabelle | Delnatte, Capucine | Akloul, Linda | Lynch, Henry T. | Snyder, Carrie L. | Buys, Saundra S. | Daly, Mary B. | Terry, MaryBeth | Chung, Wendy K. | John, Esther M. | Miron, Alexander | Southey, Melissa C. | Hopper, John L. | Goldgar, David E. | Singer, Christian F. | Rappaport, Christine | Tea, Muy-Kheng M. | Fink-Retter, Anneliese | Hansen, Thomas V. O. | Nielsen, Finn C. | Arason, Aðalgeir | Vijai, Joseph | Shah, Sohela | Sarrel, Kara | Robson, Mark E. | Piedmonte, Marion | Phillips, Kelly | Basil, Jack | Rubinstein, Wendy S. | Boggess, John | Wakeley, Katie | Ewart-Toland, Amanda | Montagna, Marco | Agata, Simona | Imyanitov, Evgeny N. | Isaacs, Claudine | Janavicius, Ramunas | Lazaro, Conxi | Blanco, Ignacio | Feliubadalo, Lidia | Brunet, Joan | Gayther, Simon A | Pharoah, Paul PD | Odunsi, Kunle O. | Karlan, Beth Y. | Walsh, Christine S. | Olah, Edith | Teo, Soo Hwang | Ganz, Patricia A. | Beattie, Mary S. | van Rensburg, Elizabeth J. | Dorfling, Cecelia M. | Diez, Orland | Kwong, Ava | Schmutzler, Rita K. | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Heidemann, Simone | Niederacher, Dieter | Preisler-Adams, Sabine | Gadzicki, Dorothea | Varon-Mateeva, Raymonda | Deissler, Helmut | Gehrig, Andrea | Sutter, Christian | Kast, Karin | Fiebig, Britta | Heinritz, Wolfram | Caldes, Trinidad | de la Hoya, Miguel | Muranen, Taru A. | Nevanlinna, Heli | Tischkowitz, Marc D. | Spurdle, Amanda B. | Neuhausen, Susan L. | Ding, Yuan Chun | Lindor, Noralane M. | Fredericksen, Zachary | Pankratz, V. Shane | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Barile, Monica | Bernard, Loris | Viel, Alessandra | Giannini, Giuseppe | Varesco, Liliana | Radice, Paolo | Greene, Mark H. | Mai, Phuong L. | Easton, Douglas F. | Chenevix-Trench, Georgia | Offit, Kenneth | Simard, Jacques
Background
Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
Methods
Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.
Results
We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers (hazard ratio (HR)=1.17; 95%CI 1.07–1.27; p=7.42×10−4) and between rs16917302 at ZNF365 (HR=0.84; 95%CI 0.73–0.97; p=0.017) but not rs311499 at 20q13.3 (HR=1.11; 95%CI 0.94–1.31; p=0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR=1.16; 95%CI 1.05–1.29; p=3.8×10−4) and BRCA2 mutation carriers (HR=1.30; 95%CI 1.10–1.52; p=1.8×10−3).
Conclusions
19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.
Impact
These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.
doi:10.1158/1055-9965.EPI-11-0888
PMCID: PMC3319317  PMID: 22351618
BRCA1; BRCA2; breast cancer risk; ovarian cancer risk; 19p13.1; ZNF365
3.  Relation between smoking history and gene expression profiles in lung adenocarcinomas 
BMC Medical Genomics  2012;5:22.
Background
Lung cancer is the worldwide leading cause of death from cancer. Tobacco usage is the major pathogenic factor, but all lung cancers are not attributable to smoking. Specifically, lung cancer in never-smokers has been suggested to represent a distinct disease entity compared to lung cancer arising in smokers due to differences in etiology, natural history and response to specific treatment regimes. However, the genetic aberrations that differ between smokers and never-smokers’ lung carcinomas remain to a large extent unclear.
Methods
Unsupervised gene expression analysis of 39 primary lung adenocarcinomas was performed using Illumina HT-12 microarrays. Results from unsupervised analysis were validated in six external adenocarcinoma data sets (n=687), and six data sets comprising normal airway epithelial or normal lung tissue specimens (n=467). Supervised gene expression analysis between smokers and never-smokers were performed in seven adenocarcinoma data sets, and results validated in the six normal data sets.
Results
Initial unsupervised analysis of 39 adenocarcinomas identified two subgroups of which one harbored all never-smokers. A generated gene expression signature could subsequently identify never-smokers with 79-100% sensitivity in external adenocarcinoma data sets and with 76-88% sensitivity in the normal materials. A notable fraction of current/former smokers were grouped with never-smokers. Intriguingly, supervised analysis of never-smokers versus smokers in seven adenocarcinoma data sets generated similar results. Overlap in classification between the two approaches was high, indicating that both approaches identify a common set of samples from current/former smokers as potential never-smokers. The gene signature from unsupervised analysis included several genes implicated in lung tumorigenesis, immune-response associated pathways, genes previously associated with smoking, as well as marker genes for alveolar type II pneumocytes, while the best classifier from supervised analysis comprised genes strongly associated with proliferation, but also genes previously associated with smoking.
Conclusions
Based on gene expression profiling, we demonstrate that never-smokers can be identified with high sensitivity in both tumor material and normal airway epithelial specimens. Our results indicate that tumors arising in never-smokers, together with a subset of tumors from smokers, represent a distinct entity of lung adenocarcinomas. Taken together, these analyses provide further insight into the transcriptional patterns occurring in lung adenocarcinoma stratified by smoking history.
doi:10.1186/1755-8794-5-22
PMCID: PMC3447685  PMID: 22676229
Lung cancer; Smoking; Gene expression analysis; Adenocarcinoma; EGFR; Never-smokers; Immune response
4.  Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 
Mulligan, Anna Marie | Couch, Fergus J | Barrowdale, Daniel | Domchek, Susan M | Eccles, Diana | Nevanlinna, Heli | Ramus, Susan J | Robson, Mark | Sherman, Mark | Spurdle, Amanda B | Wappenschmidt, Barbara | Lee, Andrew | McGuffog, Lesley | Healey, Sue | Sinilnikova, Olga M | Janavicius, Ramunas | Hansen, Thomas vO | Nielsen, Finn C | Ejlertsen, Bent | Osorio, Ana | Muñoz-Repeto, Iván | Durán, Mercedes | Godino, Javier | Pertesi, Maroulio | Benítez, Javier | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Cattaneo, Elisa | Bonanni, Bernardo | Viel, Alessandra | Pasini, Barbara | Papi, Laura | Ottini, Laura | Savarese, Antonella | Bernard, Loris | Radice, Paolo | Hamann, Ute | Verheus, Martijn | Meijers-Heijboer, Hanne EJ | Wijnen, Juul | Gómez García, Encarna B | Nelen, Marcel R | Kets, C Marleen | Seynaeve, Caroline | Tilanus-Linthorst, Madeleine MA | van der Luijt, Rob B | Os, Theo van | Rookus, Matti | Frost, Debra | Jones, J Louise | Evans, D Gareth | Lalloo, Fiona | Eeles, Ros | Izatt, Louise | Adlard, Julian | Davidson, Rosemarie | Cook, Jackie | Donaldson, Alan | Dorkins, Huw | Gregory, Helen | Eason, Jacqueline | Houghton, Catherine | Barwell, Julian | Side, Lucy E | McCann, Emma | Murray, Alex | Peock, Susan | Godwin, Andrew K | Schmutzler, Rita K | Rhiem, Kerstin | Engel, Christoph | Meindl, Alfons | Ruehl, Ina | Arnold, Norbert | Niederacher, Dieter | Sutter, Christian | Deissler, Helmut | Gadzicki, Dorothea | Kast, Karin | Preisler-Adams, Sabine | Varon-Mateeva, Raymonda | Schoenbuchner, Ines | Fiebig, Britta | Heinritz, Wolfram | Schäfer, Dieter | Gevensleben, Heidrun | Caux-Moncoutier, Virginie | Fassy-Colcombet, Marion | Cornelis, François | Mazoyer, Sylvie | Léoné, Mélanie | Boutry-Kryza, Nadia | Hardouin, Agnès | Berthet, Pascaline | Muller, Danièle | Fricker, Jean-Pierre | Mortemousque, Isabelle | Pujol, Pascal | Coupier, Isabelle | Lebrun, Marine | Kientz, Caroline | Longy, Michel | Sevenet, Nicolas | Stoppa-Lyonnet, Dominique | Isaacs, Claudine | Caldes, Trinidad | de la Hoya, Miguel | Heikkinen, Tuomas | Aittomäki, Kristiina | Blanco, Ignacio | Lazaro, Conxi | Barkardottir, Rosa B | Soucy, Penny | Dumont, Martine | Simard, Jacques | Montagna, Marco | Tognazzo, Silvia | D'Andrea, Emma | Fox, Stephen | Yan, Max | Rebbeck, Tim | Olopade, Olufunmilayo I | Weitzel, Jeffrey N | Lynch, Henry T | Ganz, Patricia A | Tomlinson, Gail E | Wang, Xianshu | Fredericksen, Zachary | Pankratz, Vernon S | Lindor, Noralane M | Szabo, Csilla | Offit, Kenneth | Sakr, Rita | Gaudet, Mia | Bhatia, Jasmine | Kauff, Noah | Singer, Christian F | Tea, Muy-Kheng | Gschwantler-Kaulich, Daphne | Fink-Retter, Anneliese | Mai, Phuong L | Greene, Mark H | Imyanitov, Evgeny | O'Malley, Frances P | Ozcelik, Hilmi | Glendon, Gordon | Toland, Amanda E | Gerdes, Anne-Marie | Thomassen, Mads | Kruse, Torben A | Jensen, Uffe Birk | Skytte, Anne-Bine | Caligo, Maria A | Soller, Maria | Henriksson, Karin | Wachenfeldt, von Anna | Arver, Brita | Stenmark-Askmalm, Marie | Karlsson, Per | Ding, Yuan Chun | Neuhausen, Susan L | Beattie, Mary | Pharoah, Paul DP | Moysich, Kirsten B | Nathanson, Katherine L | Karlan, Beth Y | Gross, Jenny | John, Esther M | Daly, Mary B | Buys, Saundra M | Southey, Melissa C | Hopper, John L | Terry, Mary Beth | Chung, Wendy | Miron, Alexander F | Goldgar, David | Chenevix-Trench, Georgia | Easton, Douglas F | Andrulis, Irene L | Antoniou, Antonis C
Breast Cancer Research : BCR  2011;13(6):R110.
Introduction
Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.
Methods
We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.
Results
The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.
Conclusions
The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.
doi:10.1186/bcr3052
PMCID: PMC3326552  PMID: 22053997
5.  Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations 
Human mutation  2010;31(10):1142-1154.
A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining ninety-three probands here. This includes nineteen probands (twelve mutations) who fulfilled clinical criteria for GCPS or PHS, forty-eight probands (sixteen mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), twenty-one probands (six mutations) with features of PHS or GCPS and oral-facial-digital syndrome and five probands (one mutation) with non-syndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the phenotype-genotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria.
doi:10.1002/humu.21328
PMCID: PMC2947617  PMID: 20672375
GLI3; Greig syndrome; Pallister-Hall syndrome; Oral-facial-digital syndrome
6.  HIF1α isoforms in benign and malignant prostate tissue and their correlation to neuroendocrine differentiation 
BMC Cancer  2010;10:385.
Background
Neuroendocrine (NE) differentiation in prostate cancer has been correlated with a poor prognosis and hormone refractory disease. In a previous report, we demonstrated the presence of immunoreactive cytoplasmic hypoxia inducible factor 1α (HIF1α), in both benign and malignant NE prostate cells. HIF1α and HIF1β are two subunits of HIF1, a transcription factor important for angiogenesis. The aim of this study was to elucidate whether the cytoplasmic stabilization of HIF1α in androgen independent NE differentiated prostate cancer is due to the presence of certain HIF1α isoforms.
Methods
We studied the HIF1α isoforms present in 8 cases of benign prostate hyperplasia (BPH) and 43 cases of prostate cancer with and without NE differentiation using RT-PCR, sequencing analysis, immunohistochemistry and in situ hybridization.
Results
We identified multiple isoforms in both benign and malignant prostate tissues. One of these isoforms, HIF1α1.2, which was previously reported to be testis specific, was found in 86% of NE-differentiated prostate tumors, 92% of HIF1α immunoreactive prostate tumors and 100% of cases of benign prostate hyperplasia. Immunohistochemistry and in situ hybridization results showed that this isoform corresponds to the cytoplasmic HIF1α present in androgen-independent NE cells of benign and malignant prostate tissue and co-localizes with immunoreactive cytoplasmic HIF1β.
Conclusion
Our results indicate that the cytoplasmic stabilization of HIF1α in NE-differentiated cells in benign and malignant prostate tissue is due to presence of an HIF1α isoform, HIF1α1.2. Co-localization of this isoform with HIF1β indicates that the HIF1α1.2 isoform might sequester HIF1β in the cytoplasm.
doi:10.1186/1471-2407-10-385
PMCID: PMC2913964  PMID: 20663134
7.  Array based characterization of a terminal deletion involving chromosome subband 15q26.2: an emerging syndrome associated with growth retardation, cardiac defects and developmental delay 
Background
Subtelomeric regions are gene rich and deletions in these chromosomal segments have been demonstrated to account for approximately 2.5% of patients displaying mental retardation with or without association of dysmorphic features. However, cases that report de novo terminal deletions on chromosome arm 15q are rare.
Methods
In this study we present the first example of a detailed molecular genetic mapping of a de novo deletion in involving 15q26.2-qter, caused by the formation of a dicentric chromosome 15, using metaphase FISH and tiling resolution (32 k) genome-wide array-based comparative genomic hybridization (CGH).
Results
After an initial characterization of the dicentric chromosome by metaphase FISH, array CGH analysis mapped the terminal deletion to encompass a 6.48 megabase (Mb) region, ranging from 93.86–100.34 Mb on chromosome 15.
Conclusion
In conclusion, we present an additional case to the growing family of reported cases with 15q26-deletion, thoroughly characterized at the molecular cytogenetic level. In the deleted regions, four candidate genes responsible for the phenotype of the patient could be delineated: IGFR1, MEF2A, CHSY1, and TM2D3. Further characterization of additional patients harboring similar 15q-aberrations might hopefully in the future lead to the description of a clear cut clinically recognizable syndrome.
doi:10.1186/1471-2350-9-2
PMCID: PMC2248164  PMID: 18194513
8.  Midline carcinoma with t(15;19) and BRD4-NUT fusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy 
BMC Cancer  2006;6:69.
Background
Poorly differentiated midline carcinoma with a translocation between chromosomes 15 and 19, i.e. t(15;19), has been recognized as a distinct clinical entity for over a decade. This tumor affects young individuals, shows a rapidly fatal clinical course despite intensive therapy. The t(15;19) results in the fusion oncogene BRD4-NUT. Information concerning treatment of this rare disorder is scarce.
Case presentation
A 30-year-old woman was admitted with a rapidly progressing tumor in the mediastinum, cervical lymph nodes, vertebral column and the epidural space. Pathological, cytogenetic, FISH and PCR analysis revealed a glycogenated carcinoma rarely expressing cytokeratins and showing t(15;19) and BRD4-NUT gene rearrangement. The patient was initially treated with a Ewing sarcoma chemotherapy regimen, but had rapid progression after two cycles. She then received docetaxel and radiotherapy, which resulted in almost complete disappearance of the tumor.
Conclusion
Docetaxel may be considered for initial chemotherapy in young patients presenting with a midline carcinoma with bone marrow involvement and cytogenetic and molecular genetic finding of a t(15;19)/BRD4-NUT-rearrangement. We herein describe, in detail, the laboratory methods by which the BRD4-NUT -rearrangement can be detected.
doi:10.1186/1471-2407-6-69
PMCID: PMC1456975  PMID: 16542442

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