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Your search keyword '"3122 Cancers"' showing total 16 results
Start Over Descriptor "3122 Cancers" Publisher biomed central ltd
16 results on '"3122 Cancers"'

1. Aberrant expression of ALK and EZH2 in Merkel cell carcinoma

Author

University of Helsinki, Medicum, University of Helsinki, Clinicum, University of Helsinki, Research Programs Unit, Veija, T., Koljonen, V., Bohling, T., Kero, M., Knuutila, S., Sarhadi, Virinder Kaur, University of Helsinki, Medicum, University of Helsinki, Clinicum, University of Helsinki, Research Programs Unit, Veija, T., Koljonen, V., Bohling, T., Kero, M., Knuutila, S., and Sarhadi, Virinder Kaur

Abstract

BACKGROUND: Distinct characteristic features categorize Merkel cell carcinoma (MCC) into two subgroups according to the Merkel cell polyomavirus infection. Many mutational studies on MCC have been carried out in recent years without identifying a prominent driver mutation. However, there is paucity reporting the expression of cancer genes at the RNA level in MCC tumors. In this study, we studied the RNA expression profiles of 26 MCC tumors, with a goal to identify prospective molecular targets that could improve the treatment strategies of MCC. METHODS: RNA expression of 50 cancer-related genes in 26 MCC tumors was analyzed by targeted amplicon based next-generation sequencing using the Ion Torrent technology and the expression compared with that of normal, non-cancerous skin samples. Sequencing data were processed using Torrent Suite Software. Expression profiles of MCV-negative and MCV-positive tumors were compared. Fluorescence in situ hybridization was performed to study ALK rearrangements and immunohistochemistry to study ALK expression in tumor tissue. RESULTS: ALK, CDKN2A, EZH2 and ERBB4 were overexpressed, and EGFR, ERBB2, PDGFRA and FGFR1 were underexpressed in MCC tumors compared to normal skin. In the MCV-negative tumors, MET, NOTCH1, FGFR3, and SMO were overexpressed and JAK3 and NPM1 were under-expressed compared to the MCV-positive tumors. CONCLUSIONS: High expression of ALK, CDKN2A and EZH2 was recorded in MCC tumors. No ALK fusion was seen by FISH analysis. Overexpression of EZH2 suggests its potential as a drug target in MCC.

Published
2017

2. Primary neuroendocrine breast carcinomas are associated with poor local control despite favourable biological profile

Author

University of Helsinki, Department of Oncology, University of Helsinki, Department of Pathology, Roininen, Nelli, Takala, Sari, Haapasaari, Kirsi-Maria, Jukkola-Vuorinen, Arja, Mattson, Johanna, Heikkila, Paivi, Karihtala, Peeter, University of Helsinki, Department of Oncology, University of Helsinki, Department of Pathology, Roininen, Nelli, Takala, Sari, Haapasaari, Kirsi-Maria, Jukkola-Vuorinen, Arja, Mattson, Johanna, Heikkila, Paivi, and Karihtala, Peeter

Abstract

Background: Breast carcinomas with neuroendocrine features (NEBC) are a very rare entity of mammary neoplasms, WHO classification of which has recently been revised. There are very limited data available about the clinical behaviour and treatment options of NEBC. Methods: We collected retrospectively patients with NEBC from Oulu and Helsinki University Hospitals in 2007-2015. There were 43 NEBC cases during the period. Results: The incidence of NEBC from all breast cancers varied from 0.1% in Helsinki to 1.3% in Oulu. The mean tumor size was 2.2 cm and 23 patients (55.8%) had no lymph node metastases when diagnosed. In total, 4 patients (9.3%) had distant metastases at the time of diagnosis. High estrogen receptor (ER) expression was observed in 41 (97.7%) patients. When non-metastatic NEBC were compared to a prospective set of ductal carcinomas (n = 506), NEBC were more often HER2 negative (p = 0.046), ER positive (p = 0.0062) and the NEBC patients were older (p <0.0005) than patients with ductal carcinomas. Plasma chromogranin A correlated only to higher age at diagnosis (p = 0. 0028). Relapse-free survival (p = 0.0013), disease-free survival (p = 0.024) and overall survival (p = 0.0028) favoured ductal carcinomas compared to NEBC, while no difference was observed in distant disease-free survival or in breast cancer-specific survival. Conclusions: There is remarkable variation in the incidence of NEBC in Finland, which is likely to be explained by differences in the use of neuroendocrine marker immunostainings. Poor local control and worse overall survival may be linked to the more aggressive biology of the disease, despite its association with apparently indolent prognostic factors.

Published
2017

3. Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Author

University of Helsinki, Department of Obstetrics and Gynecology, Rebbeck, Timothy R., Friebel, Tara M., Mitra, Nandita, Wan, Fei, Chen, Stephanie, Andrulis, Irene L., Apostolou, Paraskevi, Arnold, Norbert, Arun, Banu K., Barrowdale, Daniel, Benitez, Javier, Berger, Raanan, Berthet, Pascaline, Borg, Ake, Buys, Saundra S., Caldes, Trinidad, Carter, Jonathan, Chiquette, Jocelyne, Claes, Kathleen B. M., Couch, Fergus J., Cybulski, Cezary, Daly, Mary B., de la Hoya, Miguel, Diez, Orland, Domchek, Susan M., Nathanson, Katherine L., Durda, Katarzyna, Ellis, Steve, Evans, D. Gareth, Foretova, Lenka, Friedman, Eitan, Frost, Debra, Ganz, Patricia A., Garber, Judy, Glendon, Gord, Godwin, Andrew K., Greene, Mark H., Gronwald, Jacek, Hahnen, Eric, Hallberg, Emily, Hamann, Ute, Hansen, Thomas V. O., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, Janavicius, Ramunas, Jaworska-Bieniek, Katarzyna, John, Esther M., Karlan, Beth Y., Kaufman, Bella, Kwong, Ava, Laitman, Yael, Lasset, Christine, Lazaro, Conxi, Lester, Jenny, Loman, Niklas, Lubinski, Jan, Manoukian, Siranoush, Mitchell, Gillian, Montagna, Marco, Neuhausen, Susan L., Nevanlinna, Heli, Niederacher, Dieter, Nussbaum, Robert L., Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Park, Sue Kyung, Piedmonte, Marion, Radice, Paolo, Rappaport-Fuerhauser, Christine, Rookus, Matti A., Seynaeve, Caroline, Simard, Jacques, Singer, Christian F., Soucy, Penny, Southey, Melissa, Stoppa-Lyonnet, Dominique, Sukiennicki, Grzegorz, Szabo, Csilla I., Tancredi, Mariella, Teixeira, Manuel R., Teo, Soo-Hwang, Terry, Mary Beth, Thomassen, Mads, Tihomirova, Laima, Tischkowitz, Marc, Toland, Amanda Ewart, Toloczko-Grabarek, Aleksandra, Tung, Nadine, van Rensburg, Elizabeth J., Villano, Danylo, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Zidan, Jamal, Zorn, Kristin K., McGuffog, Lesley, Easton, Douglas, Chenevix-Trench, Georgia, Antoniou, Antonis C., Ramus, Susan J., EMBRACE, HEBON, KConFab Investigators, University of Helsinki, Department of Obstetrics and Gynecology, Rebbeck, Timothy R., Friebel, Tara M., Mitra, Nandita, Wan, Fei, Chen, Stephanie, Andrulis, Irene L., Apostolou, Paraskevi, Arnold, Norbert, Arun, Banu K., Barrowdale, Daniel, Benitez, Javier, Berger, Raanan, Berthet, Pascaline, Borg, Ake, Buys, Saundra S., Caldes, Trinidad, Carter, Jonathan, Chiquette, Jocelyne, Claes, Kathleen B. M., Couch, Fergus J., Cybulski, Cezary, Daly, Mary B., de la Hoya, Miguel, Diez, Orland, Domchek, Susan M., Nathanson, Katherine L., Durda, Katarzyna, Ellis, Steve, Evans, D. Gareth, Foretova, Lenka, Friedman, Eitan, Frost, Debra, Ganz, Patricia A., Garber, Judy, Glendon, Gord, Godwin, Andrew K., Greene, Mark H., Gronwald, Jacek, Hahnen, Eric, Hallberg, Emily, Hamann, Ute, Hansen, Thomas V. O., Imyanitov, Evgeny N., Isaacs, Claudine, Jakubowska, Anna, Janavicius, Ramunas, Jaworska-Bieniek, Katarzyna, John, Esther M., Karlan, Beth Y., Kaufman, Bella, Kwong, Ava, Laitman, Yael, Lasset, Christine, Lazaro, Conxi, Lester, Jenny, Loman, Niklas, Lubinski, Jan, Manoukian, Siranoush, Mitchell, Gillian, Montagna, Marco, Neuhausen, Susan L., Nevanlinna, Heli, Niederacher, Dieter, Nussbaum, Robert L., Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Park, Sue Kyung, Piedmonte, Marion, Radice, Paolo, Rappaport-Fuerhauser, Christine, Rookus, Matti A., Seynaeve, Caroline, Simard, Jacques, Singer, Christian F., Soucy, Penny, Southey, Melissa, Stoppa-Lyonnet, Dominique, Sukiennicki, Grzegorz, Szabo, Csilla I., Tancredi, Mariella, Teixeira, Manuel R., Teo, Soo-Hwang, Terry, Mary Beth, Thomassen, Mads, Tihomirova, Laima, Tischkowitz, Marc, Toland, Amanda Ewart, Toloczko-Grabarek, Aleksandra, Tung, Nadine, van Rensburg, Elizabeth J., Villano, Danylo, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Zidan, Jamal, Zorn, Kristin K., McGuffog, Lesley, Easton, Douglas, Chenevix-Trench, Georgia, Antoniou, Antonis C., Ramus, Susan J., EMBRACE, HEBON, and KConFab Investigators

Abstract

Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p <0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p <0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.

Published
2016

4. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Author

Blein, Sophie, Bardel, Claire, Danjean, Vincent, Mcguffog, Lesley, Healey, Sue, Barrowdale, Daniel, Lee, Andrew, Dennis, Joe, Kuchenbaecker, Karoline B., Soucy, Penny, Terry, Mary Beth, Chung, Wendy K., Goldgar, David E., Buys, Saundra S., Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Neuhausen, Susan L., Ding, Yuan Chun, Gerdes, Anne Marie, Ejlertsen, Bent, Nielsen, Finn C., Hansen, Thomas V. O., Osorio, Ana, Benitez, Javier, Conejero, Raquel Andrés, Segota, Ena, Weitzel, Jeffrey N., Thelander, Margo, Peterlongo, Paolo, Radice, Paolo, Pensotti, Valeria, Dolcetti, Riccardo, Bonanni, Bernardo, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Manoukian, Siranoush, Varesco, Liliana, Capone, Gabriele L., Papi, Laura, Ottini, Laura, Yannoukakos, Drakoulis, Konstantopoulou, Irene, Garber, Judy, Hamann, Ute, Donaldson, Alan, Brady, Angela, Brewer, Carole, Foo, Claire, Evans, D. Gareth, Frost, Debra, Eccles, Diana, Douglas, Fiona, Cook, Jackie, Adlard, Julian, Barwell, Julian, Walker, Lisa, Izatt, Louise, Side, Lucy E., Kennedy, M. John, Tischkowitz, Marc, Rogers, Mark T., Porteous, Mary E., Morrison, Patrick J., Platte, Radka, Eeles, Ros, Davidson, Rosemarie, Hodgson, Shirley, Cole, Trevor, Godwin, Andrew K., Isaacs, Claudine, Claes, Kathleen, De Leeneer, Kim, Meindl, Alfons, Gehrig, Andrea, Wappenschmidt, Barbara, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Plendl, Hansjoerg, Kast, Karin, Rhiem, Kerstin, Ditsch, Nina, Arnold, Norbert, Varon Mateeva, Raymonda, Schmutzler, Rita K., Preisler Adams, Sabine, Markov, Nadja Bogdanova, Wang Gohrke, Shan, de Pauw, Antoine, Lefol, Cédrick, Lasset, Christine, Leroux, Dominique, Rouleau, Etienne, Damiola, Francesca, Dreyfus, Hélène, Barjhoux, Laure, Golmard, Lisa, Uhrhammer, Nancy, Bonadona, Valérie, Sornin, Valérie, Bignon, Yves Jean, Carter, Jonathan, Van Le, Linda, Piedmonte, Marion, Disilvestro, Paul A., de la Hoya, Miguel, Caldes, Trinidad, Nevanlinna, Heli, Aittomäki, Kristiina, Jager, Agnes, van den Ouweland, Ans M. W., Kets, Carolien M., Aalfs, Cora M., van Leeuwen, Flora E., Hogervorst, Frans B. L., Meijers Heijboer, Hanne E. J., Oosterwijk, Jan C., van Roozendaal, Kees E. P., Rookus, Matti A., Devilee, Peter, van der Luijt, Rob B., Olah, Edith, Diez, Orland, Teulé, Alex, Lazaro, Conxi, Blanco, Ignacio, Del Valle, Jesús, Jakubowska, Anna, Sukiennicki, Grzegorz, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska Bieniek, Katarzyna, Agnarsson, Bjarni A., Maugard, Christine, Amadori, Alberto, Montagna, Marco, Teixeira, Manuel R., Spurdle, Amanda B., Foulkes, William, Olswold, Curtis, Lindor, Noralane M., Pankratz, Vernon S., Szabo, Csilla I., Lincoln, Anne, Jacobs, Lauren, Corines, Marina, Robson, Mark, Vijai, Joseph, Berger, Andreas, Fink Retter, Anneliese, Singer, Christian F., Rappaport, Christine, Kaulich, Daphne Geschwantler, Pfeiler, Georg, Tea, Muy Kheng, Greene, Mark H., Mai, Phuong L., Rennert, Gad, Imyanitov, Evgeny N., Mulligan, Anna Marie, Glendon, Gord, Andrulis, Irene L., Tchatchou, Sandrine, Toland, Amanda Ewart, Pedersen, Inge Sokilde, Thomassen, Mads, Kruse, Torben A., Jensen, Uffe Birk, Caligo, Maria A., Friedman, Eitan, Zidan, Jamal, Laitman, Yael, Lindblom, Annika, Melin, Beatrice, Arver, Brita, Loman, Niklas, Rosenquist, Richard, Olopade, Olufunmilayo I., Nussbaum, Robert L., Ramus, Susan J., Nathanson, Katherine L., Domchek, Susan M., Rebbeck, Timothy R., Arun, Banu K., Mitchell, Gillian, Karlan, Beth Y., Lester, Jenny, Orsulic, Sandra, Stoppa Lyonnet, Dominique, Thomas, Gilles, Simard, Jacques, Couch, Fergus J., Offit, Kenneth, Easton, Douglas F., Chenevix Trench, Georgia, Antoniou, Antonis C., Mazoyer, Sylvie, Phelan, Catherine M., Sinilnikova, Olga M., Cox, David G., Angelakos, Maggie, Maskiell, Judi, Dite, Gillian, Tsimiklis, Helen, Rudaitis, Vilius, Griškevicius, Laimonas, Eglitis, Drs Janis, Krilova, Anna, Stengrevics, Aivars, Ding, Chun, Steele, Linda, Barroso, Alicia, Alonso, Rosario, Pita, Guillermo, Viel, Alessandra, della Puppa, Lara, Barile, Monica, Tommasi, Stefania, Pilato, Brunella, Lambo, Rossana, Martayan, Aline, Tibiletti, Maria Grazia, Ellis, Steve, Fineberg, Elena, Miedzybrodzka, Zosia, Gregory, Helen, Jeffers, Lisa, Ong, Kai Ren, Hoffman, Jonathan, James, Margaret, Paterson, Joan, Taylor, Amy, Murray, Alexandra, Mccann, Emma, Barton, David, Drummond, Sarah, Kivuva, Emma, Searle, Anne, Goodman, Selina, Hill, Kathryn, Murday, Victoria, Bradshaw, Nicola, Snadden, Lesley, Longmuir, Mark, Watt, Catherine, Gibson, Sarah, Haque, Eshika, Tobias, Ed, Duncan, Alexis, Jacobs, Chris, Langman, Caroline, Dorkins, Huw, Serra Feliu, Gemma, Ellis, Ian, Houghton, Catherine, Lalloo, Fiona, Taylor, Jane, Male, Alison, Berlin, Cheryl, Eason, Jacqueline, Collier, Rebecca, Claber, Oonagh, Jobson, Irene, Mcleod, Diane, Halliday, Dorothy, Durell, Sarah, Stayner, Barbara, Shanley, Susan, Rahman, Nazneen, Houlston, Richard, Bancroft, Elizabeth, Page, Elizabeth, Ardern Jones, Audrey, Kohut, Kelly, Wiggins, Jennifer, Castro, Elena, Killick, Emma, Martin, Sue, Rea, Gillian, Kulkarni, Anjana, Quarrell, Oliver, Bardsley, Cathryn, Goff, Sheila, Brice, Glen, Winchester, Lizzie, Eddy, Charlotte, Tripathi, Vishakha, Attard, Virginia, Lehmann, Anna, Lucassen, Anneke, Crawford, Gillian, Mcbride, Donna, Smalley, Sarah, Weaver, Jo Ellen, Bove, Betsy, Verny Pierre, Carole, Calender, Alain, Giraud, Sophie, Léone, Mélanie, Gauthier Villars, Marion, Buecher, Bruno, Houdayer, Claude, Moncoutier, Virginie, Belotti, Muriel, Tirapo, Carole, Bressac de Paillerets, Brigitte, Caron, Olivier, Handallou, Sandrine, Hardouin, Agnès, Berthet, Pascaline, Sobol, Hagay, Bourdon, Violaine, Noguchi, Tetsuro, Remenieras, Audrey, Eisinger, François, Coupier, Isabelle, Pujol, Pascal, Peyrat, Jean Philippe, Fournier, Joëlle, Révillion, Françoise, Vennin, Philippe, Adenis, Claude, Lidereau, Rosette, Demange, Liliane, Nogues, Catherine, Muller, Danièle, Fricker, Jean Pierre, Barouk Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Longy, Michel, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Rebischung, Christine, Peysselon, Magalie, Coron, Fanny, Faivre, Laurence, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Ferrer, Sandra Fert, Frénay, Marc, Vénat Bouvet, Laurence, Delnatte, Capucine, Mortemousque, Isabelle, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Sokolowska, Johanna, Bronner, Myriam, Collonge Rame, Marie Agnès, Damette, Alexandre, Lynch, Henry T., Snyder, Carrie L., Muranen, Taru A., Blomqvist, Drs Carl, Aaltonen, Kirsimari, Erkkilä, Irja, Palola, Virpi, Verhoef, S., Schmidt, M. K., de Lange, J. L., Wijnands, R., Collée, J. M., Hooning, M. J., Seynaeve, C., van Deurzen, C. H. M., Obdeijn, I. M., van Asperen, C. J., Wijnen, J. T., Tollenaar, R. A. E. M., van Cronenburg, T. C. T. E. F., Mensenkamp, A. R., Ausems, M. G. E. M., van Os, T. A. M., Gille, J. J. P., Waisfisz, Q., Gómez Garcia, E. B., Blok, M. J., van der Hout, A. H., Mourits, M. J., de Bock, G. H., Vasen, H. F., Siesling, S., Overbeek, L. I. H., Papp, Janos, Vaszko, Tibor, Bozsik, Aniko, Pocza, Timea, Franko, Judit, Balogh, Maria, Domokos, Gabriella, Ferenczi, Judit, Balmaña, J., Capella, Gabriel, Dumont, Martine, Tranchant, Martine, Peixoto, Ana, Santos, Catarina, Rocha, Patrícia, Pinto, Pedro, Thorne, Heather, Niedermayr, Eveline, Foretova, Lenka, Machackova, Eva, Zikan, Michal, Pohlreich, Petr, Kleibl, Zdenek, Dishon, Sara, Lejbkowicz, Flavio, Pinchev, Mila, Senter, Leigha, Sweet, Kevin, Craven, Caroline, O'Conor, Michelle, Borg, Ake, Olsson, Håkan, Jernström, Helena, Henriksson, Karin, Harbst, Katja, Soller, Maria, Kristoffersson, Ulf, Öfverholm, Anna, Nordling, Margareta, Karlsson, Per, Einbeigi, Zakaria, von Wachenfeldt, Anna, Liljegren, Annelie, Bustinza, Gisela Barbany, Rantala, Johanna, Ardnor, Christina Edwinsdotter, Emanuelsson, Monica, Ehrencrona, Hans, Pigg, Maritta Hellström, Stenmark Askmalm, Marie, Liedgren, Sigrun, Zvocec, Cecilia, Niu, Qun, Seldon, Joyce, Kwan, Lorna, Crawford, Beth, Loranger, Kate, Mak, Julie, Stewart, Nicola, Lee, Robin, Blanco, Amie, Conrad, Peggy, Chan, Salina, Pharoah, Paul D. P., Gayther, Simon, Pye, Carole, Harrington, Patricia, Wozniak, Eva, Lindeman, Geoffrey, Harris, Marion, Delatycki, Martin, Sawyer, Sarah, Driessen, Rebecca, Thompson, Ella, Breast Cancer Family Registry, Null, Embrace, Null, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Medical Oncology, Clinical Genetics, Radiotherapy, MUMC+: DA KG Lab Specialisten (9), Klinische Genetica, Genetica & Celbiologie, RS: FHML non-thematic output, [ 1 ] Univ Lyon 1, Ctr Rech Cancerol Lyon, CNRS, INSERM U1052,UMR5286, F-69365 Lyon, France [ 2 ] Univ Lyon, F-69000 Lyon, France [ 3 ] Univ Lyon 1, F-69100 Villeurbanne, France [ 4 ] Univ Lyon 1, CNRS, Lab Biometrie & Biol Evolut LBBE Biometrie & Bio, UMR 5558, F-69622 Villeurbanne, France [ 5 ] Univ Grenoble Alpes, Lab Informat Grenoble LIG, Equipe Projet Multiprogrammat & Ordonnancement Re, UMR 5217, F-38041 Grenoble, France [ 6 ] INRIA Rhone Alpes, Equipe Projet MOAIS, F-38334 Saint Ismier, France [ 7 ] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England [ 8 ] QIMR Berghofer, Dept Genet & Computat Biol, Brisbane, Qld, Australia [ 9 ] Univ Laval, Ctr Hosp Univ Quebec, Ctr Rech, Charlesbourg, PQ, Canada [ 10 ] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA [ 11 ] Columbia Univ, Dept Pediat, Coll Phys & Surg, New York, NY 10027 USA [ 12 ] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY 10027 USA [ 13 ] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA [ 14 ] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Internal Med, Salt Lake City, UT USA [ 15 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA 94538 USA [ 16 ] Vilnius State Univ, Hosp Santariskiu Clin, Hematol Oncol & Transfus Med Ctr, Vilnius, Lithuania [ 17 ] State Res Inst, Ctr Innovat Med, Dept Mol & Regenerat Med, Vilnius, Lithuania [ 18 ] Latvian Biomed Res & Study Ctr, LV-1067 Riga, Latvia [ 19 ] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA [ 20 ] Univ Pretoria, Dept Genet, ZA-0028 Pretoria, South Africa [ 21 ] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA [ 22 ] Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, Copenhagen, Denmark [ 23 ] Copenhagen Univ Hosp, Rigshosp, Dept Oncol, Copenhagen, Denmark [ 24 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark [ 25 ] Spanish Natl Canc Res Ctr CNIO, Human Genet Grp, Madrid, Spain [ 26 ] Ctr Biomed Network Res Rare Dis CIBERER, Madrid, Spain [ 27 ] Hosp Clin Univ Lozano Blesa, Med Oncol Serv, Zaragoza 50009, Spain [ 28 ] Holy Cross Hosp, Michael & Dianne Bienes Comprehens Canc Ctr, Ft Lauderdale, FL USA [ 29 ] City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, Div Clin Canc Genet, Duarte, CA 91010 USA [ 30 ] John Muir 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Thessaloniki, Papageorgiou Hosp, Sch Med, Dept Med Oncol, GR-54006 Thessaloniki, Greece [ 43 ] Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens, Greece [ 44 ] Dana Farber Canc Inst, Boston, MA 02215 USA [ 45 ] Deutsch Krebsforschungszentrum DKFZ, Mol Genet Breast Canc, Heidelberg, Germany [ 46 ] St Michaels Hosp, Dept Clin Genet, Bristol BS2 8EG, Avon, England [ 47 ] Kennedy Galton Ctr, North West Thames Reg Genet Serv, Harrow, Middx, England [ 48 ] Royal Devon & Exeter Hosp, Dept Clin Genet, Exeter EX2 5DW, Devon, England [ 49 ] Liverpool Womens NHS Fdn Trust, Merseyside & Cheshire Clin Genet Serv, Liverpool L8 7SS, Merseyside, England [ 50 ] Cent Manchester Univ Hosp, NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Genet Med, Manchester, Lancs, England [ 51 ] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge CB1 8RN, England [ 52 ] Univ Southampton, Southampton Univ Hosp, NHS Trust, Fac Med, Southampton SO16 6YD, 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Subjects
Genetic modifiers, Dna haplogroups, endocrine system diseases, Genes, BRCA2, Genes, BRCA1, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], ADN mitocondrial, SUSCEPTIBILITY, VARIANTS, 0302 clinical medicine, Breast Cancer Family Registry, Brjóstakrabbamein, MULTIPLE, Aetiology, skin and connective tissue diseases, Phylogeny, Cancer, ddc:616, 0303 health sciences, Mutation, education.field_of_study, Variants, SINGLE-NUCLEOTIDE POLYMORPHISMS, Subclade, Mitochondrial DNA, 3. Good health, ddc, Damage, Oncology, Ovarian, 030220 oncology & carcinogenesis, DISEASES, Multiple, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Single-nucleotide polymorphism, Breast Neoplasms/genetics, EMBRACE, GEMO Study Collaborators, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15], Genetics, Humans, education, Cancer och onkologi, Haplotype, BRCA2, Genes, mitochondrial haplogroup T1a1, breast cancer, BRCA2, Cancer and Oncology, GENETIC MODIFIERS, Polymorphisms, Cancer Research, [SDV]Life Sciences [q-bio], medicine.disease_cause, Haplogroup, 610 Medical sciences Medicine, 3123 Gynaecology and paediatrics, Medicine and Health Sciences, 2.1 Biological and endogenous factors, OXIDATIVE STRESS, Non-U.S. Gov't, Medicine(all), Gen, BRCA1 Protein, Research Support, Non-U.S. Gov't, Cohort, OVARIAN, Mitochondria, Mitochondrial, Genes, Mitochondrial, Female, Research Article, Risk, Heterozygote, BRCA1 protein, breast neoplasms, female, genetic predisposition to disease, haplotypes, humans, phylogeny, risk, genes, BRCA2, genes, mitochondrial, heterozygote, mutation, cancer research, oncology, Population, 3122 Cancers, Oncology and Carcinogenesis, Breast Neoplasms, Biology, Research Support, Càncer de mama, Breast Cancer, medicine, Journal Article, Genetic Predisposition to Disease, ddc:610, Oncology & Carcinogenesis, HEBON, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CONSORTIUM, African, DNA HAPLOGROUPS, Arfgengi, Haplotypes, Susceptibility, BRCA1 Protein/genetics, Human mitochondrial DNA haplogroup
Abstract

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects. European Commission Seventh Framework Program 223175: HEALTH-F2-2009-223175 Cancer Research UK C12292/A11174 C1287/A10118 C1287/A11990 C5047/A8385 National Health and Medical Research Council (NHMRC) program National Health and Medical Research Council (NHMRC) American Cancer Society Early Detection Professorship SIOP-06-258-01-COUN Intramural Research Program of the National Cancer Institute, National Institutes of Health National Cancer Institute, National Institutes of Health UM1 CA164920 Lithuania (BFBOCC-LT): Research Council of Lithuania LIG-07/2012 LSC 10.0010.08 European Social Fund 2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016 Liepaja City Council, Liepaja, Latvia Breast Cancer Research Foundation Cancer Association of South Africa (CANSA) Morris and Horowitz Families Professorship in Cancer Etiology and Outcomes Research NEYE Foundation Spanish Association against Cancer (Asociacion Espanola Contra el Cancer) AECC08 Thematic Network Cooperative Research in Cancer (Red Tematica Investigacion Cooperativa en Cancer (RTICC), Centro de Investigacion Cancer, Salamanca, Spain) RTICC 06/0020/1060 Spanish Ministry of Science and Innovation FIS PI08 1120 Fondo de Investigacion Sanitaria (FIS) SAF2010-20493 Fundacion Mutua Madrilena (FMMA) City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry (COH-CCGCRN) National Cancer Institute and the Office of the Director, National Institutes of Health RC4CA153828 Italian citizens Fondazione IRCCS Istituto Nazionale Tumori Italian Association for Cancer Research (AIRC) European Union (European Social Fund (ESF) Greek national funds through the "Education and Lifelong Learning" operational program of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research and Technology: ARISTEIA "Heracleitus II: Investing in knowledge society through the European Social Fund" Deutsches Krebsforschungszentrum (DKFZ) National Institute for Health Research (NIHR) grant to the Biomedical Research Centre, Manchester, UK NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London University of Kansas Cancer Center P30 CA168524 Kansas Bioscience Authority Eminent Scholar Program Chancellors Distinguished Chair in Biomedical Sciences Professorship German Cancer Aid 109076 Center for Molecular Medicine Cologne (CMMC) Ligue National Contre le Cancer Association "Le cancer du sein, parlons-en!" Award Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program GOA BOF10/GOA/019 Ghent University Hospital National Cancer Institute grants to the GOG Administrative Office and Tissue Bank CA 27469 GOG Statistical and Data Center CA 37517 GOG's Cancer Prevention and Control Committee CA 101165 Instituto de Salud Carlos III (ISCIII), Madrid, Spain RD12/00369/0006 12/00539 European Regional Development Fund (Fonds europeen de developpement regional (FEDER)) funds Helsinki University Central Hospital Research Fund Academy of Finland 266528 Finnish Cancer Society Sigrid Juselius Foundation Dutch Cancer Society NKI1998-1854 NKI2004-3088 NKI2007-3756 Netherlands Organization of Scientific Research NWO 91109024 Pink Ribbon grant 110005 Biobanking and Molecular Resource Infrastructure (BBMRI) NWO 184.021.007/CP46 Hungarian Research and Technological Innovation Fund (KTIA)/Hungarian Scientific Research Fund (Orszagos Tudomanyos Kutatasi Alapprogramok (OTKA)) KTIA-OTKA CK-80745 KTIA-OTKA K-112228 Institut Catala d'Oncologia (ICO): contract grant sponsor: Asociacion Espanola Contra el Cancer Spanish Health Research Foundation Ramon Areces Foundation Instituto de Salud Carlos III (ISCIII) Catalan Health Institute Autonomous Government of Catalonia International Hereditary Cancer Center (Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland) PBZ_KBN_122/P05/2004 Icelandic Association "Walking for Breast Cancer Research" Landspitali University Hospital Research Fund Canadian Institutes of Health Research (CIHR) for the "CIHR Team in Familial Risks of Breast Cancer" program, Canadian Breast Cancer Research Alliance 019511 Ministry of Economic Development, Innovation and Export Trade PSR-SIIRI-701 Ministero della Salute and a "5 x 1,000" Istituto Oncologico Veneto grant Liga Portuguesa Contra o Cancro National Breast Cancer Foundation Queensland Cancer Fund Cancer Councils of New South Wales, Victoria, Tasmania and South Australia Cancer Foundation of Western Australia National Institutes of Health (NIH) through the National Cancer Institute (NCI) CA 116167 CA 128978 CA 176785 NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer CA116201 US Department of Defense Ovarian Cancer Idea award W81XWH-10-1-0341 Ministry of Health of the Czech Republic to Masaryk Memorial Cancer Institute MMCI 00209805 European Regional Development Fund State Budget of the Czech Republic (RECAMO) CZ. 1.05/2.1.00/03.0101 Charles University in Prague project UNCE204024 Robert and Kate Niehaus Clinical Cancer Genetics Initiative Intramural Research Program of the National Cancer Institute Westat, Inc, Rockville, MD, USA N02-CP-11019-50 N02-CP-65504 Clalit Health Services in Israel Israel Cancer Association Breast Cancer Research Foundation (BCRF), New York, NY, USA Russian Federation for Basic Research 11-04-00227 12-04-00928 12-04-01490 Federal Agency for Science and Innovations, Russia 02.740.11.0780 Ohio State University Comprehensive Cancer Center Istituto Toscano Tumori (ITT) Israeli Inherited Breast Cancer Consortium Swedish Breast Cancer Swedish Cancer Society Ralph and Marion Falk Medical Research Trust Entertainment Industry Fund National Women's Cancer Research Alliance University of California, Los Angeles Jonsson Comprehensive Cancer Center Foundation: Breast Cancer Research Foundation University of California, San Francisco Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center Cancer Research UK University of Pennsylvania: National Institutes of Health (NIH) R01 CA102776 R01 CA083855 Susan G Komen for the Cure, Basser Center for BRCA Victorian Familial Cancer Trials Group (VFCTG): Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation 5U01 CA113916 R01 CA140323 ISCIIIRETIC RD06/0020/1051 PI09/02483 PI10/01422 PI10/00748 PI13/00285 PI13/00189 2009SGR290 PI13/00189 2009SGR283 CA125183 R01 CA142996 1U01CA161032

Published
2015
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5. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Author

University of Helsinki, Department of Obstetrics and Gynecology, University of Helsinki, Medicum, Blein, Sophie, Bardel, Claire, Danjean, Vincent, McGuffog, Lesley, Healey, Sue, Barrowdale, Daniel, Lee, Andrew, Dennis, Joe, Kuchenbaecker, Karoline B., Soucy, Penny, Terry, Mary Beth, Chung, Wendy K., Goldgar, David E., Buys, Saundra S., Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Neuhausen, Susan L., Ding, Yuan Chun, Gerdes, Anne-Marie, Ejlertsen, Bent, Nielsen, Finn C., Hansen, Thomas V. O., Osorio, Ana, Benitez, Javier, Andres Conejero, Raquel, Segota, Ena, Weitzel, Jeffrey N., Thelander, Margo, Peterlongo, Paolo, Radice, Paolo, Pensotti, Valeria, Dolcetti, Riccardo, Bonanni, Bernardo, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Manoukian, Siranoush, Varesco, Liliana, Capone, Gabriele L., Papi, Laura, Ottini, Laura, Yannoukakos, Drakoulis, Konstantopoulou, Irene, Garber, Judy, Hamann, Ute, Donaldson, Alan, Brady, Angela, Brewer, Carole, Foo, Claire, Evans, D. Gareth, Frost, Debra, Eccles, Diana, Douglas, Fiona, Cook, Jackie, Adlard, Julian, Barwell, Julian, Walker, Lisa, Izatt, Louise, Side, Lucy E., Kennedy, M. John, Tischkowitz, Marc, Rogers, Mark T., Porteous, Mary E., Morrison, Patrick J., Platte, Radka, Eeles, Ros, Davidson, Rosemarie, Hodgson, Shirley, Cole, Trevor, Godwin, Andrew K., Isaacs, Claudine, Claes, Kathleen, De Leeneer, Kim, Meindl, Alfons, Gehrig, Andrea, Wappenschmidt, Barbara, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Plendl, Hansjoerg, Kast, Karin, Rhiem, Kerstin, Ditsch, Nina, Arnold, Norbert, Varon-Mateeva, Raymonda, Schmutzler, Rita K., Preisler-Adams, Sabine, Markov, Nadja Bogdanova, Wang-Gohrke, Shan, de Pauw, Antoine, Lefol, Cedrick, Lasset, Christine, Leroux, Dominique, Rouleau, Etienne, Damiola, Francesca, Dreyfus, Helene, Barjhoux, Laure, Golmard, Lisa, Uhrhammer, Nancy, Bonadona, Valerie, Sornin, Valerie, Bignon, Yves-Jean, Carter, Jonathan, Van Le, Linda, Piedmonte, Marion, DiSilvestro, Paul A., de la Hoya, Miguel, Caldes, Trinidad, Nevanlinna, Heli, Aittomaki, Kristiina, Jager, Agnes, van den Ouweland, Ans M. W., Kets, Carolien M., Aalfs, Cora M., van Leeuwen, Flora E., Hogervorst, Frans B. L., Meijers-Heijboer, Hanne E. J., Oosterwijk, Jan C., van Roozendaal, Kees E. P., Rookus, Matti A., Devilee, Peter, van der Luijt, Rob B., Olah, Edith, Diez, Orland, Teule, Alex, Lazaro, Conxi, Blanco, Ignacio, Del Valle, Jesus, Jakubowska, Anna, Sukiennicki, Grzegorz, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Agnarsson, Bjarni A., Maugard, Christine, Amadori, Alberto, Montagna, Marco, Teixeira, Manuel R., Spurdle, Amanda B., Foulkes, William, Olswold, Curtis, Lindor, Noralane M., Pankratz, Vernon S., Szabo, Csilla I., Lincoln, Anne, Jacobs, Lauren, Corines, Marina, Robson, Mark, Vijai, Joseph, Berger, Andreas, Fink-Retter, Anneliese, Singer, Christian F., Rappaport, Christine, Kaulich, Daphne Geschwantler, Pfeiler, Georg, Tea, Muy-Kheng, Greene, Mark H., Mai, Phuong L., Rennert, Gad, Imyanitov, Evgeny N., Mulligan, Anna Marie, Glendon, Gord, Andrulis, Irene L., Tchatchou, Sandrine, Toland, Amanda Ewart, Pedersen, Inge Sokilde, Thomassen, Mads, Kruse, Torben A., Jensen, Uffe Birk, Caligo, Maria A., Friedman, Eitan, Zidan, Jamal, Laitman, Yael, Lindblom, Annika, Melin, Beatrice, Arver, Brita, Loman, Niklas, Rosenquist, Richard, Olopade, Olufunmilayo I., Nussbaum, Robert L., Ramus, Susan J., Nathanson, Katherine L., Domchek, Susan M., Rebbeck, Timothy R., Arun, Banu K., Mitchell, Gillian, Karlan, Beth Y., Lester, Jenny, Orsulic, Sandra, Stoppa-Lyonnet, Dominique, Thomas, Gilles, Simard, Jacques, Couch, Fergus J., Offit, Kenneth, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., Mazoyer, Sylvie, Phelan, Catherine M., Sinilnikova, Olga M., Cox, David G., Breast Canc Family Registry, EMBRACE, GEMO Study Collaborators, HEBON, University of Helsinki, Department of Obstetrics and Gynecology, University of Helsinki, Medicum, Blein, Sophie, Bardel, Claire, Danjean, Vincent, McGuffog, Lesley, Healey, Sue, Barrowdale, Daniel, Lee, Andrew, Dennis, Joe, Kuchenbaecker, Karoline B., Soucy, Penny, Terry, Mary Beth, Chung, Wendy K., Goldgar, David E., Buys, Saundra S., Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Neuhausen, Susan L., Ding, Yuan Chun, Gerdes, Anne-Marie, Ejlertsen, Bent, Nielsen, Finn C., Hansen, Thomas V. O., Osorio, Ana, Benitez, Javier, Andres Conejero, Raquel, Segota, Ena, Weitzel, Jeffrey N., Thelander, Margo, Peterlongo, Paolo, Radice, Paolo, Pensotti, Valeria, Dolcetti, Riccardo, Bonanni, Bernardo, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Manoukian, Siranoush, Varesco, Liliana, Capone, Gabriele L., Papi, Laura, Ottini, Laura, Yannoukakos, Drakoulis, Konstantopoulou, Irene, Garber, Judy, Hamann, Ute, Donaldson, Alan, Brady, Angela, Brewer, Carole, Foo, Claire, Evans, D. Gareth, Frost, Debra, Eccles, Diana, Douglas, Fiona, Cook, Jackie, Adlard, Julian, Barwell, Julian, Walker, Lisa, Izatt, Louise, Side, Lucy E., Kennedy, M. John, Tischkowitz, Marc, Rogers, Mark T., Porteous, Mary E., Morrison, Patrick J., Platte, Radka, Eeles, Ros, Davidson, Rosemarie, Hodgson, Shirley, Cole, Trevor, Godwin, Andrew K., Isaacs, Claudine, Claes, Kathleen, De Leeneer, Kim, Meindl, Alfons, Gehrig, Andrea, Wappenschmidt, Barbara, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Plendl, Hansjoerg, Kast, Karin, Rhiem, Kerstin, Ditsch, Nina, Arnold, Norbert, Varon-Mateeva, Raymonda, Schmutzler, Rita K., Preisler-Adams, Sabine, Markov, Nadja Bogdanova, Wang-Gohrke, Shan, de Pauw, Antoine, Lefol, Cedrick, Lasset, Christine, Leroux, Dominique, Rouleau, Etienne, Damiola, Francesca, Dreyfus, Helene, Barjhoux, Laure, Golmard, Lisa, Uhrhammer, Nancy, Bonadona, Valerie, Sornin, Valerie, Bignon, Yves-Jean, Carter, Jonathan, Van Le, Linda, Piedmonte, Marion, DiSilvestro, Paul A., de la Hoya, Miguel, Caldes, Trinidad, Nevanlinna, Heli, Aittomaki, Kristiina, Jager, Agnes, van den Ouweland, Ans M. W., Kets, Carolien M., Aalfs, Cora M., van Leeuwen, Flora E., Hogervorst, Frans B. L., Meijers-Heijboer, Hanne E. J., Oosterwijk, Jan C., van Roozendaal, Kees E. P., Rookus, Matti A., Devilee, Peter, van der Luijt, Rob B., Olah, Edith, Diez, Orland, Teule, Alex, Lazaro, Conxi, Blanco, Ignacio, Del Valle, Jesus, Jakubowska, Anna, Sukiennicki, Grzegorz, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Agnarsson, Bjarni A., Maugard, Christine, Amadori, Alberto, Montagna, Marco, Teixeira, Manuel R., Spurdle, Amanda B., Foulkes, William, Olswold, Curtis, Lindor, Noralane M., Pankratz, Vernon S., Szabo, Csilla I., Lincoln, Anne, Jacobs, Lauren, Corines, Marina, Robson, Mark, Vijai, Joseph, Berger, Andreas, Fink-Retter, Anneliese, Singer, Christian F., Rappaport, Christine, Kaulich, Daphne Geschwantler, Pfeiler, Georg, Tea, Muy-Kheng, Greene, Mark H., Mai, Phuong L., Rennert, Gad, Imyanitov, Evgeny N., Mulligan, Anna Marie, Glendon, Gord, Andrulis, Irene L., Tchatchou, Sandrine, Toland, Amanda Ewart, Pedersen, Inge Sokilde, Thomassen, Mads, Kruse, Torben A., Jensen, Uffe Birk, Caligo, Maria A., Friedman, Eitan, Zidan, Jamal, Laitman, Yael, Lindblom, Annika, Melin, Beatrice, Arver, Brita, Loman, Niklas, Rosenquist, Richard, Olopade, Olufunmilayo I., Nussbaum, Robert L., Ramus, Susan J., Nathanson, Katherine L., Domchek, Susan M., Rebbeck, Timothy R., Arun, Banu K., Mitchell, Gillian, Karlan, Beth Y., Lester, Jenny, Orsulic, Sandra, Stoppa-Lyonnet, Dominique, Thomas, Gilles, Simard, Jacques, Couch, Fergus J., Offit, Kenneth, Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., Mazoyer, Sylvie, Phelan, Catherine M., Sinilnikova, Olga M., Cox, David G., Breast Canc Family Registry, EMBRACE, GEMO Study Collaborators, and HEBON

Abstract

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effe

Published
2015

6. Pre-diagnostic concordance with the WCRF/AICR guidelines and survival in European colorectal cancer patients

Author

University of Helsinki, Department of Medical Genetics, Romaguera, Dora, Ward, Heather, Wark, Petra A., Vergnaud, Anne-Claire, Peeters, Petra H., van Gils, Carla H., Ferrari, Pietro, Fedirko, Veronika, Jenab, Mazda, Boutron-Ruault, Marie-Christine, Dossus, Laure, Dartois, Laureen, Hansen, Camilla Plambeck, Dahm, Christina Catherine, Buckland, Genevieve, Sanchez, Maria Jose, Dorronsoro, Miren, Navarro, Carmen, Barricarte, Aurelio, Key, Timothy J., Trichopoulou, Antonia, Tsironis, Christos, Lagiou, Pagona, Masala, Giovanna, Pala, Valeria, Tumino, Rosario, Vineis, Paolo, Panico, Salvatore, Bueno-de-Mesquita, H. Bas, Siersema, Peter D., Ohlsson, Bodil, Jirstrom, Karin, Wennberg, Maria, Nilsson, Lena M., Weiderpass, Elisabete, Kuehn, Tilman, Katzke, Verena, Khaw, Kay-Tee, Wareham, Nick J., Tjonneland, Anne, Boeing, Heiner, Quiros, Jose R., Gunter, Marc J., Riboli, Elio, Norat, Teresa, University of Helsinki, Department of Medical Genetics, Romaguera, Dora, Ward, Heather, Wark, Petra A., Vergnaud, Anne-Claire, Peeters, Petra H., van Gils, Carla H., Ferrari, Pietro, Fedirko, Veronika, Jenab, Mazda, Boutron-Ruault, Marie-Christine, Dossus, Laure, Dartois, Laureen, Hansen, Camilla Plambeck, Dahm, Christina Catherine, Buckland, Genevieve, Sanchez, Maria Jose, Dorronsoro, Miren, Navarro, Carmen, Barricarte, Aurelio, Key, Timothy J., Trichopoulou, Antonia, Tsironis, Christos, Lagiou, Pagona, Masala, Giovanna, Pala, Valeria, Tumino, Rosario, Vineis, Paolo, Panico, Salvatore, Bueno-de-Mesquita, H. Bas, Siersema, Peter D., Ohlsson, Bodil, Jirstrom, Karin, Wennberg, Maria, Nilsson, Lena M., Weiderpass, Elisabete, Kuehn, Tilman, Katzke, Verena, Khaw, Kay-Tee, Wareham, Nick J., Tjonneland, Anne, Boeing, Heiner, Quiros, Jose R., Gunter, Marc J., Riboli, Elio, and Norat, Teresa

Abstract

Background: Cancer survivors are advised to follow lifestyle recommendations on diet, physical activity, and body fatness proposed by the World Cancer Research Fund/American Institute of Cancer Research (WCRF/AICR) for cancer prevention. Previous studies have demonstrated that higher concordance with these recommendations measured using an index score (the WCRF/AICR score) was associated with lower cancer incidence and mortality. The aim of this study was to evaluate the association between pre-diagnostic concordance with WCRF/AICR recommendations and mortality in colorectal cancer (CRC) patients. Methods: The association between the WCRF/AICR score (score range 0-6 in men and 0-7 in women; higher scores indicate greater concordance) assessed on average 6.4 years before diagnosis and CRC-specific (n = 872) and overall mortality (n = 1,113) was prospectively examined among 3,292 participants diagnosed with CRC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (mean follow-up time after diagnosis 4.2 years). Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality. Results: The HRs (95% CIs) for CRC-specific mortality among participants in the second (score range in men/women: 2.25-2.75/3.25-3.75), third (3-3.75/4-4.75), and fourth (4-6/5-7) categories of the score were 0.87 (0.72-1.06), 0.74 (0.61-0.90), and 0.70 (0.56-0.89), respectively (P for trend Conclusions: Greater concordance with the WCRF/AICR recommendations on diet, physical activity, and body fatness prior to CRC diagnosis is associated with improved survival among CRC patients.

Published
2015

7. Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer

Author

University of Helsinki, Clinicum, Sonnenblick, Amir, Brohee, Sylvain, Fumagalli, Debora, Vincent, Delphine, Venet, David, Ignatiadis, Michail, Salgado, Roberto, Van den Eynden, Gert, Rothe, Francoise, Desmedt, Christine, Neven, Patrick, Loibl, Sibylle, Denkert, Carsten, Joensuu, Heikki, Loi, Sherene, Sirtaine, Nicolas, Kellokumpu-Lehtinen, Pirkko-Liisa, Piccart, Martine, Sotiriou, Christos, University of Helsinki, Clinicum, Sonnenblick, Amir, Brohee, Sylvain, Fumagalli, Debora, Vincent, Delphine, Venet, David, Ignatiadis, Michail, Salgado, Roberto, Van den Eynden, Gert, Rothe, Francoise, Desmedt, Christine, Neven, Patrick, Loibl, Sibylle, Denkert, Carsten, Joensuu, Heikki, Loi, Sherene, Sirtaine, Nicolas, Kellokumpu-Lehtinen, Pirkko-Liisa, Piccart, Martine, and Sotiriou, Christos

Abstract

Background: The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance. Methods: We integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting. Results: We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This suggests that STAT3 induces a characteristic set of gene expression changes in HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated with trastuzumab resistance (log rank P = 0.049). These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and stromal reactivation. Conclusions: This study provides compelling evidence for a link between pSTAT3 and trastuzumab resistance in HER2-positive primary breast cancers. Our results suggest that it may be valuable to add agents targeting the STAT3 pathway to trastuzumab for treatment of HER2-positive breast cancer.

Published
2015

8. Annexin A1 expression in a pooled breast cancer series

Author

University of Helsinki, Department of Obstetrics and Gynecology, University of Helsinki, Haartman Institute (-2009), University of Helsinki, Department of Pathology, University of Helsinki, Medicum, University of Helsinki, Clinicum, Sobral-Leite, Marcelo, Wesseling, Jelle, Smit, Vincent T. H. B. M., Nevanlinna, Heli, van Miltenburg, Martine H., Sanders, Joyce, Hofland, Ingrid, Blows, Fiona M., Coulson, Penny, Patrycja, Gazinska, Schellens, Jan H. M., Fagerholm, Rainer, Heikkila, Paivi, Aittomaki, Kristiina, Blomqvist, Carl, Provenzano, Elena, Ali, Hamid Raza, Figueroa, Jonine, Sherman, Mark, Lissowska, Jolanta, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Phillips, Kelly-Anne, Couch, Fergus J., Olson, Janet E., Vachon, Celine, Visscher, Daniel, Brenner, Hermann, Butterbach, Katja, Arndt, Volker, Holleczek, Bernd, Hooning, Maartje J., Hollestelle, Antoinette, Martens, John W. M., van Deurzen, Carolien H. M., van de Water, Bob, Broeks, Annegien, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Easton, Douglas F., Pharoah, Paul D. P., Garcia-Closas, Montserrat, de Graauw, Marjo, Schmidt, Marjanka K., kConFab AOCS Investigators, University of Helsinki, Department of Obstetrics and Gynecology, University of Helsinki, Haartman Institute (-2009), University of Helsinki, Department of Pathology, University of Helsinki, Medicum, University of Helsinki, Clinicum, Sobral-Leite, Marcelo, Wesseling, Jelle, Smit, Vincent T. H. B. M., Nevanlinna, Heli, van Miltenburg, Martine H., Sanders, Joyce, Hofland, Ingrid, Blows, Fiona M., Coulson, Penny, Patrycja, Gazinska, Schellens, Jan H. M., Fagerholm, Rainer, Heikkila, Paivi, Aittomaki, Kristiina, Blomqvist, Carl, Provenzano, Elena, Ali, Hamid Raza, Figueroa, Jonine, Sherman, Mark, Lissowska, Jolanta, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Phillips, Kelly-Anne, Couch, Fergus J., Olson, Janet E., Vachon, Celine, Visscher, Daniel, Brenner, Hermann, Butterbach, Katja, Arndt, Volker, Holleczek, Bernd, Hooning, Maartje J., Hollestelle, Antoinette, Martens, John W. M., van Deurzen, Carolien H. M., van de Water, Bob, Broeks, Annegien, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Easton, Douglas F., Pharoah, Paul D. P., Garcia-Closas, Montserrat, de Graauw, Marjo, Schmidt, Marjanka K., and kConFab AOCS Investigators

Abstract

Background: Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods: Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results: The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05-1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91-1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17-2.45). Conclusions: ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.

Published
2015

9. Identification of sample-specific regulations using integrative network level analysis

Author

University of Helsinki, Research Programs Unit, University of Helsinki, Medicum, Liu, Chengyu, Louhimo, Riku, Laakso, Marko, Lehtonen, Rainer, Hautaniemi, Sampsa, University of Helsinki, Research Programs Unit, University of Helsinki, Medicum, Liu, Chengyu, Louhimo, Riku, Laakso, Marko, Lehtonen, Rainer, and Hautaniemi, Sampsa

Abstract

Background: Histologically similar tumors even from the same anatomical position may still show high variability at molecular level hindering analysis of genome-wide data. Leveling the analysis to a gene regulatory network instead of focusing on single genes has been suggested to overcome the heterogeneity issue although the majority of the network methods require large datasets. Network methods that are able to function at a single sample level are needed to overcome the heterogeneity and sample size issues. Methods: We present a novel network method, Differentially Expressed Regulation Analysis (DERA) that integrates expression data to biological network information at a single sample level. The sample-specific networks are subsequently used to discover samples with similar molecular functions by identification of regulations that are shared between samples or are specific for a subgroup. Results: We applied DERA to identify key regulations in triple negative breast cancer (TNBC), which is characterized by lack of estrogen receptor, progesterone receptor and HER2 expression and has poorer prognosis than the other breast cancer subtypes. DERA identified 110 core regulations consisting of 28 disconnected subnetworks for TNBC. These subnetworks are related to oncogenic activity, proliferation, cancer survival, invasiveness and metastasis. Our analysis further revealed 31 regulations specific for TNBC as compared to the other breast cancer subtypes and thus form a basis for understanding TNBC. We also applied DERA to high-grade serous ovarian cancer (HGS-OvCa) data and identified several common regulations between HGS-OvCa and TNBC. The performance of DERA was compared to two pathway analysis methods GSEA and SPIA and our results shows better reproducibility and higher sensitivity in a small sample set. Conclusions: We present a novel method called DERA to identify subnetworks that are similarly active for a group of samples. DERA was applied to breast cancer and ovar

Published
2015

10. Sequencing of breast cancer stem cell populations indicates a dynamic conversion between differentiation states in vivo

Author

University of Helsinki, Research Programs Unit, Klevebring, Daniel, Rosin, Gustaf, Ma, Ran, Lindberg, Johan, Czene, Kamila, Kere, Juha, Fredriksson, Irma, Bergh, Jonas, Hartman, Johan, University of Helsinki, Research Programs Unit, Klevebring, Daniel, Rosin, Gustaf, Ma, Ran, Lindberg, Johan, Czene, Kamila, Kere, Juha, Fredriksson, Irma, Bergh, Jonas, and Hartman, Johan

Published
2014

11. Polysialic acid is associated with better prognosis and IDH1-mutation in diffusely infiltrating astrocytomas

Author

University of Helsinki, Department of Biosciences, University of Helsinki, Neurokirurgian yksikkö, Mäkelä, Katri, Nordfors, Kristiina, Finne, Jukka, Jokilammi, Anne, Paavonen, Timo, Haapasalo, Hannu, Korja, Miikka, Haapasalo, Joonas, University of Helsinki, Department of Biosciences, University of Helsinki, Neurokirurgian yksikkö, Mäkelä, Katri, Nordfors, Kristiina, Finne, Jukka, Jokilammi, Anne, Paavonen, Timo, Haapasalo, Hannu, Korja, Miikka, and Haapasalo, Joonas

Published
2014

15. A gene signature in histologically normal surgical margins is predictive of oral carcinoma recurrence

Author

University of Helsinki, Korva-, nenä- ja kurkkutautien klinikka, Reis, Patricia P., Waldron, Levi, Perez-Ordonez, Bayardo, Pintilie, Melania, Galloni, Natalie Naranjo, Xuan, Yali, Cervigne, Nilva K., Warner, Giles C., Mäkitie, Antti Aarni, Simpson, Colleen, Goldstein, David, Brown, Dale, Gilbert, Ralph, Gullane, Patrick, Irish, Jonathan, Jurisica, Igor, Kamel-Reid, Suzanne, University of Helsinki, Korva-, nenä- ja kurkkutautien klinikka, Reis, Patricia P., Waldron, Levi, Perez-Ordonez, Bayardo, Pintilie, Melania, Galloni, Natalie Naranjo, Xuan, Yali, Cervigne, Nilva K., Warner, Giles C., Mäkitie, Antti Aarni, Simpson, Colleen, Goldstein, David, Brown, Dale, Gilbert, Ralph, Gullane, Patrick, Irish, Jonathan, Jurisica, Igor, and Kamel-Reid, Suzanne

Published
2011

16. Long-term survival of women with basal-like ductal carcinoma in situ of the breast

Author

University of Helsinki, Department of Oncology, Zhou, Wenjing, Jirstrom, Karin, Johansson, Christine, Amini, Rose-Marie, Blomqvist, Carl, Agbaje, Olorunsola, Warnberg, Fredrik, University of Helsinki, Department of Oncology, Zhou, Wenjing, Jirstrom, Karin, Johansson, Christine, Amini, Rose-Marie, Blomqvist, Carl, Agbaje, Olorunsola, and Warnberg, Fredrik

Abstract

Background: Microarray gene-profiling of invasive breast cancer has identified different subtypes including luminal A, luminal B, HER2-overexpressing and basal-like groups. Basal-like invasive breast cancer is associated with a worse prognosis. However, the prognosis of basal-like ductal carcinoma in situ (DCIS) is still unknown. Our aim was to study the prognosis of basal-like DCIS in a large population-based cohort. Methods: All 458 women with a primary DCIS diagnosed between 1986 and 2004, in Uppland and Vastmanland, Sweden were included. TMA blocks were constructed. To classify the DCIS tumors, we used immunohistochemical (IHC) markers (estrogen-, progesterone-, HER2, cytokeratin 5/6 and epidermal growth factor receptor) as a surrogate for the gene expression profiling. The association with prognosis was examined for basal-like DCIS and other subtypes using Kaplan-Meier survival analyses and Cox proportional hazards regression models. Results: IHC data were complete for 392 women. Thirty-two were basal-like (8.2%), 351 were luminal or HER2-positive (89.5%) and 9 unclassified (2.3%). Seventy-six women had a local recurrence of which 34 were invasive. Another 3 women had general metastases as first event. Basal-like DCIS showed a higher risk of local recurrence and invasive recurrence 1.8 (Confidence interval (CI) 95%, 0.8-4.2) and 1.9 (0.7-5.1), respectively. However, the difference was not statistically significant. Also, no statistically significant increased risk was seen for triple-negative or high grade DCIS. Conclusions: Basal-like DCIS showed about a doubled, however not statistically significant risk for local recurrence and developing invasive cancer compared with the other molecular subtypes. Molecular subtyping was a better prognostic parameter than histopathological grade.

Published
2010

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