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1. Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer

Author

Caroline Seynaeve, Katja Harbst, Eric A. Ross, Nandita Mitra, Elisa Alducci, Marco Montagna, Janusz Menkiszak, Marion Gauthier-Villars, Javier Benitez, Carole Brewer, Etienne Rouleau, Inge Søkilde Pedersen, Orland Diez, Anya Kushnir, Antonis C. Antoniou, Christine Rappaport, Florentia Fostira, Maurizio Genuardi, Simona Agata, Mark H. Greene, Mary Beth Terry, Nicola Dikow, David E. Goldgar, Anna Jakubowska, Min Hyuk Lee, Sylvie Mazoyer, Diana Eccles, Shirley Hodgson, Anne-Marie Gerdes, Alexander Miron, Laima Tihomirova, Alan Donaldson, Adalgeir Arason, Rosalind A. Eeles, Fergus J. Couch, Hans Jörg Plendl, Francesca Vignolo-Lutati, Ute Hamann, Jackie Cook, Torben A Kruse, Shani Paluch-Shimon, Lisa Walker, Doris Steinemann, Dorothea Gadzicki, Juul T. Wijnen, Markus C. Fleisch, Kenneth Offit, Mary B. Daly, Jamal Zidan, Georgia Chenevix-Trench, Stephanie V. Blank, Marc Tischkowitz, Esther Darder, Annette Fontaine, Louise Izatt, Elżbieta Złowocka-Perłowska, Nadia Boutry-Kryza, Frans B. L. Hogervorst, Stefanie Engert, Danièle Muller, Susan M. Domchek, Phuong L. Mai, Senno Verhoef, Bernhard H. F. Weber, Cecilia M. Dorfling, Kathleen Claes, Kristiina Aittomäki, Annemarie H. van der Hout, Sharon Sand, Olufunmilayo I. Olopade, Margreet G. E. M. Ausems, Aleksandra Tołoczko-Grabarek, Trevor Cole, Giulietta Scuvera, Ana Osorio, Niklas Loman, Timothy R. Rebbeck, Riccardo Dolcetti, Marit Beer, Harsh B. Pathak, Douglas F. Easton, Lone Sunde, Conxi Lázaro, Raanan Berger, Paolo Radice, Mads Thomassen, Ignacio Blanco, Joseph Vijai, Kristie Bobolis, János Papp, Jean-Pierre Fricker, Christine Walsh, Patricia A. Ganz, Marie Stenmark-Askmalm, Andrea Gehrig, Vernon S. Pankratz, Atocha Romero, Xianshu Wang, Loris Bernard, Viviana Gismondi, Mary Porteous, Muy-Kheng Tea, Karen H. Lu, Gustavo C. Rodriguez, Bernardo Bonanni, Christoph Mundhenke, Julian Adlard, Bent Ejlertsen, Dominique Stoppa-Lyonnet, Nadine Tung, Patrick J. Morrison, Dezheng Huo, Cezary Cybulski, Jack Basil, Georg Pfeiler, Daphne Gschwantler-Kaulich, Heli Nevanlinna, Anders Bojesen, Marion Piedmonte, Katherine L. Nathanson, Amanda E. Toland, Sung-Won Kim, Judy Garber, Amanda B. Spurdle, Noralane M. Lindor, Sanne Traasdahl Moeller, Hans Ehrencrona, Trinidad Caldés, Rosemarie Davidson, Karin Kast, Jenny Lester, Shan Wang-Gohrke, Norbert Arnold, Ana Peixoto, Christine Lasset, Andreas Berger, Olga M. Sinilnikova, Katie Wakely, Claude Houdayer, Mercedes Durán, Robert L. Nussbaum, Ramūnas Janavičius, Christina G. Selkirk, Paolo Aretini, Nina Ditsch, J. Margriet Collée, Rosa B. Barkardottir, Sue Healey, Tomasz Huzarski, Cora M. Aalfs, Gillian Mitchell, Peter J. Hulick, Encarna B. Gomez Garcia, Zakaria Einbeigi, Christian F. Singer, Leigha Senter, Yuan Chun Ding, Dieter Niederacher, Yael Laitman, Siranoush Manoukian, Christoph Engel, Anne De Paepe, Anneliese Fink-Retter, Irene L. Andrulis, Rachel Laframboise, Maria A. Caligo, Priyanka Sharma, Miguel de la Hoya, Teresa Ramón y Cajal, Bruce Poppe, Thomas Hansen, Francesca Damiola, Anne-Bine Skytte, Susan L. Neuhausen, Christian Sutter, Marie-Agnès Collonge-Rame, Johannes J. P. Gille, Barbara Pasini, Wendy K. Chung, Noah D. Kauff, M. John Kennedy, Diana Torres, Salina B. Chan, Mark E. Robson, Elizabeth J. van Rensburg, Eric Hahnen, Barbara Wappenschmidt, Grzegorz Sukiennicki, Esther M. John, Rohini Rau-Murthy, Alice S. Whittemore, Kunle Odunsi, Masoud Azodi, John F. Boggess, Sue K. Park, Rita K. Schmutzler, Muriel Belotti, Jeffrey N. Weitzel, Simon A. Gayther, Fei Wan, Andrew K. Godwin, Arjen R. Mensenkamp, Daniela Zaffaroni, Jacques Simard, Susan Peock, Soo Hwang Teo, Claus R. Bartram, Evgeny N. Imyanitov, Maria-Isabel Tejada, Giuseppe Giannini, Mónica Salinas, Banu Arun, Jan C. Oosterwijk, Jacek Gronwald, Alexandra Becker, Tara M. Friebel, Lenka Foretova, Catherine Noguès, Muhammad Usman Rashid, Valeria Pensotti, Antonella Savarese, Debra Frost, Beatrice Melin, Drakoulis Yannoukakos, Steve Ellis, Jean-Philippe Peyrat, Hagay Sobol, Kim De Leeneer, Radka Platte, Jan Lubinski, Javier Godino, Lesley McGuffog, Tomasz Byrski, Claudine Isaacs, Johanna Rantala, Kelly-Anne Phillips, Carolien M. Kets, Uffe Birk Jensen, Katarzyna Durda, Linda Steele, Beth Y. Karlan, Ava Kwong, Alfons Meindl, Lucia Guidugli, Raymonda Varon-Mateeva, D. Gareth Evans, Edith Olah, Isabelle Mortemousque, Manuel R. Teixeira, Joyce Seldon, Katarzyna Jaworska-Bieniek, Bernard Peissel, Saundra S. Buys, Peter Devilee, Kerstin Rhiem, Eitan Friedman, RS: GROW - Oncology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Cancer Research UK, National Institutes of Health (US), University of Pennsylvania, Breast Cancer Research Foundation, Human Genetics, Human genetics, and Epidemiology and Data Science

Subjects
endocrine system diseases, Genes, BRCA2, MathematicsofComputing_GENERAL, Genes, BRCA1, cancer risk, Settore MED/03 - GENETICA MEDICA, medicine.disease_cause, MOUSE MODELS, Risk Factors, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Age of Onset, POSITION, skin and connective tissue diseases, Adult, Breast Neoplasms, Female, Heterozygote, Humans, Middle Aged, Nucleotides, Ovarian Neoplasms, Genetic Predisposition to Disease, Mutation, Medicine (all), MESSENGER-RNA DECAY, UNKNOWN CLINICAL-SIGNIFICANCE, BRCA1 and BRCA2 genes, mutation type and position, cancer risk, TheoryofComputation_GENERAL, General Medicine, GERMLINE MUTATIONS, CARRIERS, 3. Good health, SUSCEPTIBILITY GENE, Medical genetics, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], medicine.medical_specialty, PROTEINS, mutation type and position, BRCA1 and BRCA2 genes, DNA-SEQUENCE VARIANTS, Article, REGION, Breast cancer, Germline mutation, medicine, BRCA1 or BRCA2, business.industry, Cancer, Heterozygote advantage, medicine.disease, Cancer research, Age of onset, Ovarian cancer, business
Abstract

CIMBA Consortium et al., PMID: 25849179, [Importance]: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. [Objective]: To identify mutation-specific cancer risks for carriers of BRCA1/2. [Design, Setting, and Participants]: Observational study ofwomen whowere ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents.We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position.We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. [Exposures]: Mutations of BRCA1 or BRCA2. [Main Outcomes and Measures]: Breast and ovarian cancer risks. [Results]: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95%CI, 1.22-1.74; P = 2 × 10-6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95%CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95%CI, 1.22-1.55; P = 6 × 10-9).We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95%CI, 0.56-0.70; P = 9 × 10-17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95%CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95%CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95%CI, 1.69-3.16; P = .00002).We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95%CI, 0.44-0.60; P = 6 × 10-17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95%CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. [Conclusions and Relevance]: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations., Dr Antoniou and the CIMBA data management are funded by Cancer Research UK. Dr Easton is a Principal Research Fellow of Cancer Research UK. Dr Rebbeck is supported by R01-CA083855, R01-CA102776, and P50-CA083638 from the National Institutes of Health (NIH). Dr Rebbeck, Dr Nathanson, Ms Friebel, and Dr Domchek are supported by the Basser Research Center at the University of Pennsylvania. Dr Nathanson is supported by the Breast Cancer Research Foundation. Drs Domchek and Nathanson are supported by the Rooney Family Foundation. Dr Poppe is supported by R01-CA112520 from NIH. Cancer Research UK provided financial support for this work. Dr Antoniou is a Senior Cancer Research UK Cancer Research Fellow. Dr Phillips is a National Breast Cancer Foundation (Australia) Practitioner Fellow.

Published
2015
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2. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author

Javier Benitez, Marie Stenmark-Askmalm, Susan L. Neuhausen, Pascal Guénel, Jane Carpenter, Christine B. Ambrosone, Dominique Stoppa-Lyonnet, Nadine Tung, Gad Rennert, Stephen J. Chanock, Andrew K. Godwin, Regina M. Santella, Brita Arver, Karoline Kuchenbaecker, Kamila Czene, Vessela N. Kristensen, Natalia Bogdanova, Nazneen Rahman, Jianjun Liu, Federico Canzian, Hoda Anton-Culver, Maya Ghoussaini, Mark E. Robson, Sue K. Park, Manjeet K. Bolla, Roger L. Milne, Veli-Matti Kosma, Siranoush Manoukian, Angela Cox, Daniel F. Schmidt, Kay-Tee Khaw, Rosario Tumino, Melissa C. Southey, Ramunas Janavicius, Irene Konstantopoulou, Carl Blomqvist, John L. Hopper, Sue Healey, Christine Rappaport, Marco Montagna, SA Gayther, Heather Eliassen, Carolien H.M. van Deurzen, Jacques Simard, Emiel J. Rutgers, Jonine Figueroa, Maria A. Caligo, Volker Arndt, Sylvie Mazoyer, Diana Eccles, M.J. Hooning, Antoinette Hollestelle, Mary B. Daly, Robert Winqvist, Antonis C. Antoniou, Patricia A. Ganz, Orland Diez, Priyanka Sharma, Ana Osorio, Daniel Barrowdale, Loic Le Marchand, Drakoulis Yannoukakos, Elinor J. Sawyer, Conxi Lázaro, Soo-Hwang Teo, Penny Soucy, Paolo Radice, John W. M. Martens, Steve Ellis, David E. Goldgar, Anna Jakubowska, Maria Kabisch, Raymonda Varon-Mateeva, Diether Lambrechts, Paul D.P. Pharoah, Leigha Senter, Anna González-Neira, Cecilia M. Dorfling, Brian E. Henderson, Rulla M. Tamimi, Sara Margolin, Susan M. Gapstur, Ian Tomlinson, Thérèse Truong, Robert A.E.M. Tollenaar, Amanda E. Toland, Anna Marie Mulligan, Irene L. Andrulis, Isabelle Romieu, Monica Barile, Florentia Fostira, Johanna Rantala, Enes Makalic, Eitan Friedman, Zhaoming Wang, Mark H. Greene, Noralane M. Lindor, Julie M. Cunningham, Riccardo Dolcetti, Steven N. Hart, Mary Beth Terry, Jenny Chang-Claude, Austin Miller, Georgia Chenevix-Trench, Asta Försti, Kathleen E. Malone, Paolo Peterlongo, Lothar Haeberle, Celine M. Vachon, Elizabeth J. van Rensburg, Michael Jones, Laima Tihomirova, Penelope Miron, Eunjung Lee, María José Sánchez, Hatef Darabi, Frans B. L. Hogervorst, Matthias W. Beckmann, Edith Olah, Annika Lindblom, Phuong L. Mai, Emily Hallberg, Alison M. Dunning, Kathleen Claes, Esther M. John, Sofia Khan, David J. Hunter, Kristiina Aittomäki, Katherine L. Nathanson, Lars Beckmann, Stephanie V. Blank, Wei Zheng, Olufunmilayo I. Olopade, Heli Nevanlinna, Miguel de la Hoya, Olga M. Sinilnikova, Bruce Poppe, Catherine M. Phelan, S. Lindstrom, Stig E. Bojesen, Curtis Olswold, Fredrick R. Schumacher, Janet E. Olson, Tuomas Heikkinen, Judy Garber, Fergus J. Couch, Tara M. Friebel, Isabel dos-Santos-Silva, Douglas F. Easton, Song Yao, Dieter Flesch-Janys, Hans Ehrencrona, Simon S. Cross, Rodney J. Scott, Kenneth Offit, Petra H.M. Peeters, Clare Turnbull, Taru A. Muranen, William J. Tapper, Trinidad Caldés, Jenny Lester, Robert L. Nussbaum, Paul A. James, Marike Gabrielson, Susan M. Domchek, Mads Thomassen, Marilie D. Gammon, Susan L. Slager, Graham G. Giles, Silje Nord, Hans Wildiers, Hiltrud Brauch, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Martine Dumont, Mark S. Goldberg, Bernardo Bonanni, Jirong Long, Kyriaki Michailidou, Ute Hamann, Wendy K. Chung, Marc J. Gunter, Mia M. Gaudet, Keith Humphreys, Per Hall, Yuan C. Ding, Simona Agata, Julia A. Knight, Robert Pilarski, Claudine Isaacs, Alvaro A.N. Monteiro, Montserrat Garcia-Closas, Rosa B. Barkardottir, Beth Y. Karlan, Uffe Birk Jensen, Arif B. Ekici, Evgeny N. Imyanitov, Alex Teulé, Anne-Marie Gerdes, Frederik Marme, Debra Frost, Anthony J. Swerdlow, Yon Ko, Xiaohong R. Yang, Jan Lubinski, Peter A. Fasching, Lesley McGuffog, Jacek Gronwald, Katri Pylkäs, Banu Arun, Josef Herzog, Gord Glendon, Doris Steinemann, Tomasz Huzarski, Peter Kraft, Anja Rudolph, Arto Mannermaa, Habibul Ahsan, Christian F. Singer, Rita K. Schmutzler, Julian Peto, Giski Ursin, Shan Wang-Gohrke, Andrea L. Richardson, Jeffrey N. Weitzel, Børge G. Nordestgaard, Marjanka K. Schmidt, Alice S. Whittemore, Hermann Brenner, Barbara Burwinkel, D Thompson, Csilla I. Szabo, M. Pilar Zamora, Janna Lilyquist, Muhammad G. Kibriya, Yael Laitman, Helen Tsimiklis, W. D. Foulkes, Thomas Hansen, Francesca Damiola, Robert N. Hoover, Ava Kwong, Alfons Meindl, Siddhartha Kar, Manuel R. Teixeira, Elisabete Weiderpass, Bernard Peissel, Saundra S. Buys, Peter Devilee, Unión Europea. Comisión Europea. 7 Programa Marco, Cancer Research UK (Reino Unido), National Institutes of Health (Estados Unidos), Canadian Institutes of Health Research, Florida Breast Cancer Foundation (Estados Unidos), Dunning, Alison [0000-0001-6651-7166], Ghoussaini, Maya [0000-0002-2415-2143], Khaw, Kay-Tee [0000-0002-8802-2903], Thompson, Deborah [0000-0003-1465-5799], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Medical Oncology, Obstetrics & Gynecology, Pathology, Cell biology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, and [ 1 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA [ 2 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA [ 3 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet 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Vesalius Res Ctr, B-3000 Leuven, Belgium [ 127 ] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, Barcelona 08908, Spain [ 128 ] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90032 USA [ 129 ] Univ Canc Ctr, Canc Epidemiol Program, Honolulu, HI 96813 USA [ 130 ] Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden [ 131 ] Mayo Clin, Hlth Sci Res, Scotsdale, AZ 85259 USA [ 132 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA [ 133 ] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore [ 134 ] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA [ 135 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA [ 136 ] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA [ 137 ] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA [ 138 ] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, I-20133 Milan, Italy [ 139 ] Tech Univ Munich, Dept Obstet & Gynaecol, D-81675 Munich, Germany [ 140 ] Roswell Pk Canc Inst, NRG Oncol Stat & Data Management Ctr, Buffalo, NY 14263 USA [ 141 ] Case Western Reserve Univ, Sch Med, Dept Genom & Genome Sci, Cleveland, OH 44106 USA [ 142 ] Univ Hlth Network, Lab Med Program, Toronto, ON M5B 1W8, Canada [ 143 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada [ 144 ] Invitae Corp, San Francisco, CA 94107 USA [ 145 ] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA [ 146 ] Natl Inst Oncol, Dept Mol Genet, H-1122 Budapest, Hungary [ 147 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 148 ] Seoul Natl Univ, Coll Med, Dept Prevent Med & Biomed Sci, Seoul 110799, South Korea [ 149 ] Seoul Natl Univ, Canc Res Inst, Seoul 110799, South Korea [ 150 ] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, NL-3508 GA Utrecht, Netherlands [ 151 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, London SW7 2AZ, England [ 152 ] Fdn Ist FIRC Oncol Mol, IFOM, I-20133 Milan, Italy [ 153 ] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA [ 154 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland [ 155 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland [ 156 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Bioctr Oulu, FI-90220 Oulu, Finland [ 157 ] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, I-20133 Milan, Italy [ 158 ] Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England [ 159 ] Karolinska Univ Hosp, Dept Clin Genet, SE-17176 Stockholm, Sweden [ 160 ] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, A-1090 Vienna, Austria [ 161 ] Clalit Natl Israeli Canc Control Ctr, IL-34362 Haifa, Israel [ 162 ] Carmel Hosp, Dept Community Med & Epidemiol, IL-34362 Haifa, Israel [ 163 ] B Rappaport Fac Med, IL-34362 Haifa, Israel [ 164 ] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA [ 165 ] Int Agcy Res Canc, F-69008 Lyon, France [ 166 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1006 BE Amsterdam, Netherlands [ 167 ] Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria Ibs GRANADA, Escuela Andaluza Salud Publ, E-18014 Granada, Spain [ 168 ] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain [ 169 ] Columbia Univ, Dept Environm Hlth Sci, New York, NY 10032 USA [ 170 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London SE1 9RT, England [ 171 ] Univ Hosp Cologne, Fac Med, Ctr Hereditary Breast & Ovarian Canc, D-50931 Cologne, Germany [ 172 ] Univ Hosp Cologne, Fac Med, CIO, D-50931 Cologne, Germany [ 173 ] Univ Cologne, CMMC, D-50931 Cologne, Germany [ 174 ] John Hunter Hosp, Hunter Area Pathol Serv, Div Genet, Newcastle, NSW 2305, Australia [ 175 ] Univ Kansas, Med Ctr, Dept Hematol & Oncol, Kansas City, KS 66205 USA [ 176 ] Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada [ 177 ] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, F-69373 Lyon, France [ 178 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 179 ] Hannover Med Sch, D-30625 Hannover, Germany [ 180 ] Linkoping Univ, Dept Clin & Expt Med, Div Clin Genet, SE-58185 Linkoping, Sweden [ 181 ] Inst Curie, Dept Tumour Biol, F-75248 Paris, France [ 182 ] Univ Paris 05, Sorbonne Paris Cite, F-75248 Paris, France [ 183 ] NHGRI, NIH, Bethesda, MD 20892 USA [ 184 ] Portuguese Oncol Inst, Dept Genet, P-4200072 Oporto, Portugal [ 185 ] Univ Porto, Biomed Sci Inst ICBAS, P-4200072 Oporto, Portugal [ 186 ] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya 47500, Malaysia [ 187 ] Univ Malaya, Med Ctr, Canc Res Inst, Fac Med, Kuala Lumpur 50603, Malaysia [ 188 ] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA [ 189 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 190 ] Latvian Biomed Res & Study Ctr, LV-1067 Riga, Latvia [ 191 ] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 192 ] Leiden Univ, Med Ctr, Dept Surg Oncol, NL-2333 ZC Leiden, Netherlands [ 193 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England [ 194 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX3 7BN, England [ 195 ] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Barcelona 08908, Spain [ 196 ] Civ MP Arezzo Hosp, Canc Registry, I-97100 Asp Ragusa, Italy [ 197 ] Civ MP Arezzo Hosp, Histopathol Unit, I-97100 Asp Ragusa, Italy [ 198 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 199 ] Inst Populat Based Canc Res, Canc Registry Norway, N-0304 Oslo, Norway [ 200 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Pathol, NL-3000 CA Rotterdam, Netherlands [ 201 ] Charite, Inst Human Genet, D-13353 Berlin, Germany [ 202 ] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA [ 203 ] Univ Hosp Ulm, D-89075 Ulm, Germany [ 204 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway [ 205 ] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki 2016, Finland [ 206 ] Stanford Univ, Sch Med, Dept Hlth Res Policy Epidemiol, Stanford, CA 94305 USA [ 207 ] Univ Hosp, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, B-3000 Leuven, Belgium [ 208 ] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA [ 209 ] Hosp Univ La Paz, Med Oncol Serv, Madrid 28046, Spain [ 210 ] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA [ 211 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld 4029, Australia [ 212 ] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA

Subjects
0301 basic medicine, Oncology, General Physics and Astronomy, Genome-wide association study, Cyclophilins, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Brjóstakrabbamein, Genotype, BRCA2 MUTATION CARRIERS, Medicine and Health Sciences, CONFER SUSCEPTIBILITY, skin and connective tissue diseases, Cancer, GENE-EXPRESSION, Genetics, RISK, tRNA Methyltransferases, Multidisciplinary, Genome, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Loci, BRCA1 Protein, Chromosome Mapping, COMMON VARIANTS, IDENTIFY, PANCREATIC-CANCER, 3. Good health, Multidisciplinary Sciences, Biological sciences, Receptors, Estrogen, Chromosomes, Human, Pair 2, Science & Technology - Other Topics, Female, NAF12, medicine.medical_specialty, Heterozygote, Science, 3122 Cancers, Locus (genetics), Breast Neoplasms, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Pancreatic cancer, MD Multidisciplinary, medicine, Genetic predisposition, Journal Article, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Cancer och onkologi, Science & Technology, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, General Chemistry, Arfgengi, medicine.disease, TRNA Methyltransferases, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, 030104 developmental biology, Cancer and Oncology, Expression quantitative trait loci, Mutation, TELOMERE LENGTH, 3111 Biomedicine, Gene expression, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Genome-Wide Association Study
Abstract

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P, B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.

Published
2018
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3. Bilateral Prophylactic Mastectomy in Swedish Women at High Risk of Breast Cancer

Author

Marie Stenmark Askmalm, Jonas Lundberg, Monica Emanuelsson, Anita Ringberg, Yvonne Brandberg, Niklas Loman, Hans Atterhem, Karin Isaksson, Kerstin Sandelin, Brita Arver, Henrik Hellborg, Karin M. Henriksson, Hans Ehrencrona, Annika Baan, Marie Wickman, Per Karlsson, and Leif Bergkvist

Subjects
Adult, Reoperation, medicine.medical_specialty, medicine.medical_treatment, Breast surgery, Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, Risk Assessment, Breast cancer, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Bilateral Prophylactic Mastectomy, Mastectomy, Aged, Sweden, business.industry, Incidence, Cancer, Middle Aged, medicine.disease, Surgery, Health Care Surveys, Adenocarcinoma, Female, Breast disease, business, Breast reconstruction
Abstract

BACKGROUND/OBJECTIVE:: This study attempted a national inventory of all bilateral prophylactic mastectomies performed in Sweden between 1995 and 2005 in high-risk women without a previous breast malignancy. The primary aim was to investigate the breast cancer incidence after surgery. Secondary aims were to describe the preoperative risk assessment, operation techniques, complications, histopathological findings, and regional differences. METHODS:: Geneticists, oncologists and surgeons performing prophylactic breast surgery were asked to identify all women eligible for inclusion in their region. The medical records were reviewed in each region and the data were analyzed centrally. The BOADICEA risk assessment model was used to calculate the number of expected/prevented breast cancers during the follow-up period. RESULTS:: A total of 223 women operated on in 8 hospitals were identified. During a mean follow-up of 6.6 years, no primary breast cancer was observed compared with 12 expected cases. However, 1 woman succumbed 9 years post mastectomy to widespread adenocarcinoma of uncertain origin. Median age at operation was 40 years. A total of 58% were BRCA1/2 mutation carriers. All but 3 women underwent breast reconstruction, 208 with implants and 12 with autologous tissue. Four small, unifocal, invasive cancers and 4 ductal carcinoma in situ were found in the mastectomy specimens. The incidence of nonbreast related complications was low (3%). Implant loss due to infection/necrosis occurred in 21 women (10%) but a majority received a new implant later. In total, 64% of the women underwent at least 1unanticipated secondary operation. CONCLUSIONS:: Bilateral prophylactic mastectomy is safe and efficacious in reducing future breast cancer in asymptomatic women at high risk. Unanticipated reoperations are common. Given the small number of patients centralization seems justified.

Published
2011
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4. Intact Mre11/Rad50/Nbs1 Complex Predicts Good Response to Radiotherapy in Early Breast Cancer

Author

Marie Stenmark Askmalm, Bo Nordenskjöld, Karin Söderlund, Lars Erik Rutqvist, Lambert Skoog, and Olle Stål

Subjects
Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Estrogen receptor, Breast Neoplasms, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Protein Serine-Threonine Kinases, Breast cancer, MRE11 Homologue Protein, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Chemotherapy, Radiation, business.industry, Tumor Suppressor Proteins, Nuclear Proteins, medicine.disease, Acid Anhydride Hydrolases, Neoplasm Proteins, DNA-Binding Proteins, Radiation therapy, DNA Repair Enzymes, Treatment Outcome, MRN complex, Rad50, Cancer research, Immunohistochemistry, Female, business
Abstract

Purpose To investigate the expression and predictive role of the Mre11/Rad50/Nbs1 (MRN) complex and the ataxia-telangiectasia mutated protein (ATM) for the outcome of radiotherapy in breast cancer patients. Methods and Materials The protein expression of ATM and the DNA repair proteins in the MRN complex were investigated using immunohistochemistry in tumors from 224 women with early breast cancer, who were randomized to receive postoperative radiotherapy or adjuvant chemotherapy. Results Compared with normal breast tissue, the staining intensity of Mre11, Rad50, Nbs1, and ATM was reduced in a majority of the tumors. Weak expression of the MRN complex was correlated with high histologic grade and estrogen receptor negativity (p = 0.01 and p = 0.0001, respectively). Radiotherapy significantly reduced the risk of local recurrence as compared with chemotherapy (p = 0.04). The greatest benefit of radiotherapy was seen in patients with moderate/strong expression of the MRN complex (relative risk = 0.27, 95% confidence interval = 0.098–0.72, p = 0.009), whereas patients with negative/weak MRN expression had no benefit of radiotherapy compared with adjuvant chemotherapy. These results suggest that an intact MRN complex is important for the tumor cell eradicating effect of radiotherapy. Conclusions Reduced expression of the MRN complex predicts a poor effect of radiotherapy in patients with early breast cancer.

Published
2007
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5. Mutation and accumulation of p53 related to results of adjuvant therapy of postmenopausal breast cancer patients

Author

Lars Erik Rutqvist, Birgit Olsson, Olle Stål, John Carstensen, Marie Stenmark Askmalm, Bo Nordenskjöld, and Lambert Skoog

Subjects
Oncology, medicine.medical_specialty, Antineoplastic Agents, Hormonal, Cyclophosphamide, medicine.medical_treatment, Breast Neoplasms, Gene mutation, Breast cancer, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Adjuvant therapy, Humans, Radiology, Nuclear Medicine and imaging, Neoplasm Metastasis, Chemotherapy, business.industry, Hematology, General Medicine, Genes, p53, medicine.disease, Combined Modality Therapy, Postmenopause, Radiation therapy, Tamoxifen, Methotrexate, Treatment Outcome, Chemotherapy, Adjuvant, Mutation, Female, Radiotherapy, Adjuvant, Fluorouracil, Neoplasm Recurrence, Local, Tumor Suppressor Protein p53, business, Adjuvant, medicine.drug
Abstract

p53 protein accumulation and gene mutation have been implicated in resistance to cytotoxic treatment. This study was performed to further assess the predictive value of p53 in breast cancer. Postmenopausal patients were randomized to adjuvant chemotherapy with cyclophosphamide, metothrexate, or 5-fluorouracil (CMF) vs. postoperative radiotherapy. The patients were also randomized to adjuvant tamoxifen vs. no endocrine treatment. Immunohistochemistry (IHC) and single-strand conformation polymorphism (SSCP), followed by direct sequencing, was performed. The p53 altered group, regarded as positive for p53 gene mutation and/or p53 protein accumulation, tended to benefit more from CMF than from radiotherapy as compared with others regarding distant recurrences. In the group lacking p53 alteration there was a significantly decreased local recurrence rate in the radiotherapy group as compared with the CMF group (RR = 0.24, 95% CI = 0.083 0.62), whereas no benefit from radiotherapy was found for patients showing p53 alterations. Tamoxifen significantly decreased the rate of distant recurrence for estrogen receptor-positive patients with no apparent difference in relation to p53 alteration. It is suggested that p53 alteration indicates benefit from CMF compared with radiotherapy regarding distant recurrence-free survival and the best local control with radiotherapy is achieved in the absence of p53 alteration. Finally, altered p53 status is probably not a marker of resistance to tamoxifen.

Published
2004
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6. p53 as a prognostic factor in stage I breast cancer

Author

Bo Nordenskjöld, K Olsen, Olle Stål, and Marie Stenmark-Askmalm

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Pathology, Frozen section procedure, Tumor suppressor gene, Mammary gland, Biology, medicine.disease, Rate ratio, medicine.anatomical_structure, Breast cancer, Internal medicine, medicine, Immunohistochemistry, Stage (cooking), Pathological
Abstract

Accumulation of the tumour-suppressor protein p53 in breast cancer is associated with several prognostic factors that indicate an aggressive, rapidly proliferating tumour with an unstable genome. To assess p53 accumulation in stage I breast cancer and to evaluate the prognostic value of both nuclear and cytoplasmic p53, 205 patients with node-negative breast cancer and tumour size less than or equal to 20 mm were examined. Immunohistochemistry was performed on frozen sections with the monoclonal antibodies PAb 1801 and DO1. Cellular p53 accumulation, within either the nucleus or the cytoplasm or in both, showed the same association with different pathobiological variables as nuclear accumulation alone. Eleven per cent of the tumours showed strong nuclear accumulation and were significantly correlated to age under 50 years, negative oestrogen receptor status, DNA aneuploidy, high S-phase fraction, high pathological grade and poor prognosis. The distant recurrence rate ratio was 6.2 (P = 0.002). It is thus concluded that p53 accumulation is of prognostic value in early stage breast cancer.

Published
1995
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7. P53 Expression and the Result of Adjuvant Therapy of Breast Cancer

Author

Sten Wingren, Marie Stenmark Askmalm, Bo Nordenskjöld, Lambert Skoog, Siw Sullivan, Olle Stål, Lars Erik Rutqvist, John Carstensen, and Lilianne Ferraud

Subjects
Oncology, Antimetabolites, Antineoplastic, medicine.medical_specialty, Cyclophosphamide, medicine.drug_class, medicine.medical_treatment, Mammary gland, Apoptosis, Breast Neoplasms, Antimetabolite, Mastectomy, Modified Radical, Breast cancer, Risk Factors, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Adjuvant therapy, Humans, Radiology, Nuclear Medicine and imaging, Antineoplastic Agents, Alkylating, Postoperative Care, Chemotherapy, business.industry, DNA, Neoplasm, Hematology, General Medicine, Aneuploidy, medicine.disease, Combined Modality Therapy, Immunohistochemistry, Gene Expression Regulation, Neoplastic, Radiation therapy, Methotrexate, medicine.anatomical_structure, Premenopause, Chemotherapy, Adjuvant, Fluorouracil, Cancer research, Female, Neoplasm Recurrence, Local, Tumor Suppressor Protein p53, business, DNA Damage, medicine.drug
Abstract

Functional p53 protein is essential for the cellular response to drug-induced DNA damage. We investigated p53 accumulation in tumour specimens from premenopausal breast cancer patients who were randomised to adjuvant chemotherapy (CMF) or postoperative radiotherapy. Of the tumours from 139 patients, 20 showed abnormal accumulation as judged with immunohistochemistry (>10% positive tumour cells). The risk of distant recurrence was similar in the two treatment groups for patients whose primary tumours lacked p53 accumulation, whereas there was a significant benefit from CMF for patients showing abnormal accumulation (relative risk 0.18, 95% CI, 0.04–0.93). This result suggests that p53–dependent apoptosis is not a general mechanism by which breast cancer cells respond during CMF chemotherapy.

Published
1995
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8. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

Author

Ramus, Susan J., Antoniou, Antonis C., Kuchenbaecker, Karoline B., Penny, Soucy, Jonathan, Beesley, Xiaoqing, Chen, Lesley, Mcguffog, Sinilnikova, Olga M., Sue, Healey, Daniel, Barrowdale, Andrew, Lee, Mads, Thomassen, Anne Marie Gerdes, Kruse, Torben A., Uffe Birk Jensen, Anne Bine Skytte, Caligo, Maria A., Annelie, Liljegren, Annika, Lindblom, Hakan, Olsson, Ulf, Kristoffersson, Marie Stenmark Askmalm, Swe Brca Melin, B., Swe, Brca, Domchek, Susan M., Domchek, Sm, Nathanson, Katherine L., Rebbeck, Timothy R., Anna, Jakubowska, Jan, Lubinski, Katarzyna, Jaworska, Katarzyna, Durda, Elzbieta, Złowocka, Jacek, Gronwald, Tomasz, Huzarski, Tomasz, Byrski, Cezary, Cybulski, Aleksandra Toloczko Grabarek, Ana, Osorio, Javier, Benitez, Mercedes, Duran, Maria Isabel Tejada, Ute, Hamann, Matti, Rookus, Van Leeuwen, Flora E., Aalfs, Cora M., Meijers Heijboer, Hanne E. J., Van Asperen, Christi J., Van Roozendaal, K. E. P., Nicoline, Hoogerbrugge, Collee, Margriet J., Margriet Collee, J., Mieke, Kriege, Hebon Van Der Luijt, R. B., Embrace, Embrace, Hebon, Susan, Peock, Debra, Frost, Ellis, Steve D., Radka, Platte, Elena, Fineberg, Gareth Evans, D., Fiona, Lalloo, Chris, Jacobs, Ros, Eeles, Julian, Adlard, Rosemarie, Davidson, Diana, Eccles, Trevor, Cole, Jackie, Cook, Joan, Paterson, Fiona, Douglas, Carole, Brewer, Shirley, Hodgson, Morrison, Patrick J., Lisa, Walker, Porteous, Mary E., John Kennedy, M., Harsh, Pathak, Godwin, Andrew K., Dominique Stoppa Lyonnet, Virginie Caux Moncoutier, Antoine Pauw, D. E., De Pauw, A., Marion Gauthier Villars, Sylvie, Mazoyer, Melanie, Leone, Alain, Calender, Christine, Lasset, Valerie, Bonadona, Agnes, Hardouin, Pascaline, Berthet, Yves Jean Bignon, Nancy, Uhrhammer, Laurence, Faivre, Catherine, Loustalot, Gemo, Saundra, Buys, Mary, Daly, Buys, Daly, S., Alex, Miron, Beth, Terry M., Mary Beth Terry, Terry, M. B., Chung, Wendy K., Esther, John M., John, Em, Melissa, Southey, David, Goldgar, Singer, Christian F., Muy Kheng Tea, Georg, Pfeiler, Anneliese Fink Retter, Hansen, Thomas V. O., Hansen, Tv, Bent, Ejlertsen, Oskar Th Johannsson, Kenneth, Offit, Tomas, Kirchhoff, Gaudet, Mia M., Joseph, Vijai, Mark, Robson, Marion, Piedmonte, Kelly Anne Phillips, Linda Van Le, Hoffman, James S., Amanda Ewart Toland, Ewart Toland, A., Marco, Montagna, Silvia, Tognazzo, Evgeny, Imyanitov, Claudine, Isaacs, Issacs, C., Ramunas, Janavicius, Conxi, Lazaro, Ignacio, Blanco, Eva, Tornero, Matilde, Navarro, Moysich, Kirsten B., Karlan, Beth Y., Jenny, Gross, Edith, Olah, Tibor, Vaszko, Soo Hwang Teo, Ganz, Patricia A., Beattie, Mary S., Dorfling, Cecelia M., Van Rensburg, Elizabeth J., Orland, Diez, Ava, Kwong, Schmutzler, Rita K., Barbara, Wappenschmidt, Christoph, Engel, Alfons, Meindl, Nina, Ditsch, Norbert, Arnold, Simone, Heidemann, Dieter, Niederacher, Sabine Preisler Adams, Dorotehea, Gadzicki, Raymonda Varon Mateeva, Helmut, Deissler, Andrea, Gehrig, Christian, Sutter, Karin, Kast, Britta, Fiebig, Dieter, Schafer, Trinidad, Caldes, Miguel De La Hoya, Heli, Nevanlinna, Kristiina, Aittomaki, Marie, Plante, Kconfab Spurdle, A. B., Kconfab, Neuhausen, Susan L., Neuhausen, Sl, Yuan Chun Ding, Xianshu, Wang, Noralane, Lindor, Zachary, Fredericksen, Shane Pankratz, V., Paolo, Peterlongo, Siranoush, Manoukian, Bernard, Peissel, Daniela, Zaffaroni, Bernardo, Bonanni, Loris, Bernard, Riccardo, Dolcetti, Laura, Papi, Ottini, Laura, Paolo, Radice, Greene, Mark H., Mai, Phuong L., Andrulis, Irene L., Gord, Glendon, Ocgn Ozcelik, H., Ocgn, Pharoah, Paul D. P., Pharoah, Pd, Gayther, Simon A., Jacques, Simard, Easton, Douglas F., Couch, Fergus J., Georgia Chenevix Trench, Behalf Of The Consortium Of Investigators Of Modifiers Of Brca1/2, O. N., 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), Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Universitat de Barcelona, Genetica & Celbiologie, MUMC+: DA KG Lab Centraal Lab (9), RS: CARIM School for Cardiovascular Diseases, RS: GROW - School for Oncology and Reproduction, and Clinical Genetics

Subjects
Oncology, endocrine system diseases, [SDV]Life Sciences [q-bio], Càncer d'ovari, DCN PAC - Perception action and control, Cohort Studies, Breast cancer, 0302 clinical medicine, brca1, brca2, Odds Ratio, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Ovarian Neoplasms, Genetics, 0303 health sciences, education.field_of_study, BRCA1 Protein, Hazard ratio, Middle Aged, 3. Good health, ovarian cancer, 030220 oncology & carcinogenesis, Female, Adult, Heterozygote, medicine.medical_specialty, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], Population, Single-nucleotide polymorphism, Biology, Ovarian Neoplasms - genetics, Polymorphism, Single Nucleotide, Article, Càncer de mama, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Ovarian cancer, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], education, Retrospective Studies, 030304 developmental biology, BRCA2 Protein, Hereditary cancer and cancer-related syndromes [ONCOL 1], association, Retrospective cohort study, snp, Odds ratio, BRCA1 Protein - genetics, medicine.disease, BRCA2 Protein - genetics, Mutation
Abstract

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 x 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 x 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 x 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer., link_to_OA_fulltext

Published
2012
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9. Cellular accumulation of p53 protein: an independent prognostic factor in stage II breast cancer

Author

Olle Stål, Lilianne Ferraud, Marie Stenmark-Askmalm, Xiao-Feng Sun, John Carstensen, Bo Nordenskjöld, and Siw Sullivan

Subjects
Cytoplasm, Cancer Research, Receptor, ErbB-2, medicine.drug_class, Mammary gland, Breast Neoplasms, Biology, Monoclonal antibody, Gene product, Breast cancer, Proto-Oncogene Proteins, Gene expression, medicine, Humans, Lymph node, Cell Nucleus, DNA, Neoplasm, Middle Aged, Prognosis, medicine.disease, Immunohistochemistry, Survival Analysis, ErbB Receptors, medicine.anatomical_structure, Receptors, Estrogen, Oncology, Cancer research, Female, Tumor Suppressor Protein p53
Abstract

The p53 gene product is a tumour suppressor protein, and alterations of the protein are common in human cancer. Previous studies have focused on nuclear accumulation of p53. To investigate if cytoplasmic accumulation of p53 strengthens the relationships to different pathobiological variables and distant recurrence-free survival in breast cancer, tumours from 164 stage II patients were examined with the monoclonal antibody PAb1801. Nine per cent of the tumours were nuclear positive and 21% were cytoplasmic positive. Cellular p53 accumulation, related to the nucleus or the cytoplasm or both, showed stronger associations with pathobiological variables than nuclear accumulation alone. Accumulation of p53 was significantly correlated to tumour size over 20 mm, negative oestrogen receptor (ER) status, DNA aneuploidy, high S-phase fraction and positive erbB-2 status. Cytoplasmic p53 was significantly correlated to distance recurrence-free survival in patients negative for nuclear p53 (P < 0.0001). Cellular p53 accumulation was an independent prognostic factor, in addition to lymph node status and ER content. We conclude that consideration of cytoplasmic staining enhances the clinical importance of p53.

Published
1994
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10. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

Author

Thomas v O Hansen, Amanda B. Spurdle, Anne-Marie Gerdes, Sue Healey, Per Karlsson, Tomasz Huzarski, Mary B. Daly, Mary Porteous, T. Caldes, Ulf Kristoffersson, Ignacio Blanco, A. Miron, Laurence Faivre, Barbara Wappenschmidt, Laurence Venat-Bouvet, Marie Stenmark Askmalm, Olga M. Sinilnikova, Susan Peock, Alessandra Viel, Conxi Lázaro, Katherine L. Nathanson, Laurent Castera, Douglas F. Easton, Susan L. Neuhausen, Jan Lubinski, Phuong L. Mai, Virginie Moncoutier, Paolo Radice, Heli Nevanlinna, Christi J Asperen, Xianshu Wang, Brita Arver, Christian Sutter, Senno Verhoef, Rosette Lidereau, Mary S Beattie, Bjarni A Agnarsson, Ina Ruehl, Monica Barile, Bent Ejlertsen, Laura Ottini, Catherine Noguès, Jennifer A. Przybylo, Cinzia Casella, Trevor Cole, Norbert Arnold, Sandra Fert-Ferrer, Hilmi Ozcelik, Irene L. Andrulis, Susan M. Domchek, Valérie Bonadona, Kirsten B. Moysich, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Beth Y. Karlan, Jenny Gross, Gaia Roversi, Tadeusz Dębniak, Hanne Meijers-Heijboer, Susan J. Ramus, Dorthe G. Crüger, Zachary S. Fredericksen, Siranoush Manoukian, Viviana Gismondi, Maria A. Caligo, Helene Holland, Laure Barjhoux, Gord Glendon, Ana Osorio, Jacques Simard, John L. Hopper, Mercedes Durán, Kristiina Aittomäki, Håkan Olsson, Mads Thomassen, Fabio Capra, Patrick J. Morrison, Britta Fiebig, Mary Beth Terry, Marinus J. Blok, Evgeny N. Imyanitov, Joseph Vijai, Javier Benitez, Mark T. Rogers, D. Gareth Evans, Helmut Deissler, Tomasz Byrski, Sylvie Mazoyer, Laura Papi, Dominique Stoppa-Lyonnet, Marco Montagna, Kenneth Offit, Cezary Cybulski, Dominique Leroux, Georgia Chenevix-Trench, Danielle Bodmer, Lucy Side, Margaret Cook, Ros Eeles, Alan Donaldson, Christiana Kartsonaki, Carole Brewer, Matti A. Rookus, Jacek Gronwald, Dorothea Gadzicki, Shirley Hodgson, Jonathan Beesley, Gabriella Pichert, Andrew K. Godwin, Dieter Niederacher, Yuan Chun Ding, Torben A Kruse, Paolo Peterlongo, Rita K. Schmutzler, Xiaoqing Chen, Annika Lindblom, Fergus J. Couch, Maaike P.G. Vreeswijk, Mark H. Greene, Esther M. John, Raymonda Varon-Mateeva, Simon A. Gayther, Margreet G. E. M. Ausems, Tomas Kirchhoff, Lars Jønson, Madeleine M. A. Tilanus-Linthorst, Ute Hamann, Marie-Agnès Collonge-Rame, Antonis C. Antoniou, M John Kennedy, Karin Kast, Theo A. M. van Os, Penny Soucy, Debra Frost, Alison M. Dunning, Daniela Zaffaroni, Anna Allavena, Maria-Isabel Tejada, Yves-Jean Bignon, Lesley McGuffog, Bohdan Górski, Åke Borg, Fabienne Prieur, Bernard Peissel, Helen Gregory, Clare Oliver, Saundra S. Buys, Ana Dutra-Clarke, Alfons Meindl, Ramunas Janavicius, Uffe Birk Jensen, Miguel de la Hoya, Ramus, S, Kartsonaki, C, Gayther, S, Pharoah, P, Sinilnikova, O, Beesley, J, Chen, X, Mcguffog, L, Healey, S, Couch, F, Wang, X, Fredericksen, Z, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Allavena, A, Ottini, L, Papi, L, Gismondi, V, Capra, F, Radice, P, Greene, M, Mai, P, Andrulis, I, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A, Kruse, T, Cruger, D, Jensen, U, Caligo, M, Olsson, H, Kristoffersson, U, Lindblom, A, Arver, B, Karlsson, P, Stenmark Askmalm, M, Borg, A, Neuhausen, S, Ding, Y, Nathanson, K, Domchek, S, Jakubowska, A, Lubiński, J, Huzarski, T, Byrski, T, Gronwald, J, Górski, B, Cybulski, C, Dębniak, T, Osorio, A, Durán, M, Tejada, M, Benítez, J, Hamann, U, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Bodmer, D, Ausems, M, van Os, T, Asperen, C, Blok, M, Meijers Heijboer, H, Peock, S, Cook, M, Oliver, C, Frost, D, Dunning, A, Evans, D, Eeles, R, Pichert, G, Cole, T, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Kennedy, M, Rogers, M, Side, L, Donaldson, A, Gregory, H, Godwin, A, Stoppa Lyonnet, D, Moncoutier, V, Castera, L, Mazoyer, S, Barjhoux, L, Bonadona, V, Leroux, D, Faivre, L, Lidereau, R, Nogues, C, Bignon, Y, Prieur, F, Collonge Rame, M, Venat Bouvet, L, Fert Ferrer, S, Miron, A, Buys, S, Hopper, J, Daly, M, John, E, Terry, M, Goldgar, D, Hansen, T, Jønson, L, Ejlertsen, B, Agnarsson, B, Offit, K, Kirchhoff, T, Vijai, J, Dutra Clarke, A, Przybylo, J, Montagna, M, Casella, C, Imyanitov, E, Janavicius, R, Blanco, I, Lázaro, C, Moysich, K, Karlan, B, Gross, J, Beattie, M, Schmutzler, R, Wappenschmidt, B, Meindl, A, Ruehl, I, Fiebig, B, Sutter, C, Arnold, N, Deissler, H, Varon Mateeva, R, Kast, K, Niederacher, D, Gadzicki, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Aittomäki, K, Simard, J, Soucy, P, Spurdle, A, Holland, H, Chenevix Trench, G, Easton, D, Antoniou, A, Faculteit Medische Wetenschappen/UMCG, 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), Klinische Genetica, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Clinical Genetics, Pediatric Surgery, Human genetics, CCA - Oncogenesis, and Human Genetics

Subjects
Oncology, Cancer Research, endocrine system diseases, Genes, BRCA2, Genes, BRCA1, Genome-wide association study, FAMILIES, 0302 clinical medicine, Risk Factors, Retrospective Studie, Genotype, Odds Ratio, skin and connective tissue diseases, POPULATION, Genetics, Ovarian Neoplasms, Aged, 80 and over, Allele, 0303 health sciences, education.field_of_study, Likelihood Functions, Articles, GERMLINE MUTATIONS, Middle Aged, Likelihood Function, female genital diseases and pregnancy complications, 3. Good health, 030220 oncology & carcinogenesis, Female, Chromosomes, Human, Pair 9, Human, Adult, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], medicine.medical_specialty, Heterozygote, SUSCEPTIBILITY LOCI, PROTEINS, Population, Biology, Polymorphism, Single Nucleotide, BASONUCLIN-2, 03 medical and health sciences, Breast cancer, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, medicine, BREAST-CANCER, Humans, GENOME-WIDE ASSOCIATION, education, Alleles, Germ-Line Mutation, 030304 developmental biology, Retrospective Studies, Aged, IDENTIFICATION, Risk Factor, Ovarian Neoplasm, Editorials, Cancer, medicine.disease, Minor allele frequency, Ovarian cancer
Abstract

[Background]: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. [Methods]: We genotyped rs3814113 in 10 029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. [Results]: The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. [Conclusion]: Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation., Spanish National Cancer Center (CNIO) and the Spanish Consortium: Partially supported by Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, and the Spanish Ministry of Science and Innovation (FIS PI08 1120).

Published
2011
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11. Low expression of Ku70/80, but high expression of DNA-PKcs, predict good response to radiotherapy in early breast cancer

Author

Marie Stenmark Askmalm, Tommy Fornander, Siv Queseth, and Karin Söderlund Leifler

Subjects
Cancer Research, Cyclophosphamide, DNA repair, medicine.medical_treatment, Down-Regulation, Breast Neoplasms, DNA-Activated Protein Kinase, Biology, Disease-Free Survival, Breast cancer, medicine, Humans, Breast, Ku Autoantigen, Randomized Controlled Trials as Topic, Chemotherapy, Oncogene, Carcinoma, Cancer, Nuclear Proteins, Antigens, Nuclear, medicine.disease, Prognosis, Immunohistochemistry, Up-Regulation, Radiation therapy, DNA-Binding Proteins, Treatment Outcome, Oncology, Tissue Array Analysis, Cancer research, Disease Progression, Female, Breast disease, Tumor Suppressor Protein p53, medicine.drug
Abstract

The purpose was to study the prognostic and predictive roles of DNA protein kinase catalytic subunit (DNA-PKcs), Ku70/80 and p53 for the effect of radiotherapy in breast cancer patients. Protein expressions of Ku70/80, DNA-PKcs and p53 were examined using immunohistochemistry in tumours from 224 breast cancer patients, who were randomised to receive post-operative radiotherapy or adjuvant chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracil). One hundred and twenty-nine (60%) of the tumours had low expression of Ku70/80, 122 (57%) had low expression of DNA-PKcs and 65 (30%) had altered p53 expression. None of the proteins were indicative to the prognosis of local recurrence-free survival. Even though the expression of Ku70/80 and DNA-PKcs correlated well, they were not associated with treatment outcome in the same way. Low expression of Ku70/80 predicted good effect of radiotherapy (RR=0.31, 95% CI 0.13-0.76, p=0.01). In contrast, the greatest benefit of radiotherapy over chemotherapy was seen in patients with high DNA-PKcs expression (RR=0.25, 95% CI 0.07-0.84, p=0.02). Altered p53 expression predicted poor response to radiotherapy. We believe that the results reflect the different roles of DNA-PKcs and Ku70/80 in repair and cell death regulation after DNA damage. These differences could be of importance when developing drugs that target DNA repair.

Published
2010

12. Improved survival for women with stage I breast cancer in south-east Sweden: a comparison between two time periods before and after increased use of adjuvant systemic therapy

Author

Patrik Johansson, Helena Fohlin, Lars-Gunnar Arnesson, Monika Dufmats, Kerstin Nordenskjöld, Bo Nordenskjöld, Olle Stål, null The South-East Sweden Breast Cancer, Måns Agrup, Bengt Asking, Tord Blomkvist, Harald Bång, Charlotta Dabrosin, Eibert Einarsson, Rune Gustavsson, Claes Klintenberg, Barbro Linderholm, Annika Malmström, Rebecka Malterling, Marie Sundquist, Bengt Norberg, Ann Rundcrantz, Peter Skoog, Hans Starkhammar, Marie Stenmark Askmalm, Göran Tejler, Sten Thorstenson, Susanne Vahlin, and Bedrich Vitak

Subjects
Adult, medicine.medical_specialty, Antineoplastic Agents, Hormonal, medicine.medical_treatment, Population, Breast Neoplasms, Kaplan-Meier Estimate, Mastectomy, Segmental, Systemic therapy, Risk Assessment, Disease-Free Survival, Breast cancer, Risk Factors, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Odds Ratio, Humans, Radiology, Nuclear Medicine and imaging, education, Neoplasm Staging, Proportional Hazards Models, Gynecology, Sweden, education.field_of_study, business.industry, MEDICINE, Cytotoxins, Mortality rate, Hematology, General Medicine, Odds ratio, Middle Aged, medicine.disease, MEDICIN, Treatment Outcome, Oncology, Receptors, Estrogen, Chemotherapy, Adjuvant, Cohort, Multivariate Analysis, Female, business, Receptors, Progesterone, Tamoxifen, Mastectomy, medicine.drug
Abstract

Purpose. Continuous minor steps of improvement in the management of breast cancer have resulted in decreased mortality rates during the last decades. The aim of this study was to compare the clinical outcome of patients with stage I breast cancer diagnosed during two time periods that differed with respect to adjuvant systemic therapy. Material and methods. The studied population consisted of all women 60 years of age, who were diagnosed breast cancer stage I between 1986 and 1999 in south-east Sweden, a total of 1 407 cases. The cohort was divided into two groups based on the management programmes of 1986 and 1992, hereafter referred to as Period 1 and Period 2. Before 1992 the only adjuvant systemic therapy recommended was tamoxifen for hormone receptor positive patients aged 50 years or older. During Period 2 the use of adjuvant treatment was extended to younger patients at high risk, identified by a high tumour S-phase fraction, with either hormonal or cytotoxic treatment. Results. The estimated distant recurrence-free survival rate was significantly higher during Period 2 than during Period 1 (p = 0.008). Subgroup analysis showed that the most evident reduction of distant recurrence risk was among hormone receptor-negative patients (HR = 0.58, 95% CI 0.31-1.09, p = 0.09) and among patients with a high tumour S-phase fraction (HR = 0.53, 0.30-0.93, p = 0.028). The risk reduction between the periods was still statistically significant in multivariate analysis when adjusting for different tumour characteristics and treatment modalities, indicating an influence of other factors not controlled for. One such factor may be the duration of tamoxifen treatment, which likely was more frequently five years during Period 2 than during Period 1. Conclusions. We conclude that the causes of the increase in distant recurrence free survival for women with breast cancer stage I are complex. The results support though that high-risk subgroups of stage I breast cancer patients did benefit from increased use of systemic therapy as a consequence of an updated management programme. This is an electronic version of an article published in: Patrik Johansson, Helena Fohlin, Lars-Gunnar Arnesson, Monika Dufmats, Kerstin Nordenskjoeld, Bo Nordenskjöld and Olle Stål, Improved survival for women with stage I breast cancer in south-east Sweden: A comparison between two time periods before and after increased use of adjuvant systemic therapy, 2009, ACTA ONCOLOGICA, (48), 4, 504-513. ACTA ONCOLOGICA is available online at informaworldTM: http://dx.doi.org/10.1080/02841860902718754 Copyright: Taylor & Francis http://www.tandf.co.uk/journals/default.aspGroup Author(s):The South-East Sweden Breast Cancer Study GroupAnnika Malmström, Linköping University

Published
2009

13. A new polymorphism in the coding region of exon four in HSD17B2 in relation to risk of sporadic and hereditary breast cancer

Author

Agneta Jansson, Sara Margolin, Petter Storm, Marie Stenmark-Askmalm, Anette Olsson, Jonas Carlsson, Cecilia Gunnarsson, Annika Lindblom, Bengt Persson, and Olle Stål

Subjects
Models, Molecular, Cancer Research, medicine.medical_specialty, Protein Conformation, DNA Mutational Analysis, Breast Neoplasms, Biology, Risk Assessment, Gene Expression Regulation, Enzymologic, Estradiol Dehydrogenases, Exon, Breast cancer, Risk Factors, Internal medicine, Catalytic Domain, Cell Line, Tumor, Genotype, medicine, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, Gene, Polymorphism, Single-Stranded Conformational, Aged, Regulation of gene expression, Case-control study, Cancer, Single-strand conformation polymorphism, Exons, Middle Aged, medicine.disease, Pedigree, Gene Expression Regulation, Neoplastic, Endocrinology, Oncology, Case-Control Studies, Cancer research, Female
Abstract

In situ synthesis of oestrogens is of great importance in the development and progression of breast cancer. 17beta-hydroxysteroid dehydrogenase (17HSD) type 2 catalyses oxidation from oestradiol to oestrone, and thereby protects the breast epithelial cells from oestradiol. Low expression of 17HSD type 2 has been associated with decreased survival in breast cancer, but no studies have investigated the mechanism behind the low expression. The 17HSD type 2 gene (HSD17B2) was screened for mutations with Single Stranded Conformation Polymorphism (SSCP)-DNA sequencing in 59 sporadic breast cancer cases, 19 hereditary breast cancer cases and seven breast cancer cell lines. DNA samples from 226 healthy individuals were used to identify if changes were previously unknown polymorphisms. No mutation was detected and therefore mutations in HSD17B2 do not explain why some breast tumours exhibit low 17HSD type 2 expression. However, a previously unknown polymorphism was found in exon four (Met226Val). Using molecular modelling, we found that the substituted residue is located at the outer part of the steroid binding site, probably causing minor alterations in the substrate binding. We further studied if the polymorphism contributes to breast cancer susceptibility in a larger material, but did not find an increased risk in the group of 317 sporadic breast cancer patients, 188 breast cancer patients with two close relatives with breast cancer or 122 hereditary breast cancer patients, compared to the healthy control group. We suggest that the detected polymorphism does not contribute to a higher risk of developing breast cancer.

Published
2006

14. p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients

Author

Sten Wingren, Pia Wegman, Marie Stenmark Askmalm, Bo Nordenskjöld, L E Rutqvist, and Olle Stål

Subjects
medicine.medical_specialty, Tumor suppressor gene, Antineoplastic Agents, Hormonal, Breast Neoplasms, Biology, Breast cancer, Internal medicine, Genetics, medicine, Humans, General Pharmacology, Toxicology and Pharmaceutics, Aromatase, skin and connective tissue diseases, Receptor, Codon, Molecular Biology, Genetics (clinical), Alleles, Predictive marker, Polymorphism, Genetic, Genetic Variation, medicine.disease, Genes, p53, Menopause, Tamoxifen, Endocrinology, Treatment Outcome, Chemotherapy, Adjuvant, biology.protein, Molecular Medicine, Female, Radiotherapy, Adjuvant, medicine.drug, Hormone
Abstract

Oestrogen is one of the most important hormonal regulators and is known to play a key role in the development and growth of breast cancer. The majority of tumours have a hormone dependent growth, and this is indicated by the presence of oestrogen receptors (ERs). About two thirds of breast cancers occur after the menopause when the ovaries have ceased to produce oestrogen and despite the low levels of circulating oestrogen’s the tumour concentrations of oestrone, oestradiol and their sulfates have been shown to be significant. Patients with hormone dependent tumours are candidates for treatment with the anti-oestrogen tamoxifen, which acts by competing with oestrogen for binding to the ER thereby, diminish the transcription of oestrogen regulated genes. The drug is mainly metabolised by cytochrome P450 enzymes in the liver and to a lesser extent locally in the breast, where upon several produced metabolites have higher affinity for the ER than the mother substance. Patients treated with tamoxifen have in general a prolonged disease-free survival. Even if most patients respond well to tamoxifen about 30-50 % either fail to respond or become resistant by incompletely understood mechanisms. Therefore, the aim of this thesis was to investigate possible mechanisms responsible for tamoxifen resistance. In paper I and II we studied genetic variants of enzymes participating in the metabolism of tamoxifen and assessed whether these variants correlated to breast cancer prognosis and/or to the benefit of tamoxifen. The results indicate an influence of CYP2D6, CYP3A5, and SULT1A1 genotypes in tamoxifen response. Further, tamoxifen has shown to compete with oestrogen for the binding to ER. In paper III we measured the expression levels of enzymes involved in the local synthesis of oestrogens in order to see if they correlated to clinical outcome. The protein expression of stromal aromatase was shown to have a prognostic significance, especially in ER-positive patients. Finally, tamoxifen and its ER-active metabolites have shown to induce both cell cycle arrest and apoptosis and one central mediator in these processes is the tumour suppressor protein p53. The proapoptotic activity of p53 is dependent on a proline rich domain containing a common Pro-to-Arg polymorphism. In paper IV we examined the value of this genetic variant as a predictive marker for anti-cancer therapy and found that patients carrying the Pro-allele might be good responders of tamoxifen therapy. The present thesis further indicates the complexity of the mechanisms underlying tamoxifen resistance. In summary, genetic variants of metabolic enzymes, genetic variants in p53, as well as expression levels of enzymes involved in local oestrogen synthesis, may have influence on breast cancer prognosis and may be useful markers in the prediction of tamoxifen response.

Published
2006

15. A new polymorphism in the coding region of exon four in HSD17B2 in relation to risk of sporadic and hereditary breast cancer.

Author

Agneta Jansson, Jonas Carlsson, Anette Olsson, Petter Storm, Sara Margolin, Cecilia Gunnarsson, Marie Stenmark-Askmalm, Annika Lindblom, Bengt Persson, and Olle Stål

Subjects
EXONS (Genetics), BREAST cancer, GENETIC polymorphisms, SPLIT genes
Abstract

Abstract  In situ synthesis of oestrogens is of great importance in the development and progression of breast cancer. 17β-hydroxysteroid dehydrogenase (17HSD) type 2 catalyses oxidation from oestradiol to oestrone, and thereby protects the breast epithelial cells from oestradiol. Low expression of 17HSD type 2 has been associated with decreased survival in breast cancer, but no studies have investigated the mechanism behind the low expression. The 17HSD type 2 gene (HSD17B2) was screened for mutations with Single Stranded Conformation Polymorphism (SSCP)-DNA sequencing in 59 sporadic breast cancer cases, 19 hereditary breast cancer cases and seven breast cancer cell lines. DNA samples from 226 healthy individuals were used to identify if changes were previously unknown polymorphisms. No mutation was detected and therefore mutations in HSD17B2 do not explain why some breast tumours exhibit low 17HSD type 2 expression. However, a previously unknown polymorphism was found in exon four (Met226Val). Using molecular modelling, we found that the substituted residue is located at the outer part of the steroid binding site, probably causing minor alterations in the substrate binding. We further studied if the polymorphism contributes to breast cancer susceptibility in a larger material, but did not find an increased risk in the group of 317 sporadic breast cancer patients, 188 breast cancer patients with two close relatives with breast cancer or 122 hereditary breast cancer patients, compared to the healthy control group. We suggest that the detected polymorphism does not contribute to a higher risk of developing breast cancer. [ABSTRACT FROM AUTHOR]

Published
2007
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16. Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer

Author

Anna Öfverholm, Therese Törngren, Anna Rosén, Brita Arver, Zakaria Einbeigi, Karin Haraldsson, Anne Kinhult Ståhlbom, Ekaterina Kuchinskaya, Annika Lindblom, Beatrice Melin, Ylva Paulsson-Karlsson, Marie Stenmark-Askmalm, Emma Tham, Anna von Wachenfeldt, Anders Kvist, Åke Borg, and Hans Ehrencrona

Subjects
BRCA1, BRCA2, Genetic testing, Cancer, Breast cancer, Ovarian cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Genetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting. Methods Women with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records. Results In 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding. Conclusions This study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.

Published
2023
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