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6 results on '"Pohlreich Petr"'

1. The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer.

Author

Janatova M, Kleibl Z, Stribrna J, Panczak A, Vesela K, Zimovjanova M, Kleiblova P, Dundr P, Soukupova J, and Pohlreich P

Subjects
Base Sequence, Breast Neoplasms pathology, Case-Control Studies, DNA Mutational Analysis methods, Fanconi Anemia Complementation Group N Protein, Female, Gene Deletion, Genetic Predisposition to Disease, Humans, Molecular Sequence Data, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Pedigree, Prevalence, Risk Factors, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Nuclear Proteins genetics, Tumor Suppressor Proteins genetics
Abstract

Background: Several reports indicate that inherited mutations in the PALB2 gene predispose to breast cancer. However, there is little agreement about the clinical relevance and usefulness of mutation screening in this gene. We analyzed the prevalence and spectrum of germline mutations in PALB2 to estimate their contribution to hereditary breast and/or ovarian cancer in the Czech Republic., Methods: The entire PALB2 coding region was sequenced in 409 breast/ovarian cancer patients negative for BRCA1 and BRCA2 mutations. Testing for large genomic rearrangements (LGR) was performed by multiplex ligation-dependent probe amplification (MLPA) analysis., Results: We have identified 13 different pathogenic alterations including 10 truncating mutations and three LGRs in 16 of 409 patients (3.9%), whereas one truncating mutation was found in a group of 1,226 controls (0.08%; P = 2.6 × 10(-9)). Three novel LGRs included deletions involving exons 7-8 and 9-10, respectively, and a duplication spanning exons 9-11. Five frameshift and two nonsense mutations were novel, whereas three truncating mutations were described previously. The only recurrent mutation was the c.172_175delTTGT detected in four unrelated breast cancer individuals., Conclusions: Our analyses demonstrated the significant role of the PALB2 gene in breast cancer susceptibility. The highest frequency of PALB2 mutations (comparable with that previously reported for BRCA2) was found in a subgroup of patients with hereditary breast cancer (HBC) (13/235; 5.5%)., Impact: Our results show that mutation analysis of the PALB2 gene, including the analysis of LGRs, is primarily indicated in patients with HBC in case of their BRCA1 and BRCA2 negativity., (©2013 AACR.)

Published
2013
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2. Novel complex genomic rearrangement of the BRCA1 gene.

Author

Zikan M, Pohlreich P, Stribrna J, Kleibl Z, and Cibula D

Subjects
Czech Republic, Female, Gene Rearrangement, Genes, BRCA2, Humans, Breast Neoplasms genetics, Genes, BRCA1, Germ-Line Mutation, Ovarian Neoplasms genetics
Abstract

Initial BRCA1 and BRCA2 analyses conducted in breast and ovarian cancer families were focused on identification of mutations in coding sequences and splicing sites of the genes. Large genomic rearrangements as well as mutations in promoter or untranslated regions have been missed by standard detection strategies. Nevertheless, in Western countries, a detailed study of families with strong linkage to BRCA1 identified large genomic deletions and rearrangements in this gene as early as 1997. To date, no such gene alteration has been described in Central and Eastern European populations. In our study of BRCA1/2 genes in the Czech population, we have detected a complex genomic rearrangement in BRCA1 using RNA-based analysis for mutation screening. This rearrangement involves exons 21 and 22 and results in a protein product lacking BRCT domain important for its function.

Published
2008
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4. Novel somatic mutations in the BRCA1 gene in sporadic breast tumors.

Author

Janatova M, Zikan M, Dundr P, Matous B, and Pohlreich P

Subjects
Adult, Aged, BRCA1 Protein physiology, Carcinoma, Ductal, Breast genetics, Cell Transformation, Neoplastic genetics, Codon, Nonsense, DNA Mutational Analysis, DNA, Neoplasm genetics, Female, Genes, BRCA2, Humans, Loss of Heterozygosity, Microsatellite Repeats, Middle Aged, Sequence Analysis, DNA, Breast Neoplasms genetics, Frameshift Mutation, Genes, BRCA1
Abstract

Germline mutations in two major susceptibility genes BRCA1 and BRCA2 contribute to the majority of inherited breast and ovarian cancers. Besides the germline mutation, tumor progression depends on the loss of a wild-type allele. Allelic losses in the BRCA1 and BRCA2 loci have also been detected in a high proportion of sporadic breast tumors, suggesting the role of these genes in the development of non-inherited breast cancer. Forty unselected breast tumors were analyzed for the loss of heterozygosity (LOH) at BRCA1 and BRCA2 regions and tumors with allelic deletions were screened for the presence of acquired genetic alterations in respective genes. 21.1% of 38 informative tumor samples carried LOH at the BRCA1 locus whereas 33.3% of 39 informative samples showed LOH at the BRCA2 locus. Pathogenic truncating mutations in the BRCA1 gene were found in two tumor samples with allelic losses, whereas no mutations were identified in the BRCA2 gene. Mutations were not detected in non-tumor samples from the same individuals, which indicated that the BRCA1 allele was inactivated by somatic mutations in tumor tissue. The c.1116G>A (1235G>A) nonsense mutation (p.W372X) belongs to the genetic abnormalities detected infrequently in hereditary tumors; the c.3862delG (3981delG) frameshift mutation (p.E1288fsX1306) is a novel gene alteration. The occurrence of inactivating somatic mutations in sporadic breast tumors suggested the role of the BRCA1 gene in tumorigenesis in at least a minor group of patients with non-familial breast cancer., ((c) 2005 Wiley-Liss, Inc.)

Published
2005
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5. High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area.

Author

Pohlreich P, Zikan M, Stribrna J, Kleibl Z, Janatova M, Kotlas J, Zidovska J, Novotny J, Petruzelka L, Szabo C, and Matous B

Subjects
Czech Republic epidemiology, DNA Mutational Analysis, DNA, Neoplasm blood, DNA, Neoplasm genetics, Ethnicity genetics, Exons, Family, Female, Gene Amplification, Genes, BRCA2, Humans, Polymerase Chain Reaction, RNA, Neoplasm blood, RNA, Neoplasm genetics, Risk Factors, Breast Neoplasms genetics, Genes, BRCA1, Ovarian Neoplasms genetics
Abstract

Background: Germline mutations in the BRCA1 and BRCA2 genes have been shown to account for the majority of hereditary breast and ovarian cancers. The purpose of our study was to estimate the incidence and spectrum of pathogenic mutations in BRCA1/2 genes in high-risk Czech families., Methods: A total of 96 Czech families with recurrent breast and/or ovarian cancer and 55 patients considered to be at high-risk but with no reported family history of cancer were screened for mutations in the BRCA1/2 genes. The entire coding sequence of each gene was analyzed using a combination of the protein truncation test and direct DNA sequencing., Results: A total of 35 mutations in the BRCA1/2 genes were identified in high-risk families (36.5%). Pathogenic mutations were found in 23.3% of breast cancer families and in 59.4% of families with the occurrence of both breast and ovarian cancer. In addition, four mutations were detected in 31 (12.9%) women with early onset breast cancer. One mutation was detected in seven (14.3%) patients affected with both a primary breast and ovarian cancer and another in three (33.3%) patients with a bilateral breast cancer. A total of 3 mutations in BRCA1 were identified among 14 (21.4%) women with a medullary breast carcinoma. Of 151 analyzed individuals, 35 (23.2%) carried a BRCA1 mutation and 9 (6.0%) a BRCA2 mutation. One novel truncating mutation was found in BRCA1 (c.1747A>T) and two in BRCA2 (c.3939delC and c.5763dupT). The 35 identified BRCA1 mutations comprised 13 different alterations. Three recurrent mutations accounted for 71.4% of unrelated individuals with detected gene alterations. The BRCA1 c.5266dupC (5382insC) was detected in 51.4% of mutation positive women. The mutations c.3700_3704del5 and c.181T>G (300T>G) contributed to 11.4% and 8.6% of pathogenic mutations, respectively. A total of eight different mutations were identified in BRCA2. The novel c.5763dupT mutation, which appeared in two unrelated families, was the only recurrent alteration of the BRCA2 gene identified in this study., Conclusion: Mutational analysis of BRCA1/2 genes in 151 high-risk patients characterized the spectrum of gene alterations and demonstrated the dominant role of the BRCA1 c.5266dupC allele in hereditary breast and ovarian cancer.

Published
2005
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6. 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 Med Ctr, Walnut Creek, CA USA [ 31 ] City Hope Natl Med Ctr, Clin Canc Genet Community Res Network, Duarte, CA 91010 USA [ 32 ] Ist FIRC Oncol Mol IFOM, I-20139 Milan, Italy [ 33 ] Ist Nazl Tumori, IRCCS, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, I-20133 Milan, Italy [ 34 ] Cogentech Canc Genet Test Lab, I-20139 Milan, Italy [ 35 ] Ctr Riferimento Oncol CRO, Canc Bioimmunotherapy Unit, I-33081 Aviano, Italy [ 36 ] Ist Europeo Oncol, Div Canc Prevent & Genet, I-20141 Milan, Italy [ 37 ] Ist Nazl Tumori, IRCCS, Dept Prevent & Predict Med, Unit Med Genet, I-20133 Milan, Italy [ 38 ] Azienda Osped Univ San Martino Genova, IST Ist Nazl Ric Cancro, IRCCS, Dept Epidemiol Prevent & Special Funct,Unit Hered, I-16132 Genoa, Italy [ 39 ] FiorGen Fdn Pharmacogen, I-50019 Sesto Fiorentino, Italy [ 40 ] Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy [ 41 ] Univ Roma La Sapienza, Dept Mol Med, I-00185 Rome, Italy [ 42 ] Aristotle Univ 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, Hants, England [ 53 ] Newcastle Upon Tyne Hosp, NHS Trust, Int Ctr Life, Inst Human Genet,Northern Genet Serv, Newcastle Upon Tyne NE1 4EP, Tyne & Wear, England [ 54 ] Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England [ 55 ] Leeds Teaching Hosp, NHS Trust, Old Med Sch, Yorkshire Reg Genet Serv, Leeds LS1 3EX, W Yorkshire, England [ 56 ] Univ Hosp Leicester, NHS Trust, Leicester Royal Infirm, Dept Clin Genet,Leicestershire Clin Genet Serv, Leicester LE1 5WW, Leics, England [ 57 ] Churchill Hosp, Oxford Reg Genet Serv, Oxford OX3 7LE, England [ 58 ] Guys Hosp, Guys & St Thomas NHS Fdn Trust, Clin Genet Serv, London SE1 9RT, England [ 59 ] Great Ormond St Hosp Sick Children, NHS Trust, North East Thames Reg Genet Serv, London WC1N 3BH, England [ 60 ] Trinity Coll Dublin, Acad Unit Clin & Mol Oncol, Dublin 2, Ireland [ 61 ] St James Hosp, Med Oncol Serv, Dublin 8, Ireland [ 62 ] Cambridge Univ Hosp, Addenbrookes Hosp, NHS Fdn Trust, Addenbrookes Treatment Ctr,Dept Clin Genet,East A, Cambridge CB2 0QQ, England [ 63 ] Univ Wales Hosp, All Wales Med Genet Serv, Cardiff CF14 4XW, S Glam, Wales [ 64 ] Western Gen Hosp, South East Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland [ 65 ] Queens Univ Belfast, Sch Med Dent & Biomed Sci, Ctr Canc Res & Cell Biol, Belfast BT9 7AE, Antrim, North Ireland [ 66 ] Belfast City Hosp, Belfast Hlth & Social Care Trust, Dept Med Genet, Belfast BT9 7AB, Antrim, North Ireland [ 67 ] Inst Canc Res, Oncogenet Team, London SW7 3RP, England [ 68 ] Royal Marsden NHS Fdn Trust, London SW7 3RP, England [ 69 ] Yorkhill Hosp, Ferguson Smith Ctr Clin Genet, Glasgow G3 8SJ, Lanark, Scotland [ 70 ] Univ London St Georges Hosp, Dept Med Genet, South West Thames Reg Genet Serv, London SW17 0RE, England [ 71 ] Birmingham Womens Hosp, Healthcare NHS Trust, West Midlands Reg Genet Serv, Birmingham B15 2TG, W Midlands, England [ 72 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66160 USA [ 73 ] MedStar Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA [ 74 ] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium [ 75 ] Tech Univ Munich, Univ Hosp Klinikum Rechts Isar, Dept Obstet & Gynaecol, Div Tumor Genet, D-81675 Munich, Germany [ 76 ] Univ Wurzburg, Inst Humangenet, Ctr Familial Breast & Ovarian Canc, Biozentrum,Dept Med Genet, D-97074 Wurzburg, Germany [ 77 ] Univ Hosp Cologne, Fac Med, Canc Ctr Cologne, CIO,Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany [ 78 ] Univ Cologne, CMMC, D-50931 Cologne, Germany [ 79 ] Univ Heidelberg Hosp, Inst Human Genet, Dept Human Genet, Heidelberg, Germany [ 80 ] Univ Leipzig, Fac Med, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany [ 81 ] Univ Dusseldorf, Univ Hosp Dusseldorf, Dept Obstet & Gynaecol, D-40225 Dusseldorf, Germany [ 82 ] Hannover Med Sch, Ctr Pathol & Forens & Genet Med, Inst Cell & Mol Pathol, D-30625 Hannover, Germany [ 83 ] Univ Med Ctr Schleswig Holstein, Inst Human Genet, 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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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