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Browsing by Author "Antoniou, Antonis C."

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  • Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers
    Publication . Peterlongo, Paolo; Chang-Claude, Jenny; Moysich, Kirsten B.; Rudolph, Anja; Schmutzler, Rita K.; Simard, Jacques; Soucy, Penny; Eeles, Rosalind A.; Easton, Douglas F.; Hamann, Ute; Wilkening, Stefan; Nevanlinna, Heli; Aittomaeki, Kristiina; van Os, Theo A. M.; Jensen, Uffe Birk; Meijers-Heijboer, Hanne E. J.; van der Hout, Annemarie H.; Vreeswijk, Maaike P. G.; Rappaport, Christine; Hoogerbrugge, Nicoline; Arason, Adalgeir; Jonson, Lars; Ausems, Margreet G. E. M.; van der Baan, Frederieke H.; van Doorn, Helena C.; Collee, J. Margriet; Olah, Edith; Diez, Orland; Laitman, Yael; Blanco, Ignacio; Lazaro, Conxi; Lose, Felicity; Osorio, Ana; Kaulich, Daphne Geschwantler; Brunet, Joan; Giannini, Giuseppe; Chiquette, Jocelyne; Teixeira, Manuel R.; Olswold, Curtis; Couch, Fergus J.; Lindor, Noralane M.; Wang, Xianshu; Walker, Logan C.; Martinez-Bouzas, Cristina; Szabo, Csilla I.; Offit, Kenneth; von Wachenfeldt, Anna; Papi, Laura; Ehrencrona, Hans; Corines, Marina; Barwell, Julian; Pfeiler, Georg; Tea, Muy-Kheng M.; Phelan, Catherine M.; Rhiem, Kerstin; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Mulligan, Anna Marie; Martayan, Aline; Glendon, Gord; Tchatchou, Sandrine; Maia, Ana-Teresa; Walker, Lisa; Montagna, Marco; Benitez, Javier; Andrulis, Irene L.; Niederacher, Dieter; Askmalm, Marie Stenmark; Borg, Ake; Kuchenbaecker, Karoline B.; Tibiletti, Maria Grazia; McGuffog, Lesley; Barrowdale, Daniel; Healey, Sue; Lee, Andrew; Conway, Edye E.; Izatt, Louise; Pharoah, Paul D. P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Steinemann, Doris; Matricardi, Laura; Radice, Paolo; Friedman, Eitan; Lubinski, Jan; Jakubowska, Anna; Blazer, Kathleen R.; Garcia, Encarna B. Gomez; Olopade, Olufunmilayo I.; Side, Lucy E.; Nussbaum, Robert L.; Nathanson, Katherine L.; Domchek, Susan M.; Rebbeck, Timothy R.; Vratimos, Athanassios; Plendl, Hansjoerg; Arun, Banu K.; Porteous, Mary E.; Karlan, Beth Y.; Orsulic, Sandra; Lester, Jenny; Chung, Wendy K.; Kennedy, M. John; Miron, Alex; Southey, Melissa C.; Goldgar, David E.; Fostira, Florentia; Buys, Saundra S.; Weitzel, Jeffrey N.; Janavicius, Ramunas; Kast, Karin; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Ding, Yuan Chun; Neuhausen, Susan L.; Rogers, Mark T.; Hansen, Thomas V. O.; Gerdes, Anne-Marie; Arnold, Norbert; Garber, Judy E.; Ejlertsen, Bent; Feliubadalo, Lidia; Manoukian, Siranoush; Peissel, Bernard; Zaffaroni, Daniela; Scuvera, Giulietta; Barile, Monica; Ficarazzi, Filomena; Ditsch, Nina; Mariette, Frederique; Fortuzzi, Stefano; Morrison, Patrick J.; Cybulski, Cezary; Platte, Radka; Viel, Alessandra; Jacobs, Lauren; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D. Gareth R.; Frost, Debra; Eccles, Diana; Brady, Angela; Gronwald, Jacek; Cook, Jackie; Tischkowitz, Marc; Varon-Mateeva, Raymonda; Robson, Mark E.; Wappenschmidt, Barbara; Adlard, Julian; Toland, Amanda Ewart; Davidson, Rosemarie; Hodgson, Shirley V.; Ellis, Steve; Spurdle, Amanda B.; Cole, Trevor; Godwin, Andrew K.; Claes, Kathleen; Van Maerken, Tom; Zhang, Liying; Meindl, Alfons; Gehrig, Andrea; Sutter, Christian; Bojesen, Anders; Wang-Gohrke, Shan; Durda, Katarzyna; Engel, Christoph; Chen, Bowang; Bressac-de Paillerets, Brigitte; Buecher, Bruno; Delnatte, Capucine; Joseph, Vijai; Houdayer, Claude; Stoppa-Lyonnet, Dominique; Damiola, Francesca; Coupier, Isabelle; Jaworska-Bieniek, Katarzyna; Pedersen, Inge Sokilde; Barjhoux, Laure; Venat-Bouvet, Laurence; Golmard, Lisa; Rookus, Matti A.; Boutry-Kryza, Nadia; Berger, Andreas; Sinilnikova, Olga M.; Caron, Olivier; Pujol, Pascal; Sukiennicki, Grzegorz; Mazoyer, Sylvie; Belotti, Muriel; Thomassen, Mads; Piedmonte, Marion; Friedlander, Michael L.; Rodriguez, Gustavo C.; Copeland, Larry J.; Singer, Christian F.; Schmidt, MarjankaK.; de la Hoya, Miguel; Rantala, Johanna; Perez Segura, Pedro
    Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. (C)2014 AACR.
    2015-01Journal article Open Access Show more
  • Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers
    Publication . Maia, Ana-Teresa; Antoniou, Antonis C.; O'Reilly, Martin; Samarajiwa, Shamith; Dunning, Mark; Kartsonaki, Christiana; Chin, Suet-Feung; Curtis, Christina; McGuffog, Lesley; Domchek, Susan M.; Easton, Douglas F.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Adlard, Julian; Eccles, Diana; Sinilnikova, Olga M.; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Gauthier-Villars, Marion; Faivre, Laurence; Venat-Bouvet, Laurence; Delnatte, Capucine; Nevanlinna, Heli; Couch, Fergus J.; Godwin, Andrew K.; Caligo, Maria Adelaide; Barkardottir, Rosa B.; Chen, Xiaoqing; Beesley, Jonathan; Healey, Sue; Caldas, Carlos; Chenevix-Trench, Georgia; Ponder, Bruce A. J.
    Introduction: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. Methods: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBP alpha, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048). Conclusions: Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.
    2012Journal article Open Access Show more