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1.  DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers 
Osorio, Ana | Milne, Roger L. | Kuchenbaecker, Karoline | Vaclová, Tereza | Pita, Guillermo | Alonso, Rosario | Peterlongo, Paolo | Blanco, Ignacio | de la Hoya, Miguel | Duran, Mercedes | Díez, Orland | Ramón y Cajal, Teresa | Konstantopoulou, Irene | Martínez-Bouzas, Cristina | Andrés Conejero, Raquel | Soucy, Penny | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | SWE-BRCA,  | Arver, Brita | Rantala, Johanna | Loman, Niklas | Ehrencrona, Hans | Olopade, Olufunmilayo I. | Beattie, Mary S. | Domchek, Susan M. | Nathanson, Katherine | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | John, Esther M. | Whittemore, Alice S. | Daly, Mary B. | Southey, Melissa | Hopper, John | Terry, Mary B. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Steele, Linda | Neuhausen, Susan L. | Ding, Yuan Chun | Hansen, Thomas v. O. | Jønson, Lars | Ejlertsen, Bent | Gerdes, Anne-Marie | Infante, Mar | Herráez, Belén | Moreno, Leticia Thais | Weitzel, Jeffrey N. | Herzog, Josef | Weeman, Kisa | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Bonanni, Bernardo | Mariette, Frederique | Volorio, Sara | Viel, Alessandra | Varesco, Liliana | Papi, Laura | Ottini, Laura | Tibiletti, Maria Grazia | Radice, Paolo | Yannoukakos, Drakoulis | Garber, Judy | Ellis, Steve | Frost, Debra | Platte, Radka | Fineberg, Elena | Evans, Gareth | Lalloo, Fiona | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Eccles, Diana | Cook, Jackie | Hodgson, Shirley | Brewer, Carole | Tischkowitz, Marc | Douglas, Fiona | Porteous, Mary | Side, Lucy | Walker, Lisa | Morrison, Patrick | Donaldson, Alan | Kennedy, John | Foo, Claire | Godwin, Andrew K. | Schmutzler, Rita Katharina | Wappenschmidt, Barbara | Rhiem, Kerstin | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hans Jörg | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Gehrig, Andrea | Stoppa-Lyonnet, Dominique | Sinilnikova, Olga M. | Mazoyer, Sylvie | Damiola, Francesca | Poppe, Bruce | Claes, Kathleen | Piedmonte, Marion | Tucker, Kathy | Backes, Floor | Rodríguez, Gustavo | Brewster, Wendy | Wakeley, Katie | Rutherford, Thomas | Caldés, Trinidad | Nevanlinna, Heli | Aittomäki, Kristiina | Rookus, Matti A. | van Os, Theo A. M. | van der Kolk, Lizet | de Lange, J. L. | Meijers-Heijboer, Hanne E. J. | van der Hout, A. H. | van Asperen, Christi J. | Gómez Garcia, Encarna B. | Hoogerbrugge, Nicoline | Collée, J. Margriet | van Deurzen, Carolien H. M. | van der Luijt, Rob B. | Devilee, Peter | HEBON,  | Olah, Edith | Lázaro, Conxi | Teulé, Alex | Menéndez, Mireia | Jakubowska, Anna | Cybulski, Cezary | Gronwald, Jacek | Lubinski, Jan | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Johannsson, Oskar Th. | Maugard, Christine | Montagna, Marco | Tognazzo, Silvia | Teixeira, Manuel R. | Healey, Sue | Investigators, kConFab | Olswold, Curtis | Guidugli, Lucia | Lindor, Noralane | Slager, Susan | Szabo, Csilla I. | Vijai, Joseph | Robson, Mark | Kauff, Noah | Zhang, Liying | Rau-Murthy, Rohini | Fink-Retter, Anneliese | Singer, Christian F. | Rappaport, Christine | Geschwantler Kaulich, Daphne | Pfeiler, Georg | Tea, Muy-Kheng | Berger, Andreas | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Lejbkowicz, Flavio | Andrulis, Irene | Mulligan, Anna Marie | Glendon, Gord | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Sunde, Lone | Thomassen, Mads | Kruse, Torben A. | Jensen, Uffe Birk | Friedman, Eitan | Laitman, Yael | Shimon, Shani Paluch | Simard, Jacques | Easton, Douglas F. | Offit, Kenneth | Couch, Fergus J. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Benitez, Javier
PLoS Genetics  2014;10(4):e1004256.
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03–1.16), p = 2.7×10−3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21, p = 4.8×10−3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
Author Summary
Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.
doi:10.1371/journal.pgen.1004256
PMCID: PMC3974638  PMID: 24698998
2.  Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers 
Antoniou, Antonis C | Kartsonaki, Christiana | Sinilnikova, Olga M. | Soucy, Penny | McGuffog, Lesley | Healey, Sue | Lee, Andrew | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Cattaneo, Elisa | Barile, Monica | Pensotti, Valeria | Pasini, Barbara | Dolcetti, Riccardo | Giannini, Giuseppe | Laura Putignano, Anna | Varesco, Liliana | Radice, Paolo | Mai, Phuong L. | Greene, Mark H. | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Thomassen, Mads | Gerdes, Anne-Marie | Kruse, Torben A. | Birk Jensen, Uffe | Crüger, Dorthe G. | Caligo, Maria A. | Laitman, Yael | Milgrom, Roni | Kaufman, Bella | Paluch-Shimon, Shani | Friedman, Eitan | Loman, Niklas | Harbst, Katja | Lindblom, Annika | Arver, Brita | Ehrencrona, Hans | Melin, Beatrice | Nathanson, Katherine L. | Domchek, Susan M. | Rebbeck, Timothy | Jakubowska, Ania | Lubinski, Jan | Gronwald, Jacek | Huzarski, Tomasz | Byrski, Tomasz | Cybulski, Cezary | Gorski, Bohdan | Osorio, Ana | Ramón y Cajal, Teresa | Fostira, Florentia | Andrés, Raquel | Benitez, Javier | Hamann, Ute | Hogervorst, Frans B. | Rookus, Matti A. | Hooning, Maartje J. | Nelen, Marcel R. | van der Luijt, Rob B. | van Os, Theo A.M. | van Asperen, Christi J. | Devilee, Peter | Meijers-Heijboer, Hanne E.J. | Gómez Garcia, Encarna B. | Peock, Susan | Cook, Margaret | Frost, Debra | Platte, Radka | Leyland, Jean | Gareth Evans, D. | Lalloo, Fiona | Eeles, Ros | Izatt, Louise | Adlard, Julian | Davidson, Rosemarie | Eccles, Diana | Ong, Kai-ren | Cook, Jackie | Douglas, Fiona | Paterson, Joan | John Kennedy, M. | Miedzybrodzka, Zosia | Godwin, Andrew | Stoppa-Lyonnet, Dominique | Buecher, Bruno | Belotti, Muriel | Tirapo, Carole | Mazoyer, Sylvie | Barjhoux, Laure | Lasset, Christine | Leroux, Dominique | Faivre, Laurence | Bronner, Myriam | Prieur, Fabienne | Nogues, Catherine | Rouleau, Etienne | Pujol, Pascal | Coupier, Isabelle | Frénay, Marc | Hopper, John L. | Daly, Mary B. | Terry, Mary B. | John, Esther M. | Buys, Saundra S. | Yassin, Yosuf | Miron, Alexander | Goldgar, David | Singer, Christian F. | Tea, Muy-Kheng | Pfeiler, Georg | Catharina Dressler, Anne | Hansen, Thomas v.O. | Jønson, Lars | Ejlertsen, Bent | Bjork Barkardottir, Rosa | Kirchhoff, Tomas | Offit, Kenneth | Piedmonte, Marion | Rodriguez, Gustavo | Small, Laurie | Boggess, John | Blank, Stephanie | Basil, Jack | Azodi, Masoud | Ewart Toland, Amanda | Montagna, Marco | Tognazzo, Silvia | Agata, Simona | Imyanitov, Evgeny | Janavicius, Ramunas | Lazaro, Conxi | Blanco, Ignacio | Pharoah, Paul D.P. | Sucheston, Lara | Karlan, Beth Y. | Walsh, Christine S. | Olah, Edith | Bozsik, Aniko | Teo, Soo-Hwang | Seldon, Joyce L. | Beattie, Mary S. | van Rensburg, Elizabeth J. | Sluiter, Michelle D. | Diez, Orland | Schmutzler, Rita K. | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Ruehl, Ina | Varon-Mateeva, Raymonda | Kast, Karin | Deissler, Helmut | Niederacher, Dieter | Arnold, Norbert | Gadzicki, Dorothea | Schönbuchner, Ines | Caldes, Trinidad | de la Hoya, Miguel | Nevanlinna, Heli | Aittomäki, Kristiina | Dumont, Martine | Chiquette, Jocelyne | Tischkowitz, Marc | Chen, Xiaoqing | Beesley, Jonathan | Spurdle, Amanda B. | Neuhausen, Susan L. | Chun Ding, Yuan | Fredericksen, Zachary | Wang, Xianshu | Pankratz, Vernon S. | Couch, Fergus | Simard, Jacques | Easton, Douglas F. | Chenevix-Trench, Georgia
Human Molecular Genetics  2011;20(16):3304-3321.
Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r2 = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11–1.23, P-trend = 4.5 × 10−9 for rs2046210; HR = 1.28, 95% CI: 1.18–1.40, P-trend = 1.3 × 10−8 for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01–1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02–1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92–1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
doi:10.1093/hmg/ddr226
PMCID: PMC3652640  PMID: 21593217
3.  Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction 
Antoniou, Antonis C | Beesley, Jonathan | McGuffog, Lesley | Sinilnikova, Olga M. | Healey, Sue | Neuhausen, Susan L. | Ding, Yuan Chun | Rebbeck, Timothy R. | Weitzel, Jeffrey N. | Lynch, Henry T. | Isaacs, Claudine | Ganz, Patricia A. | Tomlinson, Gail | Olopade, Olufunmilayo I. | Couch, Fergus J. | Wang, Xianshu | Lindor, Noralane M. | Pankratz, Vernon S. | Radice, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Barile, Monica | Viel, Alessandra | Allavena, Anna | Dall’Olio, Valentina | Peterlongo, Paolo | Szabo, Csilla I. | Zikan, Michal | Claes, Kathleen | Poppe, Bruce | Foretova, Lenka | Mai, Phuong L. | Greene, Mark H. | Rennert, Gad | Lejbkowicz, Flavio | Glendon, Gord | Ozcelik, Hilmi | Andrulis, Irene L. | Thomassen, Mads | Gerdes, Anne-Marie | Sunde, Lone | Cruger, Dorthe | Jensen, Uffe Birk | Caligo, Maria | Friedman, Eitan | Kaufman, Bella | Laitman, Yael | Milgrom, Roni | Dubrovsky, Maya | Cohen, Shimrit | Borg, Ake | Jernström, Helena | Lindblom, Annika | Rantala, Johanna | Stenmark-Askmalm, Marie | Melin, Beatrice | Nathanson, Kate | Domchek, Susan | Jakubowska, Ania | Lubinski, Jan | Huzarski, Tomasz | Osorio, Ana | Lasa, Adriana | Durán, Mercedes | Tejada, Maria-Isabel | Godino, Javier | Benitez, Javier | Hamann, Ute | Kriege, Mieke | Hoogerbrugge, Nicoline | van der Luijt, Rob B | van Asperen, Christi J | Devilee, Peter | Meijers-Heijboer, E.J. | Blok, Marinus J | Aalfs, Cora M. | Hogervorst, Frans | Rookus, Matti | Cook, Margaret | Oliver, Clare | Frost, Debra | Conroy, Don | Evans, D. Gareth | Lalloo, Fiona | Pichert, Gabriella | Davidson, Rosemarie | Cole, Trevor | Cook, Jackie | Paterson, Joan | Hodgson, Shirley | Morrison, Patrick J. | Porteous, Mary E. | Walker, Lisa | Kennedy, M. John | Dorkins, Huw | Peock, Susan | Godwin, Andrew K. | Stoppa-Lyonnet, Dominique | de Pauw, Antoine | Mazoyer, Sylvie | Bonadona, Valérie | Lasset, Christine | Dreyfus, Hélène | Leroux, Dominique | Hardouin, Agnès | Berthet, Pascaline | Faivre, Laurence | Loustalot, Catherine | Noguchi, Tetsuro | Sobol, Hagay | Rouleau, Etienne | Nogues, Catherine | Frénay, Marc | Vénat-Bouvet, Laurence | Hopper, John L. | Daly, Mary B. | Terry, Mary B. | John, Esther M. | Buys, Saundra S. | Yassin, Yosuf | Miron, Alex | Goldgar, David | Singer, Christian F. | Dressler, Anne Catharina | Gschwantler-Kaulich, Daphne | Pfeiler, Georg | Hansen, Thomas V. O. | Jønson, Lars | Agnarsson, Bjarni A. | Kirchhoff, Tomas | Offit, Kenneth | Devlin, Vincent | Dutra-Clarke, Ana | Piedmonte, Marion | Rodriguez, Gustavo C. | Wakeley, Katie | Boggess, John F. | Basil, Jack | Schwartz, Peter E. | Blank, Stephanie V. | Toland, Amanda Ewart | Montagna, Marco | Casella, Cinzia | Imyanitov, Evgeny | Tihomirova, Laima | Blanco, Ignacio | Lazaro, Conxi | Ramus, Susan J. | Sucheston, Lara | Karlan, Beth Y. | Gross, Jenny | Schmutzler, Rita | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Lochmann, Magdalena | Arnold, Norbert | Heidemann, Simone | Varon-Mateeva, Raymonda | Niederacher, Dieter | Sutter, Christian | Deissler, Helmut | Gadzicki, Dorothea | Preisler-Adams, Sabine | Kast, Karin | Schönbuchner, Ines | Caldes, Trinidad | de la Hoya, Miguel | Aittomäki, Kristiina | Nevanlinna, Heli | Simard, Jacques | Spurdle, Amanda B. | Holland, Helene | Chen, Xiaoqing | Platte, Radka | Chenevix-Trench, Georgia | Easton, Douglas F.
Cancer research  2010;70(23):9742-9754.
The known breast cancer (BC) susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1,LSP1 and 2q35 confer increased risks of BC for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of three additional SNPs, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 at 5p12 and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased BC risk for BRCA2 carriers (per-allele Hazard Ratio (HR)=1.10, 95%CI:1.03-1.18, p=0.006 and HR=1.09, 95%CI:1.01-1.19, p=0.03, respectively). Neither SNP was associated with BC risk for BRCA1 carriers and rs6504950 was not associated with BC for either BRCA1 or BRCA2 carriers. Of the nine polymorphisms investigated, seven were associated with BC for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, p-values:7×10−11-0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (p=0.0049, 0.03 respectively). All risk associated polymorphisms appear to interact multiplicatively on BC risk for mutation carriers. Based on the joint genotype distribution of the seven risk associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e. between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing BC by age 80, compared with 42-50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences may be sufficient to influence the clinical management of mutation carriers.
doi:10.1158/0008-5472.CAN-10-1907
PMCID: PMC2999830  PMID: 21118973
BRCA1; BRCA2; genetic modifier; common variant; genome-wide association study; penetrance; genetic counseling
4.  Development of a Communication Protocol for Telephone Disclosure of Genetic Test Results for Cancer Predisposition 
JMIR Research Protocols  2014;3(4):e49.
Background
Dissemination of genetic testing for disease susceptibility, one application of “personalized medicine”, holds the potential to empower patients and providers through informed risk reduction and prevention recommendations. Genetic testing has become a standard practice in cancer prevention for high-risk populations. Heightened consumer awareness of “cancer genes” and genes for other diseases (eg, cardiovascular and Alzheimer’s disease), as well as the burgeoning availability of increasingly complex genomic tests (ie, multi-gene, whole-exome and -genome sequencing), has escalated interest in and demand for genetic risk assessment and the specialists who provide it. Increasing demand is expected to surpass access to genetic specialists. Thus, there is urgent need to develop effective and efficient models of delivery of genetic information that comparably balance the risks and benefits to the current standard of in-person communication.
Objective
The aim of this pilot study was to develop and evaluate a theoretically grounded and rigorously developed protocol for telephone communication of BRCA1/2 (breast cancer) test results that might be generalizable to genetic testing for other hereditary cancer and noncancer syndromes.
Methods
Stakeholder data, health communication literature, and our theoretical model grounded in Self-Regulation Theory of Health Behavior were used to develop a telephone communication protocol for the communication of BRCA1/2 genetic test results. Framework analysis of selected audiotapes of disclosure sessions and stakeholders’ feedback were utilized to evaluate the efficacy and inform refinements to this protocol.
Results
Stakeholder feedback (n=86) and audiotapes (38%, 33/86) of telephone disclosures revealed perceived disadvantages and challenges including environmental factors (eg, non-private environment), patient-related factors (eg, low health literacy), testing-related factors (eg, additional testing needed), and communication factors (eg, no visual cues). Resulting modifications to the communication protocol for BRCA1/2 test results included clarified patient instructions, scheduled appointments, refined visual aids, expanded disclosure checklist items, and enhanced provider training.
Conclusions
Analyses of stakeholders’ experiences and audiotapes of telephone disclosure of BRCA1/2 test results informed revisions to communication strategies and a protocol to enhance patient outcomes when utilizing telephone to disclose genetic test results.
doi:10.2196/resprot.3337
PMCID: PMC4259920  PMID: 25355401
genetic testing; test result disclosure; communication; telemedicine; cancer risk assessment; self-regulation theory of health behavior
5.  Preparing Individuals to Communicate Genetic Test Results to Their Relatives: Report of a Randomized Control Trial 
Familial cancer  2013;12(3):537-546.
Background
This study reports a randomized clinical trial evaluating the efficacy of an intervention to prepare individuals to communicate BRCA1/BRCA2 results to family members.
Methods
Women aged 18 years and older, who had genetic testing, and who had adult first-degree relatives (FDRs), were randomly assigned to a communication skills-building intervention or a wellness control session. Primary outcomes were the percentage of probands sharing test results, and the level of distress associated with sharing. The ability of the Theory of Planned Behavior variables to predict the outcomes was explored.
Results
Four hundred twenty-two women were enrolled in the study, 219 (intervention) and 203 (control). Data from 137 in the intervention group and 112 in the control group were analyzed. Two hundred forty-nine probands shared test results with 838 relatives (80.1%). There were no significant differences between study groups in the primary outcomes. Combining data from both arms revealed that perceived control and specific social influence were associated with sharing. Probands were more likely to share genetic test results with their children, female relatives and relatives who they perceived had a favorable opinion about learning the results.
Conclusion
The communication skills intervention did not impact sharing of test results. The proband’s perception of her relative’s opinion of genetic testing and her sense of control in relaying this information influenced sharing. Communication of test results is selective, with male relatives and parents less likely to be informed.
Impact
Prevalent psychosocial factors play a role in the communication of genetic test results within families.
doi:10.1007/s10689-013-9609-z
PMCID: PMC3706561  PMID: 23420550
Genetic testing; BRCA1/2; family communication; theory of planned behavior; social pressure
6.  Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers 
Journal of Clinical Oncology  2013;31(25):3091-3099.
Purpose
To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.
Methods
Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up.
Results
Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases).
Conclusion
This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses.
doi:10.1200/JCO.2012.47.8313
PMCID: PMC3753701  PMID: 23918944
7.  Identifying a Highly-Aggressive DCIS Subgroup by Studying Intra-Individual DCIS Heterogeneity among Invasive Breast Cancer Patients 
PLoS ONE  2014;9(6):e100488.
The heterogeneity among multiple ductal carcinoma in situ (DCIS) lesions within the same patient also diagnosed with invasive ductal carcinoma (IDC) has not been well evaluated, leaving research implications of intra-individual DCIS heterogeneity yet to be explored. In this study formalin-fixed paraffin embedded sections from 36 patients concurrently diagnosed with DCIS and IDC were evaluated by immunohistochemistry. Ten DCIS lesions from each patient were then randomly selected and scored. Our results showed that expression of PR, HER2, Ki-67, and p16 varied significantly within DCIS lesions from a single patient (P<0.05 for PR; P<1×10−8 for HER2, Ki-67 and p16). In addition, seventy-two percent of the individuals had heterogeneous expression of at least 2/6 markers. Importantly, by evaluating the expression of promising DCIS risk biomarkers (Ki-67, p53 and p16) among different DCIS subgroups classified by comparing DCIS molecular subtypes with those of adjacent normal terminal duct lobular units (TDLU) and IDC, our results suggest the existence of a highly-aggressive DCIS subgroup, which had the same molecular subtype as the adjacent IDC but not the same subtype as the adjacent normal TDLU. By using a systematic approach, our results clearly demonstrate that intra-individual heterogeneity in DCIS is very common in patients concurrently diagnosed with IDC. Our novel findings of a DCIS subpopulation with aggressive characteristics will provide a new paradigm for mechanistic studies of breast tumor progression and also have broad implications for prevention research as heterogeneous pre-invasive lesions are present in many other cancer types.
doi:10.1371/journal.pone.0100488
PMCID: PMC4076240  PMID: 24978026
8.  Knowledge and perceptions of familial and genetic risks for breast cancer risk in adolescent girls 
Background
Evidence suggests early events might modify adult breast cancer risk and many adolescents learn of familial and genetic risks for breast cancer. Little is known about how adolescent girls understand and respond to breast cancer risk.
Methods
Semi-structured interviews with 11-19 year-old girls at high-risk and population-risk for breast cancer evaluated knowledge and perceptions of breast cancer risk and risk modification. Framework analysis and descriptive statistics were utilized to analyze open-ended responses. Risk group and age differences were evaluated by Fisher’s exact and McNemar’s tests.
Results
54 girls (86% of invited), 35 high-risk (65%) and 19 population-risk (35%) completed interviews. The most frequently reported risk for breast cancer was family history/hereditary predisposition (66%). Only 17% of girls were aware of BRCA1/2 genes. The majority (76%) of high-risk girls perceive themselves to be at increased risk for breast cancer, compared to 22% of population-risk girls (p=0.001). Half of girls reported that women can get breast cancer before 20 years old. The majority believe there are things women (70%) and girls (67%) can do to prevent breast cancer. Mother was the most frequently reported source of information for breast cancer among both high-risk (97%) and population-risk (89%) girls.
Conclusion
In this study, many high-risk girls perceive themselves to be at increased risk for breast cancer, and many girls believe that breast cancer can occur in teens. Yet, most girls believe there are things women and girls can do to prevent breast cancer. Research evaluating the impact of awareness and perceptions of breast cancer risk on psychosocial, health and risk behaviors is needed to develop strategies to optimize responses to cancer risk.
doi:10.1007/s10549-012-2254-7
PMCID: PMC3513641  PMID: 23065030
Adolescents; Breast cancer; Breast cancer prevention; Cancer Risk Assessment; Perceived risk of cancer
9.  Interpretation of single and serial measures of HE4 and CA125 in asymptomatic women at high risk for ovarian cancer 
Background
Human epididymis protein 4 (HE4) is approved for clinical use with CA125 to predict epithelial ovarian cancer (EOC) in women with a pelvic mass or in remission after chemotherapy. Previously reported reference ranges for HE4 are inconsistent.
Methods
We report positivity thresholds yielding 90%, 95%, 98% and 99% specificity for age-defined populations of healthy women for HE4, CA125 and Risk of Malignancy Algorithm (ROMA), a weighted average of HE4 and CA125. HE4 and CA125 were measured in 1780 samples from 778 healthy women aged >25 years with a documented deleterious mutation, or aged >35 years with a significant family history. Effects on marker levels of a woman’s age, ethnicity and epidemiologic characteristics were estimated, as were the population-specific means, variances and within- and between-woman variances used to generate longitudinal screening algorithms for these markers.
Results
CA125 levels were lower with Black ethnicity (p=0.008). Smoking was associated with higher HE4 (p=0.007) and ROMA (p<0.019). Continuous oral contraceptive use decreased levels of CA125 (p=0.041), and ROMA (p=0.12). CA125 was lower in women age ≥55, and HE4 increased with age (p<0.01), particularly among women age ≥55.
Conclusions
Due to the strong effect of age on HE4, thresholds for HE4 are best defined for women of specific ages. Age-specific population thresholds for HE4 for 95% specificity ranged from 41.4 pmol/L for women age 30 to 82.1 pmol/L for women age 80.
Impact
Incorporation of serial marker values from screening history reduces personalized thresholds for CA125 and HE4 but is inappropriate for ROMA.
doi:10.1158/1055-9965.EPI-12-0616
PMCID: PMC3493821  PMID: 22962406
ovarian cancer; screening; longitudinal algorithm; HE4; CA125; early detection; high-risk
10.  Association Between BRCA1 and BRCA2 Mutations and Survival in Women with Invasive Epithelial Ovarian Cancer 
Bolton, Kelly L. | Chenevix-Trench, Georgia | Goh, Cindy | Sadetzki, Siegal | Ramus, Susan J. | Karlan, Beth Y. | Lambrechts, Diether | Despierre, Evelyn | Barrowdale, Daniel | McGuffog, Lesley | Healey, Sue | Easton, Douglas F. | Sinilnikova, Olga | Benitez, Javier | García, María J. | Neuhausen, Susan | Gail, Mitchell H. | Hartge, Patricia | Peock, Susan | Frost, Debra | Evans, D. Gareth | Eeles, Ros | Godwin, Andrew K. | Daly, Mary B. | Kwong, Ava | Ma, Edmond SK | Lázaro, Conxi | Blanco, Ignacio | Montagna, Marco | D’Andrea, Emma | Nicoletto, Ornella | Investigators, kConFab | Johnatty, Sharon E. | Kjær, Susanne Krüger | Jensen, Allan | Høgdall, Estrid | Goode, Ellen L. | Fridley, Brooke L. | Loud, Jennifer T. | Greene, Mark H. | Mai, Phuong L. | Chetrit, Angela | Lubin, Flora | Hirsh-Yechezkel, Galit | Glendon, Gord | Andrulis, Irene L. | Toland, Amanda E. | Senter, Leigha | Gore, Martin E. | Gourley, Charlie | Michie, Caroline O | Song, Honglin | Tyrer, Jonathan | Whittemore, Alice S. | McGuire, Valerie | Sieh, Weiva | Kristoffersson, Ulf | Olsson, Håkan | Borg, Åke | Levine, Douglas A. | Steele, Linda | Beattie, Mary S. | Chan, Salina | Nussbaum, Robert | Moysich, Kirsten B. | Gross, Jenny | Cass, Ilana | Walsh, Christine | Li, Andrew J. | Leuchter, Ronald | Gordon, Ora | Garcia-Closas, Montserrat | Gayther, Simon A. | Chanock, Stephen J. | Antoniou, Antonis C. | Pharoah, Paul D.P.
Context
Approximately 10 percent of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent report suggested that BRCA2 related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear.
Objective
To characterize the survival of BRCA carriers with EOC compared to non-carriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns.
Design, Setting, and Participants
We pooled data from 26 studies on the survival of women with ovarian cancer. This included data on 1,213 EOC cases with pathogenic germline mutations in BRCA1 (909) or BRCA2 (304) and 2,666 non-carriers recruited and followed for variable times between 1987 and 2010; the median year of diagnosis was 1998.
Main Outcome Measures
Five year overall mortality.
Results
The five-year overall survival was 36 percent (95% CI: 34–38) for non-carriers, 44 percent (95% CI: 40–48) for BRCA1 carriers and 52 percent (95% CI: 46–58) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 carriers showed a more favorable survival than non-carriers (BRCA1, HR=0.78; 95% CI=0.68–0.89, P=2×10−4; BRCA2, HR = 0.61; 95% CI=0.50–0.76, P=6×10−6). These survival differences remained after additional adjustment for stage, grade, histology and age at diagnosis (BRCA1, HR=0.73, 95% CI=0.64–0.84, P=2×10−5; BRCA2, HR = 0.49, 95% CI=0.39–0.61, P=3×10−10).
Conclusions
Among patients with invasive epithelial ovarian cancer, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival.
doi:10.1001/jama.2012.20
PMCID: PMC3727895  PMID: 22274685
11.  When parents disclose BRCA1/2 test results: Their communication and perceptions of offspring response 
Cancer  2012;118(13):3417-3425.
Background
BRCA1/2 testing is not recommended for children, as risk reduction measures and screening are not generally recommended before 25 years old (YO). Little is known about the prevalence and predictors of parent communication to offspring and how offspring respond to this communication.
Methods
Semi-structured interviews were conducted with parents who had BRCA1/2 testing and at least one child <25 YO. Logistic regressions were utilized to evaluate associations with communication. Framework analysis was utilized to analyze open-ended responses.
Results
253 parents completed interviews (61% response rate), reporting on 505 offspring. 29% of parents were BRCA1/2 mutation carriers. 334 (66%) offspring learned of their parent’s test result. Older offspring age (p<=0.01), offspring gender (female, p=0.05), parents’ negative test result (p=0.03) and parents’ education (high-school only, p=0.02) were associated with communication to offspring. The most frequently reported initial offspring responses were neutral (41%) or relief (28%). 13% of offspring were reported to experience concern or distress (11%) in response to parental communication of their test results. Distress was more frequently perceived among offspring learning of their parent’s BRCA1/2 positive or variant of uncertain significance result.
Conclusion
Many parents communicate their BRCA1/2 test results to young offspring. Parents’ perceptions of offspring responses appear to vary by offspring age and parent test result. A better understanding of how young offspring respond to information about hereditary risk for adult cancer could provide opportunities to optimize adaptive psychosocial responses to risk information and performance of health behaviors, in adolescence and throughout an at-risk lifespan.
doi:10.1002/cncr.26471
PMCID: PMC3326182  PMID: 22231763
12.  Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers with Cancer Risk and Mortality 
Context
Risk-reducing mastectomy (RRM) and salpingo-oophorectomy (RRSO) are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer.
Objectives
To estimate risk and mortality reduction stratified by mutation and prior cancer status.
Design
A prospective multi-center cohort study was used to assess the relationship of RRM and RRSO on cancer outcomes.
Setting
Twenty-two clinical and research genetics centers in Europe and North America.
Participants
2,482 women identified 1974-2008 and followed until the end of 2009 who tested positive for BRCA1 or BRCA2 mutations.
Interventions
257 (10%) underwent RRM and 993 (40%) underwent RRSO.
Main outcomes measures
Breast and ovarian cancer risk; cancer-specific and overall mortality.
Results
No breast cancers were diagnosed in women with RRM compared to 7% of women without RRM. In women who underwent RRSO, 1.1% were subsequently diagnosed with ovarian cancer, 11.4% were subsequently diagnosed with breast cancer, and 3% subsequently died from any cause, compared with 5.8% ovarian cancer, 19.2% breast cancer, and 10% overall mortality in women who did not undergo RRSO. RRSO was associated with a lower risk of ovarian cancer in those with (Hazard Ratio (HR) 0.31, 95% CI 0.12-0.82) and without a prior breast cancer (HR 0.15, 0.04-0.63), and a lower risk of first breast cancer in both BRCA1 (HR 0.63, 0.41-0.96) and BRCA2 (HR 0.36, 0.16-0.82) mutation carriers. RRSO was associated with a reduction in all-cause (HR 0.40, 0.26-0.61), breast cancer-specific (HR 0.44, 0.26-0.76), and ovarian cancer-specific (HR 0.25, 0.08-0.75) mortality.
Conclusions
Among a cohort of women with BRCA1 and BRCA2 mutations, the use of RRM was associated with a lower risk of breast cancer, and RRSO was associated with a lower risk of ovarian cancer, first breast cancer, and overall, breast-, and ovarian-cancer specific mortality.
doi:10.1001/jama.2010.1237
PMCID: PMC2948529  PMID: 20810374
13.  A prospective study of quality of life among women undergoing risk-reducing salpingo-oophorectomy versus gynecologic screening for ovarian cancer 
Gynecologic oncology  2009;112(3):594-600.
Objective
The primary objective of the study was to prospectively assess quality of life (QOL) among women at increased risk of ovarian cancer who are undergoing risk-reducing salpingo-oophorectomy (RRSO) or serial screening.
Methods
Women at increased risk of ovarian cancer who were undergoing RRSO were recruited into the study. At-risk women undergoing serial screening for early detection of ovarian cancer served as a comparison group. Participants completed measures of QOL, sexual functioning, body image, depressive symptoms, and a symptom checklist at baseline (prior to surgery for women obtaining RRSO), and then at 1-month, 6-months, and 12-months post baseline.
Results
Women who underwent surgery reported poorer physical functioning, more physical role limitations, greater pain, less vitality, poorer social functioning, and greater discomfort and less satisfaction with sexual activities at 1-month assessment compared to baseline. In contrast, women undergoing screening experienced no significant decrements in QOL or sexual functioning at 1-month assessment. Most QOL deficits observed in the surgical group were no longer apparent by 6-month assessment. Women in the surgery group were more likely to report hot flashes and vaginal dryness, but over time, symptoms of vaginal discomfort decreased to a greater extent in women who had RRSO compared to women undergoing screening. No differences in body image or depressive symptoms were observed between the two groups at any time point.
Conclusions
Short-term deficits in physical functioning and other specific domains of QOL were observed following RRSO, but most women recovered baseline functioning by 6- and 12-month assessments. Issues regarding the potential impact of surgery on short-term sexual functioning should be considered and weighed carefully, particularly among younger women.
doi:10.1016/j.ygyno.2008.11.039
PMCID: PMC2697574  PMID: 19141360
quality of life; ovarian cancer; prophylactic surgery; screening
14.  Breast and Ovarian Cancer Risk and Risk Reduction in Jewish BRCA1/2 Mutation Carriers 
Journal of Clinical Oncology  2012;30(12):1321-1328.
Purpose
Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction.
Methods
Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status.
Results
Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively; odds ratio, 1.87; 95% CI, 1.44 to 2.42). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). No significant difference was seen in cancer risk reduction after RRSO among subgroups.
Conclusion
Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care.
doi:10.1200/JCO.2011.37.8133
PMCID: PMC3341145  PMID: 22430266
15.  Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk 
Couch, Fergus J. | Wang, Xianshu | McGuffog, Lesley | Lee, Andrew | Olswold, Curtis | Kuchenbaecker, Karoline B. | Soucy, Penny | Fredericksen, Zachary | Barrowdale, Daniel | Dennis, Joe | Gaudet, Mia M. | Dicks, Ed | Kosel, Matthew | Healey, Sue | Sinilnikova, Olga M. | Lee, Adam | Bacot, François | Vincent, Daniel | Hogervorst, Frans B. L. | Peock, Susan | Stoppa-Lyonnet, Dominique | Jakubowska, Anna | Investigators, kConFab | Radice, Paolo | Schmutzler, Rita Katharina | Domchek, Susan M. | Piedmonte, Marion | Singer, Christian F. | Friedman, Eitan | Thomassen, Mads | Hansen, Thomas V. O. | Neuhausen, Susan L. | Szabo, Csilla I. | Blanco, Ignacio | Greene, Mark H. | Karlan, Beth Y. | Garber, Judy | Phelan, Catherine M. | Weitzel, Jeffrey N. | Montagna, Marco | Olah, Edith | Andrulis, Irene L. | Godwin, Andrew K. | Yannoukakos, Drakoulis | Goldgar, David E. | Caldes, Trinidad | Nevanlinna, Heli | Osorio, Ana | Terry, Mary Beth | Daly, Mary B. | van Rensburg, Elizabeth J. | Hamann, Ute | Ramus, Susan J. | Ewart Toland, Amanda | Caligo, Maria A. | Olopade, Olufunmilayo I. | Tung, Nadine | Claes, Kathleen | Beattie, Mary S. | Southey, Melissa C. | Imyanitov, Evgeny N. | Tischkowitz, Marc | Janavicius, Ramunas | John, Esther M. | Kwong, Ava | Diez, Orland | Balmaña, Judith | Barkardottir, Rosa B. | Arun, Banu K. | Rennert, Gad | Teo, Soo-Hwang | Ganz, Patricia A. | Campbell, Ian | van der Hout, Annemarie H. | van Deurzen, Carolien H. M. | Seynaeve, Caroline | Gómez Garcia, Encarna B. | van Leeuwen, Flora E. | Meijers-Heijboer, Hanne E. J. | Gille, Johannes J. P. | Ausems, Margreet G. E. M. | Blok, Marinus J. | Ligtenberg, Marjolijn J. L. | Rookus, Matti A. | Devilee, Peter | Verhoef, Senno | van Os, Theo A. M. | Wijnen, Juul T. | Frost, Debra | Ellis, Steve | Fineberg, Elena | Platte, Radka | Evans, D. Gareth | Izatt, Louise | Eeles, Rosalind A. | Adlard, Julian | Eccles, Diana M. | Cook, Jackie | Brewer, Carole | Douglas, Fiona | Hodgson, Shirley | Morrison, Patrick J. | Side, Lucy E. | Donaldson, Alan | Houghton, Catherine | Rogers, Mark T. | Dorkins, Huw | Eason, Jacqueline | Gregory, Helen | McCann, Emma | Murray, Alex | Calender, Alain | Hardouin, Agnès | Berthet, Pascaline | Delnatte, Capucine | Nogues, Catherine | Lasset, Christine | Houdayer, Claude | Leroux, Dominique | Rouleau, Etienne | Prieur, Fabienne | Damiola, Francesca | Sobol, Hagay | Coupier, Isabelle | Venat-Bouvet, Laurence | Castera, Laurent | Gauthier-Villars, Marion | Léoné, Mélanie | Pujol, Pascal | Mazoyer, Sylvie | Bignon, Yves-Jean | Złowocka-Perłowska, Elżbieta | Gronwald, Jacek | Lubinski, Jan | Durda, Katarzyna | Jaworska, Katarzyna | Huzarski, Tomasz | Spurdle, Amanda B. | Viel, Alessandra | Peissel, Bernard | Bonanni, Bernardo | Melloni, Giulia | Ottini, Laura | Papi, Laura | Varesco, Liliana | Tibiletti, Maria Grazia | Peterlongo, Paolo | Volorio, Sara | Manoukian, Siranoush | Pensotti, Valeria | Arnold, Norbert | Engel, Christoph | Deissler, Helmut | Gadzicki, Dorothea | Gehrig, Andrea | Kast, Karin | Rhiem, Kerstin | Meindl, Alfons | Niederacher, Dieter | Ditsch, Nina | Plendl, Hansjoerg | Preisler-Adams, Sabine | Engert, Stefanie | Sutter, Christian | Varon-Mateeva, Raymonda | Wappenschmidt, Barbara | Weber, Bernhard H. F. | Arver, Brita | Stenmark-Askmalm, Marie | Loman, Niklas | Rosenquist, Richard | Einbeigi, Zakaria | Nathanson, Katherine L. | Rebbeck, Timothy R. | Blank, Stephanie V. | Cohn, David E. | Rodriguez, Gustavo C. | Small, Laurie | Friedlander, Michael | Bae-Jump, Victoria L. | Fink-Retter, Anneliese | Rappaport, Christine | Gschwantler-Kaulich, Daphne | Pfeiler, Georg | Tea, Muy-Kheng | Lindor, Noralane M. | Kaufman, Bella | Shimon Paluch, Shani | Laitman, Yael | Skytte, Anne-Bine | Gerdes, Anne-Marie | Pedersen, Inge Sokilde | Moeller, Sanne Traasdahl | Kruse, Torben A. | Jensen, Uffe Birk | Vijai, Joseph | Sarrel, Kara | Robson, Mark | Kauff, Noah | Mulligan, Anna Marie | Glendon, Gord | Ozcelik, Hilmi | Ejlertsen, Bent | Nielsen, Finn C. | Jønson, Lars | Andersen, Mette K. | Ding, Yuan Chun | Steele, Linda | Foretova, Lenka | Teulé, Alex | Lazaro, Conxi | Brunet, Joan | Pujana, Miquel Angel | Mai, Phuong L. | Loud, Jennifer T. | Walsh, Christine | Lester, Jenny | Orsulic, Sandra | Narod, Steven A. | Herzog, Josef | Sand, Sharon R. | Tognazzo, Silvia | Agata, Simona | Vaszko, Tibor | Weaver, Joellen | Stavropoulou, Alexandra V. | Buys, Saundra S. | Romero, Atocha | de la Hoya, Miguel | Aittomäki, Kristiina | Muranen, Taru A. | Duran, Mercedes | Chung, Wendy K. | Lasa, Adriana | Dorfling, Cecilia M. | Miron, Alexander | Benitez, Javier | Senter, Leigha | Huo, Dezheng | Chan, Salina B. | Sokolenko, Anna P. | Chiquette, Jocelyne | Tihomirova, Laima | Friebel, Tara M. | Agnarsson, Bjarni A. | Lu, Karen H. | Lejbkowicz, Flavio | James, Paul A. | Hall, Per | Dunning, Alison M. | Tessier, Daniel | Cunningham, Julie | Slager, Susan L. | Wang, Chen | Hart, Steven | Stevens, Kristen | Simard, Jacques | Pastinen, Tomi | Pankratz, Vernon S. | Offit, Kenneth | Easton, Douglas F. | Chenevix-Trench, Georgia | Antoniou, Antonis C.
PLoS Genetics  2013;9(3):e1003212.
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Author Summary
BRCA1 mutation carriers have increased and variable risks of breast and ovarian cancer. To identify modifiers of breast and ovarian cancer risk in this population, a multi-stage GWAS of 14,351 BRCA1 mutation carriers was performed. Loci 1q32 and TCF7L2 at 10q25.3 were associated with breast cancer risk, and two loci at 4q32.2 and 17q21.31 were associated with ovarian cancer risk. The 4q32.3 ovarian cancer locus was not associated with ovarian cancer risk in the general population or in BRCA2 carriers and is the first indication of a BRCA1-specific risk locus for either breast or ovarian cancer. Furthermore, modeling the influence of these modifiers on cumulative risk of breast and ovarian cancer in BRCA1 mutation carriers for the first time showed that a wide range of individual absolute risks of each cancer can be estimated. These differences suggest that genetic risk modifiers may be incorporated into the clinical management of BRCA1 mutation carriers.
doi:10.1371/journal.pgen.1003212
PMCID: PMC3609646  PMID: 23544013
16.  Identifying putative breast cancer-associated long intergenic non-coding RNA loci by high density SNP array analysis 
Frontiers in Genetics  2012;3:299.
Recent high-throughput transcript discoveries have yielded a growing recognition of long intergenic non-coding RNAs (lincRNAs), a class of arbitrarily defined transcripts (>200 nt) that are primarily produced from the intergenic space. lincRNAs have been increasingly acknowledged for their expressional dynamics and likely functional associations with cancers. However, differential gene dosage of lincRNA genes between cancer genomes is less studied. By using the high-density Human Omni5-Quad BeadChips (Illumina), we investigated genomic copy number aberrations in a set of seven tumor-normal paired primary human mammary epithelial cells (HMECs) established from patients with invasive ductal carcinoma. This Beadchip platform includes a total of 2,435,915 SNP loci dispersed at an average interval of ~700 nt throughout the intergenic region of the human genome. We mapped annotated or putative lincRNA genes to a subset of 332,539 SNP loci, which were included in our analysis for lincRNA-associated copy number variations (CNV). We have identified 122 lincRNAs, which were affected by somatic CNV with overlapped aberrations ranging from 0.14% to 100% in length. lincRNA-associated aberrations were detected predominantly with copy number losses and preferential clustering to the ends of chromosomes. Interestingly, lincRNA genes appear to be less susceptible to CNV in comparison to both protein-coding and intergenic regions (CNV affected segments in percentage: 1.8%, 37.5%, and 60.6%, respectively). In summary, our study established a novel approach utilizing high-resolution SNP array to identify lincRNA candidates, which could functionally link to tumorigenesis, and provide new strategies for the diagnosis and treatment of breast cancer.
doi:10.3389/fgene.2012.00299
PMCID: PMC3528021  PMID: 23267367
long intergenic non-coding RNA (lincRNA); copy number variation (CNV); SNP array; breast cancer
17.  Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers 
Im, Kate M. | Kirchhoff, Tomas | Wang, Xianshu | Green, Todd | Chow, Clement Y. | Vijai, Joseph | Korn, Joshua | Gaudet, Mia M. | Fredericksen, Zachary | Pankratz, V. Shane | Guiducci, Candace | Crenshaw, Andrew | McGuffog, Lesley | Kartsonaki, Christiana | Morrison, Jonathan | Healey, Sue | Sinilnikova, Olga M. | Mai, Phuong L. | Greene, Mark H. | Piedmonte, Marion | Rubinstein, Wendy S. | Hogervorst, Frans B. | Rookus, Matti A. | Collée, J. Margriet | Hoogerbrugge, Nicoline | van Asperen, Christi J. | Meijers-Heijboer, Hanne E. J. | Van Roozendaal, Cees E. | Caldes, Trinidad | Perez-Segura, Pedro | Jakubowska, Anna | Lubinski, Jan | Huzarski, Tomasz | Blecharz, Paweł | Nevanlinna, Heli | Aittomäki, Kristiina | Lazaro, Conxi | Blanco, Ignacio | Barkardottir, Rosa B. | Montagna, Marco | D'Andrea, Emma | Devilee, Peter | Olopade, Olufunmilayo I. | Neuhausen, Susan L. | Peissel, Bernard | Bonanni, Bernardo | Peterlongo, Paolo | Singer, Christian F. | Rennert, Gad | Lejbkowicz, Flavio | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Toland, Amanda Ewart | Caligo, Maria Adelaide | Beattie, Mary S. | Chan, Salina | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Timothy R. | Phelan, Catherine | Narod, Steven | John, Esther M. | Hopper, John L. | Buys, Saundra S. | Daly, Mary B. | Southey, Melissa C. | Terry, Mary-Beth | Tung, Nadine | Hansen, Thomas v. O. | Osorio, Ana | Benitez, Javier | Durán, Mercedes | Weitzel, Jeffrey N. | Garber, Judy | Hamann, Ute | Peock, Susan | Cook, Margaret | Oliver, Clare T. | Frost, Debra | Platte, Radka | Evans, D. Gareth | Eeles, Ros | Izatt, Louise | Paterson, Joan | Brewer, Carole | Hodgson, Shirley | Morrison, Patrick J. | Porteous, Mary | Walker, Lisa | Rogers, Mark T. | Side, Lucy E. | Godwin, Andrew K. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Laitman, Yael | Meindl, Alfons | Deissler, Helmut | Varon-Mateeva, Raymonda | Preisler-Adams, Sabine | Kast, Karin | Venat-Bouvet, Laurence | Stoppa-Lyonnet, Dominique | Chenevix-Trench, Georgia | Easton, Douglas F. | Klein, Robert J. | Daly, Mark J. | Friedman, Eitan | Dean, Michael | Clark, Andrew G. | Altshuler, David M. | Antoniou, Antonis C. | Couch, Fergus J. | Offit, Kenneth | Gold, Bert
Human genetics  2011;130(5):685-699.
Abstract Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage dis-equilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
doi:10.1007/s00439-011-1003-z
PMCID: PMC3196382  PMID: 21597964
18.  Identifying breast cancer risk loci by global differential allele-specific expression (DASE) analysis in mammary epithelial transcriptome 
BMC Genomics  2012;13:570.
Background
The significant mortality associated with breast cancer (BCa) suggests a need to improve current research strategies to identify new genes that predispose women to breast cancer. Differential allele-specific expression (DASE) has been shown to contribute to phenotypic variables in humans and recently to the pathogenesis of cancer. We previously reported that nonsense-mediated mRNA decay (NMD) could lead to DASE of BRCA1/2, which is associated with elevated susceptibility to breast cancer. In addition to truncation mutations, multiple genetic and epigenetic factors can contribute to DASE, and we propose that DASE is a functional index for cis-acting regulatory variants and pathogenic mutations, and that global analysis of DASE in breast cancer precursor tissues can be used to identify novel causative alleles for breast cancer susceptibility.
Results
To test our hypothesis, we employed the Illumina® Omni1-Quad BeadChip in paired genomic DNA (gDNA) and double-stranded cDNA (ds-cDNA) samples prepared from eight BCa patient-derived normal mammary epithelial lines (HMEC). We filtered original array data according to heterozygous genotype calls and calculated DASE values using the Log ratio of cDNA allele intensity, which was normalized to the corresponding gDNA. We developed two statistical methods, SNP- and gene-based approaches, which allowed us to identify a list of 60 candidate DASE loci (DASE ≥ 2.00, P ≤ 0.01, FDR ≤ 0.05) by both methods. Ingenuity Pathway Analysis of DASE loci revealed one major breast cancer-relevant interaction network, which includes two known cancer causative genes, ZNF331 (DASE = 2.31, P = 0.0018, FDR = 0.040) and USP6 (DASE = 4.80, P = 0.0013, FDR = 0.013), and a breast cancer causative gene, DMBT1 (DASE=2.03, P = 0.0017, FDR = 0.014). Sequence analysis of a 5′ RACE product of DMBT1 demonstrated that rs2981745, a putative breast cancer risk locus, appears to be one of the causal variants leading to DASE in DMBT1.
Conclusions
Our study demonstrated for the first time that global DASE analysis is a powerful new approach to identify breast cancer risk allele(s).
doi:10.1186/1471-2164-13-570
PMCID: PMC3532379  PMID: 23107584
Differential allele-specific expression; Breast cancer susceptibility; SNP array; DMBT1
19.  Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 
Couch, Fergus J. | Gaudet, Mia M. | Antoniou, Antonis C. | Ramus, Susan J. | Kuchenbaecker, Karoline B. | Soucy, Penny | Beesley, Jonathan | Chen, Xiaoqing | Wang, Xianshu | Kirchhoff, Tomas | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | Healey, Sue | Sinilnikova, Olga M. | Andrulis, Irene L. | Ozcelik, Hilmi | Mulligan, Anna Marie | Thomassen, Mads | Gerdes, Anne-Marie | Jensen, Uffe Birk | Skytte, Anne-Bine | Kruse, Torben A. | Caligo, Maria A. | von Wachenfeldt, Anna | Barbany-Bustinza, Gisela | Loman, Niklas | Soller, Maria | Ehrencrona, Hans | Karlsson, Per | Nathanson, Katherine L. | Rebbeck, Timothy R. | Domchek, Susan M. | Jakubowska, Ania | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Złowocka, Elżbieta | Huzarski, Tomasz | Byrski, Tomasz | Gronwald, Jacek | Cybulski, Cezary | Górski, Bohdan | Osorio, Ana | Durán, Mercedes | Tejada, María Isabel | Benitez, Javier | Hamann, Ute | Hogervorst, Frans B.L. | van Os, Theo A. | van Leeuwen, Flora E. | Meijers-Heijboer, Hanne E.J. | Wijnen, Juul | Blok, Marinus J. | Kets, Marleen | Hooning, Maartje J. | Oldenburg, Rogier A. | Ausems, Margreet G.E.M. | Peock, Susan | Frost, Debra | Ellis, Steve D. | Platte, Radka | Fineberg, Elena | Evans, D. Gareth | Jacobs, Chris | Eeles, Rosalind A. | Adlard, Julian | Davidson, Rosemarie | Eccles, Diana M. | Cole, Trevor | Cook, Jackie | Paterson, Joan | Brewer, Carole | Douglas, Fiona | Hodgson, Shirley V. | Morrison, Patrick J. | Walker, Lisa | Porteous, Mary E. | Kennedy, M. John | Side, Lucy E. | Bove, Betsy | Godwin, Andrew K. | Stoppa-Lyonnet, Dominique | Fassy-Colcombet, Marion | Castera, Laurent | Cornelis, François | Mazoyer, Sylvie | Léoné, Mélanie | Boutry-Kryza, Nadia | Bressac-de Paillerets, Brigitte | Caron, Olivier | Pujol, Pascal | Coupier, Isabelle | Delnatte, Capucine | Akloul, Linda | Lynch, Henry T. | Snyder, Carrie L. | Buys, Saundra S. | Daly, Mary B. | Terry, MaryBeth | Chung, Wendy K. | John, Esther M. | Miron, Alexander | Southey, Melissa C. | Hopper, John L. | Goldgar, David E. | Singer, Christian F. | Rappaport, Christine | Tea, Muy-Kheng M. | Fink-Retter, Anneliese | Hansen, Thomas V. O. | Nielsen, Finn C. | Arason, Aðalgeir | Vijai, Joseph | Shah, Sohela | Sarrel, Kara | Robson, Mark E. | Piedmonte, Marion | Phillips, Kelly | Basil, Jack | Rubinstein, Wendy S. | Boggess, John | Wakeley, Katie | Ewart-Toland, Amanda | Montagna, Marco | Agata, Simona | Imyanitov, Evgeny N. | Isaacs, Claudine | Janavicius, Ramunas | Lazaro, Conxi | Blanco, Ignacio | Feliubadalo, Lidia | Brunet, Joan | Gayther, Simon A | Pharoah, Paul PD | Odunsi, Kunle O. | Karlan, Beth Y. | Walsh, Christine S. | Olah, Edith | Teo, Soo Hwang | Ganz, Patricia A. | Beattie, Mary S. | van Rensburg, Elizabeth J. | Dorfling, Cecelia M. | Diez, Orland | Kwong, Ava | Schmutzler, Rita K. | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Heidemann, Simone | Niederacher, Dieter | Preisler-Adams, Sabine | Gadzicki, Dorothea | Varon-Mateeva, Raymonda | Deissler, Helmut | Gehrig, Andrea | Sutter, Christian | Kast, Karin | Fiebig, Britta | Heinritz, Wolfram | Caldes, Trinidad | de la Hoya, Miguel | Muranen, Taru A. | Nevanlinna, Heli | Tischkowitz, Marc D. | Spurdle, Amanda B. | Neuhausen, Susan L. | Ding, Yuan Chun | Lindor, Noralane M. | Fredericksen, Zachary | Pankratz, V. Shane | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Barile, Monica | Bernard, Loris | Viel, Alessandra | Giannini, Giuseppe | Varesco, Liliana | Radice, Paolo | Greene, Mark H. | Mai, Phuong L. | Easton, Douglas F. | Chenevix-Trench, Georgia | Offit, Kenneth | Simard, Jacques
Background
Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
Methods
Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.
Results
We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers (hazard ratio (HR)=1.17; 95%CI 1.07–1.27; p=7.42×10−4) and between rs16917302 at ZNF365 (HR=0.84; 95%CI 0.73–0.97; p=0.017) but not rs311499 at 20q13.3 (HR=1.11; 95%CI 0.94–1.31; p=0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR=1.16; 95%CI 1.05–1.29; p=3.8×10−4) and BRCA2 mutation carriers (HR=1.30; 95%CI 1.10–1.52; p=1.8×10−3).
Conclusions
19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.
Impact
These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers.
doi:10.1158/1055-9965.EPI-11-0888
PMCID: PMC3319317  PMID: 22351618
BRCA1; BRCA2; breast cancer risk; ovarian cancer risk; 19p13.1; ZNF365
20.  Large Prospective Study of Ovarian Cancer Screening in High-risk Women: CA125 Cut-point Defined by Menopausal Status 
Background
Previous screening trials for early detection of ovarian cancer in postmenopausal women have used the standard CA125 cut-point of 35 U/mL, the 98th percentile in this population yielding a 2% false positive rate, while the same cut-point in trials of premenopausal women results in substantially higher false positive rates. We investigated demographic and clinical factors predicting CA125 distributions, including 98th percentiles, in a large population of high-risk women participating in two ovarian cancer screening studies with common eligibility criteria and screening protocols.
Methods
Baseline CA125 values and clinical and demographic data from 3,692 women participating in screening studies conducted by the NCI-sponsored Cancer Genetics Network and Gynecologic Oncology Group were combined for this pre-planned analysis. Due to the large effect of menopausal status on CA125 levels, statistical analyses were conducted separately in pre- and postmenopausal subjects to determine the impact of other baseline factors on predicted CA125 cut-points based on the 98th percentile.
Results
The primary clinical factor affecting CA125 cut-points was menopausal status, with premenopausal women having a significantly higher cut-point of 50 U/mL while in postmenopausal subjects the standard cut-point of 35 U/mL was recapitulated. In premenopausal women, current oral contraceptive (OC) users had a cut-point of 40 U/mL.
Conclusions
To achieve a 2% false positive rate in ovarian cancer screening trials and in high-risk women choosing to be screened, the cut-point for initial CA125 testing should be personalized primarily for menopausal status (~ 50 for premenopausal women, 40 for premenopausal on OC, 35 for postmenopausal women).
doi:10.1158/1940-6207.CAPR-10-0402
PMCID: PMC3172691  PMID: 21893500
CA125; ovarian cancer screening; biomarker
21.  Genetic Variation in IGF2 and HTRA1 and Breast Cancer Risk among BRCA1 and BRCA2 Carriers 
Background
BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers.
Methods
A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made.
Results
Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2).
Conclusions
We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers.
Impact
These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers.
doi:10.1158/1055-9965.EPI-10-1336
PMCID: PMC3352680  PMID: 21708937
22.  Risk-Reducing Salpingo-Oophorectomy for the Prevention of BRCA1- and BRCA2-Associated Breast and Gynecologic Cancer: A Multicenter, Prospective Study 
Journal of Clinical Oncology  2008;26(8):1331-1337.
Purpose
Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCA-associated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers.
Patients and Methods
A total of 1,079 women 30 years of age and older with ovaries in situ and a deleterious BRCA1 or BRCA2 mutation were enrolled onto prospective follow-up studies at one of 11 centers from November 1, 1994 to December 1, 2004. Women self-selected RRSO or observation. Follow-up information through November 30, 2005, was collected by questionnaire and medical record review. The effect of RRSO on time to diagnosis of breast or BRCA-associated gynecologic cancer was analyzed using a Cox proportional-hazards model.
Results
During 3-year follow-up, RRSO was associated with an 85% reduction in BRCA1-associated gynecologic cancer risk (hazard ratio [HR] = 0.15; 95% CI, 0.04 to 0.56) and a 72% reduction in BRCA2-associated breast cancer risk (HR = 0.28; 95% CI, 0.08 to 0.92). While protection against BRCA1-associated breast cancer (HR = 0.61; 95% CI, 0.30 to 1.22) and BRCA2-associated gynecologic cancer (HR = 0.00; 95% CI, not estimable) was suggested, neither effect reached statistical significance.
Conclusion
The protection conferred by RRSO against breast and gynecologic cancers may differ between carriers of BRCA1 and BRCA2 mutations. Further studies evaluating the efficacy of risk-reduction strategies in BRCA mutation carriers should stratify by the specific gene mutated.
doi:10.1200/JCO.2007.13.9626
PMCID: PMC3306809  PMID: 18268356
23.  Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1 Interacting Genes 
Cancer research  2011;71(17):5792-5805.
Inherited BRCA1 mutations confer elevated breast cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, TOPBP1 and time to breast and ovarian cancer diagnosis. False Discovery Rate (FDR) adjusted p-value for overall association of haplotypes (pFDR) with breast cancer were identified at ATM (pFDR =0.029), BRCC45 (pFDR=0.0.19), BRIP1 (pFDR =0.008), CTIP (pFDR =0.017), MERIT40 (pFDR =0.019), NBS1 (pFDR=0.003), RAD50 (pFDR=0.014), and TOPBP1 (pFDR =0.011) and were associated with breast cancer risk. Haplotypes at ABRA1 (pFDR=0.007), BRCC45 (pFDR=0.016 and pFDR=0.005 in two haplotype blocks) and RAP80 (pFDR<0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.
doi:10.1158/0008-5472.CAN-11-0773
PMCID: PMC3170727  PMID: 21799032
24.  Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1 Interacting Genes 
Cancer research  2011;71(17):5792-5805.
Inherited BRCA1 mutations confer elevated breast cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, TOPBP1 and time to breast and ovarian cancer diagnosis. False Discovery Rate (FDR) adjusted p-value for overall association of haplotypes (pFDR) with breast cancer were identified at ATM (pFDR =0.029), BRCC45 (pFDR=0.0.19), BRIP1 (pFDR =0.008), CTIP (pFDR =0.017), MERIT40 (pFDR =0.019), NBS1 (pFDR=0.003), RAD50 (pFDR=0.014), and TOPBP1 (pFDR =0.011) and were associated with breast cancer risk. Haplotypes at ABRA1 (pFDR=0.007), BRCC45 (pFDR=0.016 and pFDR=0.005 in two haplotype blocks) and RAP80 (pFDR<0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.
doi:10.1158/0008-5472.CAN-11-0773
PMCID: PMC3170727  PMID: 21799032
25.  Genetic counselor opinions of, and experiences with telephone communication of BRCA1/2 test results 
Clinical genetics  2010;79(2):125-131.
Purpose
BRCA1/2 test disclosure has, historically, been conducted in-person by genetics professionals. Given increasing demand for, and access to, genetic testing, interest in telephone and Internet genetic services, including disclosure of test results, has increased.
Methods
Semi-structured interviews with genetic counselors were conducted to determine interest in, and experiences with telephone disclosure of BRCA1/2 test results. Descriptive data are summarized with response proportions.
Results
194 genetic counselors completed self-administered surveys via the web. Although 98% had provided BRCA1/2 results by telephone, 77% had never provided pre-test counseling by telephone. Genetic counselors reported perceived advantages and disadvantages to telephone disclosure. Thirty-two percent of participants described experiences that made them question this practice. Genetic counselors more frequently reported discomfort with telephone disclosure of a positive result or variant of uncertain significance (p<0.01) than other results. Overall, 73% of participants reported interest in telephone disclosure.
Conclusion
Many genetic counselors have provided telephone disclosure, however, most, infrequently. Genetic counselors identify potential advantages and disadvantages to telephone disclosure, and recognize the potential for testing and patient factors to impact patient outcomes. Further research evaluating the impact of testing and patient factors on cognitive, affective, social and behavioral outcomes of alternative models of communicating genetic information is warranted.
doi:10.1111/j.1399-0004.2010.01540.x
PMCID: PMC3059740  PMID: 21039431
BRCA 1/2; communication; genetic counselors; genetic testing; telephone

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