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1.  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
2.  Chemotherapy-Induced Amenorrhea in Patients With Breast Cancer With a BRCA1 or BRCA2 Mutation 
Journal of Clinical Oncology  2013;31(31):3914-3919.
Purpose
To determine the likelihood of long-term amenorrhea after treatment with chemotherapy in women with breast cancer who carry a BRCA1 or BRCA2 mutation.
Patients and Methods
We conducted a multicenter survey of 1,954 young women with a BRCA1 or BRCA2 mutation who were treated for breast cancer. We included premenopausal women who were diagnosed with invasive breast cancer between 26 and 47 years of age. We determined the age of onset of amenorrhea after breast cancer for women who were and were not treated with chemotherapy, alone or with tamoxifen. We considered chemotherapy-induced amenorrhea to have occurred when the patient experienced ≥ 2 years of amenorrhea, commencing within 2 years of initiating chemotherapy, with no resumption of menses.
Results
Of the 1,426 women who received chemotherapy, 35% experienced long-term amenorrhea. Of the 528 women who did not receive chemotherapy, 5.3% developed long-term amenorrhea. The probabilities of chemotherapy-induced amenorrhea were 7.2% for women diagnosed before age 30 years, 33% for women age 31 to 44 years, and 79% for women diagnosed after age 45 years (P trend < .001). The probability of induced amenorrhea was higher for women who received tamoxifen than for those who did not (52% v 29%; P < .001).
Conclusion
Age at treatment and use of tamoxifen are important predictors of chemotherapy-induced amenorrhea in women who carry a BRCA1 or BRCA2 mutation. The risk of induced long-term amenorrhea does not seem to be greater among mutation carriers than among women who do not carry a mutation.
doi:10.1200/JCO.2012.47.7893
PMCID: PMC3805929  PMID: 23980083
3.  Prevalence and Type of BRCA Mutations in Hispanics Undergoing Genetic Cancer Risk Assessment in the Southwestern United States: A Report From the Clinical Cancer Genetics Community Research Network 
Journal of Clinical Oncology  2012;31(2):210-216.
Purpose
To determine the prevalence and type of BRCA1 and BRCA2 (BRCA) mutations among Hispanics in the Southwestern United States and their potential impact on genetic cancer risk assessment (GCRA).
Patients and Methods
Hispanics (n = 746) with a personal or family history of breast and/or ovarian cancer were enrolled in an institutional review board–approved registry and received GCRA and BRCA testing within a consortium of 14 clinics. Population-based Hispanic breast cancer cases (n = 492) enrolled in the Northern California Breast Cancer Family Registry, negative by sequencing for BRCA mutations, were analyzed for the presence of the BRCA1 ex9-12del large rearrangement.
Results
Deleterious BRCA mutations were detected in 189 (25%) of 746 familial clinic patients (124 BRCA1, 65 BRCA2); 21 (11%) of 189 were large rearrangement mutations, of which 62% (13 of 21) were BRCA1 ex9-12del. Nine recurrent mutations accounted for 53% of the total. Among these, BRCA1 ex9-12del seems to be a Mexican founder mutation and represents 10% to 12% of all BRCA1 mutations in clinic- and population-based cohorts in the United States.
Conclusion
BRCA mutations were prevalent in the largest study of Hispanic breast and/or ovarian cancer families in the United States to date, and a significant proportion were large rearrangement mutations. The high frequency of large rearrangement mutations warrants screening in every case. We document the first Mexican founder mutation (BRCA1 ex9-12del), which, along with other recurrent mutations, suggests the potential for a cost-effective panel approach to ancestry-informed GCRA.
doi:10.1200/JCO.2011.41.0027
PMCID: PMC3532393  PMID: 23233716
4.  Identification of six new susceptibility loci for invasive epithelial ovarian cancer 
Kuchenbaecker, Karoline B. | Ramus, Susan J. | Tyrer, Jonathan | Lee, Andrew | Shen, Howard C. | Beesley, Jonathan | Lawrenson, Kate | McGuffog, Lesley | Healey, Sue | Lee, Janet M. | Spindler, Tassja J. | Lin, Yvonne G. | Pejovic, Tanja | Bean, Yukie | Li, Qiyuan | Coetzee, Simon | Hazelett, Dennis | Miron, Alexander | Southey, Melissa | Terry, Mary Beth | Goldgar, David E. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Neuhausen, Susan L. | Ding, Yuan Chun | Hansen, Thomas V. O. | Jønson, Lars | Gerdes, Anne-Marie | Ejlertsen, Bent | Barrowdale, Daniel | Dennis, Joe | Benitez, Javier | Osorio, Ana | Garcia, Maria Jose | Komenaka, Ian | Weitzel, Jeffrey N. | Ganschow, Pamela | Peterlongo, Paolo | Bernard, Loris | Viel, Alessandra | Bonanni, Bernardo | Peissel, Bernard | Manoukian, Siranoush | Radice, Paolo | Papi, Laura | Ottini, Laura | Fostira, Florentia | Konstantopoulou, Irene | Garber, Judy | Frost, Debra | Perkins, Jo | Platte, Radka | Ellis, Steve | Godwin, Andrew K. | Schmutzler, Rita Katharina | Meindl, Alfons | Engel, Christoph | Sutter, Christian | Sinilnikova, Olga M. | Damiola, Francesca | Mazoyer, Sylvie | Stoppa-Lyonnet, Dominique | Claes, Kathleen | De Leeneer, Kim | Kirk, Judy | Rodriguez, Gustavo C. | Piedmonte, Marion | O'Malley, David M. | de la Hoya, Miguel | Caldes, Trinidad | Aittomäki, Kristiina | Nevanlinna, Heli | Collée, J. Margriet | Rookus, Matti A. | Oosterwijk, Jan C. | Tihomirova, Laima | Tung, Nadine | Hamann, Ute | Isaacs, Claudine | Tischkowitz, Marc | Imyanitov, Evgeny N. | Caligo, Maria A. | Campbell, Ian | Hogervorst, Frans B.L. | Olah, Edith | Diez, Orland | Blanco, Ignacio | Brunet, Joan | Lazaro, Conxi | Pujana, Miquel Angel | Jakubowska, Anna | Gronwald, Jacek | Lubinski, Jan | Sukiennicki, Grzegorz | Barkardottir, Rosa B. | Plante, Marie | Simard, Jacques | Soucy, Penny | Montagna, Marco | Tognazzo, Silvia | Teixeira, Manuel R. | Pankratz, Vernon S. | Wang, Xianshu | Lindor, Noralane | Szabo, Csilla I. | Kauff, Noah | Vijai, Joseph | Aghajanian, Carol A. | Pfeiler, Georg | Berger, Andreas | Singer, Christian F. | Tea, Muy-Kheng | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Rennert, Gad | Mulligan, Anna Marie | Tchatchou, Sandrine | Andrulis, Irene L. | Glendon, Gord | Toland, Amanda Ewart | Jensen, Uffe Birk | Kruse, Torben A. | Thomassen, Mads | Bojesen, Anders | Zidan, Jamal | Friedman, Eitan | Laitman, Yael | Soller, Maria | Liljegren, Annelie | Arver, Brita | Einbeigi, Zakaria | Stenmark-Askmalm, Marie | Olopade, Olufunmilayo I. | Nussbaum, Robert L. | Rebbeck, Timothy R. | Nathanson, Katherine L. | Domchek, Susan M. | Lu, Karen H. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Fasching, Peter A. | Lambrechts, Diether | Nieuwenhuysen, Els Van | Vergote, Ignace | Lambrechts, Sandrina | Dicks, Ed | Doherty, Jennifer A. | Wicklund, Kristine G. | Rossing, Mary Anne | Rudolph, Anja | Chang-Claude, Jenny | Wang-Gohrke, Shan | Eilber, Ursula | Moysich, Kirsten B. | Odunsi, Kunle | Sucheston-Campbell, Lara | Lele, Shashi | Wilkens, Lynne R. | Goodman, Marc T. | Thompson, Pamela J. | Shvetsov, Yurii B. | Runnebaum, Ingo B. | Dürst, Matthias | Hillemanns, Peter | Dörk, Thilo | Antonenkova, Natalia | Bogdanova, Natalia | Leminen, Arto | Pelttari, Liisa M. | Butzow, Ralf | Modugno, Francesmary | Kelley, Joseph L. | Edwards, Robert P. | Ness, Roberta B. | du Bois, Andreas | Heitz, Florian | Schwaab, Ira | Harter, Philipp | Matsuo, Keitaro | Hosono, Satoyo | Orsulic, Sandra | Jensen, Allan | Kjaer, Susanne Kruger | Hogdall, Estrid | Hasmad, Hanis Nazihah | Noor Azmi, Mat Adenan | Teo, Soo-Hwang | Woo, Yin-Ling | Fridley, Brooke L. | Goode, Ellen L. | Cunningham, Julie M. | Vierkant, Robert A. | Bruinsma, Fiona | Giles, Graham G. | Liang, Dong | Hildebrandt, Michelle A.T. | Wu, Xifeng | Levine, Douglas A. | Bisogna, Maria | Berchuck, Andrew | Iversen, Edwin S. | Schildkraut, Joellen M. | Concannon, Patrick | Weber, Rachel Palmieri | Cramer, Daniel W. | Terry, Kathryn L. | Poole, Elizabeth M. | Tworoger, Shelley S. | Bandera, Elisa V. | Orlow, Irene | Olson, Sara H. | Krakstad, Camilla | Salvesen, Helga B. | Tangen, Ingvild L. | Bjorge, Line | van Altena, Anne M. | Aben, Katja K.H. | Kiemeney, Lambertus A. | Massuger, Leon F.A.G. | Kellar, Melissa | Brooks-Wilson, Angela | Kelemen, Linda E. | Cook, Linda S. | Le, Nhu D. | Cybulski, Cezary | Yang, Hannah | Lissowska, Jolanta | Brinton, Louise A. | Wentzensen, Nicolas | Hogdall, Claus | Lundvall, Lene | Nedergaard, Lotte | Baker, Helen | Song, Honglin | Eccles, Diana | McNeish, Ian | Paul, James | Carty, Karen | Siddiqui, Nadeem | Glasspool, Rosalind | Whittemore, Alice S. | Rothstein, Joseph H. | McGuire, Valerie | Sieh, Weiva | Ji, Bu-Tian | Zheng, Wei | Shu, Xiao-Ou | Gao, Yu-Tang | Rosen, Barry | Risch, Harvey A. | McLaughlin, John R. | Narod, Steven A. | Monteiro, Alvaro N. | Chen, Ann | Lin, Hui-Yi | Permuth-Wey, Jenny | Sellers, Thomas A. | Tsai, Ya-Yu | Chen, Zhihua | Ziogas, Argyrios | Anton-Culver, Hoda | Gentry-Maharaj, Aleksandra | Menon, Usha | Harrington, Patricia | Lee, Alice W. | Wu, Anna H. | Pearce, Celeste L. | Coetzee, Gerhard A. | Pike, Malcolm C. | Dansonka-Mieszkowska, Agnieszka | Timorek, Agnieszka | Rzepecka, Iwona K. | Kupryjanczyk, Jolanta | Freedman, Matt | Noushmehr, Houtan | Easton, Douglas F. | Offit, Kenneth | Couch, Fergus J. | Gayther, Simon | Pharoah, Paul P. | Antoniou, Antonis C. | Chenevix-Trench, Georgia
Nature genetics  2015;47(2):164-171.
doi:10.1038/ng.3185
PMCID: PMC4445140  PMID: 25581431
5.  Human Nail Clippings as a Source of DNA for Genetic Studies 
Open journal of epidemiology  2015;5(1):41-50.
Blood samples have traditionally been used as the main source of DNA for genetic analysis. However, this source can be difficult in terms of collection, transportation, and long-term storage. In this study, we investigated whether human nail clippings could be used as a source of DNA for SNP genotyping, null-allele detection, and whole-genome amplification. From extracted nail DNA, we achieved amplicons up to a length of ~400 bp and >96% concordance for SNP genotyping and 100% concordance for null-allele detection compared to DNA derived from matched blood samples. For whole-genome amplification, OmniPlex performed better than Multiple Displacement Amplification with a success rate of 89.3% and 76.8% for SNP genotyping and null-allele detection, respectively. Concordance was ~98% for both methods. When combined with OmniPlex whole-genome amplification, human nail clippings could potentially be used as an alternative to whole blood as a less invasive and more convenient source of DNA for genotyping studies.
doi:10.4236/ojepi.2015.51006
PMCID: PMC4499506  PMID: 26180661
Single Nucleotide Polymorphism (SNP); Nail Clippings; Genotyping; Whole Genome Amplification (WGA)
6.  Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 
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 | Chen, Bowang | Rookus, Matti A. | Schmidt, Marjanka K | van der Baan, Frederieke H. | Spurdle, Amanda B. | Walker, Logan C. | Lose, Felicity | Maia, Ana-Teresa | Montagna, Marco | Matricardi, Laura | Lubinski, Jan | Jakubowska, Anna | Gómez Garcia, Encarna B. | Olopade, Olufunmilayo I. | Nussbaum, Robert L. | Nathanson, Katherine L. | Domchek, Susan M. | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Orsulic, Sandra | Lester, Jenny | Chung, Wendy K. | Miron, Alex | Southey, Melissa C. | Goldgar, David E. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Ding, Yuan Chun | Neuhausen, Susan L. | Hansen, Thomas V. O. | Gerdes, Anne-Marie | Ejlertsen, Bent | Jønson, Lars | Osorio, Ana | Martínez-Bouzas, Cristina | Benitez, Javier | Conway, Edye E. | Blazer, Kathleen R. | Weitzel, Jeffrey N. | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Barile, Monica | Ficarazzi, Filomena | Mariette, Frederique | Fortuzzi, Stefano | Viel, Alessandra | Giannini, Giuseppe | Papi, Laura | Martayan, Aline | Tibiletti, Maria Grazia | Radice, Paolo | Vratimos, Athanassios | Fostira, Florentia | Garber, Judy E. | Donaldson, Alan | Brewer, Carole | Foo, Claire | Evans, D. Gareth R. | Frost, Debra | Eccles, Diana | Brady, Angela | Cook, Jackie | Tischkowitz, Marc | Adlard, Julian | Barwell, Julian | Walker, Lisa | Izatt, Louise | Side, Lucy E. | Kennedy, M. John | Rogers, Mark T. | Porteous, Mary E. | Morrison, Patrick J. | Platte, Radka | Davidson, Rosemarie | Hodgson, Shirley V. | Ellis, Steve | Cole, Trevor | Godwin, Andrew K. | Claes, Kathleen | Van Maerken, Tom | Meindl, Alfons | Gehrig, Andrea | Sutter, Christian | Engel, Christoph | Niederacher, Dieter | Steinemann, Doris | Plendl, Hansjoerg | Kast, Karin | Rhiem, Kerstin | Ditsch, Nina | Arnold, Norbert | Varon-Mateeva, Raymonda | Wappenschmidt, Barbara | Wang-Gohrke, Shan | Paillerets, Brigitte Bressac-de | Buecher, Bruno | Delnatte, Capucine | Houdayer, Claude | Stoppa-Lyonnet, Dominique | Damiola, Francesca | Coupier, Isabelle | Barjhoux, Laure | Venat-Bouvet, Laurence | Golmard, Lisa | Boutry-Kryza, Nadia | Sinilnikova, Olga M. | Caron, Olivier | Pujol, Pascal | Mazoyer, Sylvie | Belotti, Muriel | Piedmonte, Marion | Friedlander, Michael L. | Rodriguez, Gustavo C. | Copeland, Larry J | de la Hoya, Miguel | Segura, Pedro Perez | Nevanlinna, Heli | Aittomäki, Kristiina | van Os, Theo A.M. | Meijers-Heijboer, Hanne E.J. | van der Hout, Annemarie H. | Vreeswijk, Maaike P.G. | Hoogerbrugge, Nicoline | Ausems, Margreet G.E.M. | van Doorn, Helena C. | Collée, J. Margriet | Olah, Edith | Diez, Orland | Blanco, Ignacio | Lazaro, Conxi | Brunet, Joan | Feliubadalo, Lidia | Cybulski, Cezary | Gronwald, Jacek | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Sukiennicki, Grzegorz | Arason, Adalgeir | Chiquette, Jocelyne | Teixeira, Manuel R. | Olswold, Curtis | Couch, Fergus J. | Lindor, Noralane M. | Wang, Xianshu | Szabo, Csilla I. | Offit, Kenneth | Corines, Marina | Jacobs, Lauren | Robson, Mark E. | Zhang, Liying | Joseph, Vijai | Berger, Andreas | Singer, Christian F. | Rappaport, Christine | Kaulich, Daphne Geschwantler | Pfeiler, Georg | Tea, Muy-Kheng M. | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Rennert, Gad | Mulligan, Anna Marie | Glendon, Gord | Tchatchou, Sandrine | Andrulis, Irene L. | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Thomassen, Mads | Jensen, Uffe Birk | Laitman, Yael | Rantala, Johanna | von Wachenfeldt, Anna | Ehrencrona, Hans | Askmalm, Marie Stenmark | Borg, Åke | Kuchenbaecker, Karoline B. | McGuffog, Lesley | Barrowdale, Daniel | Healey, Sue | Lee, Andrew | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Friedman, Eitan
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 non-genetic 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 0.005–1.000. 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.
doi:10.1158/1055-9965.EPI-14-0532
PMCID: PMC4294951  PMID: 25336561
BRCA1 BRCA2 mutations; BRCA-mutation carriers; Breast cancer risk; Ovarian cancer risk; Candidate genetic risk modifiers
7.  Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 
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 | Chen, Bowang | Rookus, Matti A. | Schmidt, Marjanka K | van der Baan, Frederieke H. | Spurdle, Amanda B. | Walker, Logan C. | Lose, Felicity | Maia, Ana-Teresa | Montagna, Marco | Matricardi, Laura | Lubinski, Jan | Jakubowska, Anna | Gómez Garcia, Encarna B. | Olopade, Olufunmilayo I. | Nussbaum, Robert L. | Nathanson, Katherine L. | Domchek, Susan M. | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Orsulic, Sandra | Lester, Jenny | Chung, Wendy K. | Miron, Alex | Southey, Melissa C. | Goldgar, David E. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Ding, Yuan Chun | Neuhausen, Susan L. | Hansen, Thomas V. O. | Gerdes, Anne-Marie | Ejlertsen, Bent | Jønson, Lars | Osorio, Ana | Martínez-Bouzas, Cristina | Benitez, Javier | Conway, Edye E. | Blazer, Kathleen R. | Weitzel, Jeffrey N. | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Barile, Monica | Ficarazzi, Filomena | Mariette, Frederique | Fortuzzi, Stefano | Viel, Alessandra | Giannini, Giuseppe | Papi, Laura | Martayan, Aline | Tibiletti, Maria Grazia | Radice, Paolo | Vratimos, Athanassios | Fostira, Florentia | Garber, Judy E. | Donaldson, Alan | Brewer, Carole | Foo, Claire | Evans, D. Gareth R. | Frost, Debra | Eccles, Diana | Brady, Angela | Cook, Jackie | Tischkowitz, Marc | Adlard, Julian | Barwell, Julian | Walker, Lisa | Izatt, Louise | Side, Lucy E. | Kennedy, M. John | Rogers, Mark T. | Porteous, Mary E. | Morrison, Patrick J. | Platte, Radka | Davidson, Rosemarie | Hodgson, Shirley V. | Ellis, Steve | Cole, Trevor | Godwin, Andrew K. | Claes, Kathleen | Van Maerken, Tom | Meindl, Alfons | Gehrig, Andrea | Sutter, Christian | Engel, Christoph | Niederacher, Dieter | Steinemann, Doris | Plendl, Hansjoerg | Kast, Karin | Rhiem, Kerstin | Ditsch, Nina | Arnold, Norbert | Varon-Mateeva, Raymonda | Wappenschmidt, Barbara | Wang-Gohrke, Shan | Bressac-de Paillerets, Brigitte | Buecher, Bruno | Delnatte, Capucine | Houdayer, Claude | Stoppa-Lyonnet, Dominique | Damiola, Francesca | Coupier, Isabelle | Barjhoux, Laure | Venat-Bouvet, Laurence | Golmard, Lisa | Boutry-Kryza, Nadia | Sinilnikova, Olga M. | Caron, Olivier | Pujol, Pascal | Mazoyer, Sylvie | Belotti, Muriel | Piedmonte, Marion | Friedlander, Michael L. | Rodriguez, Gustavo C. | Copeland, Larry J | de la Hoya, Miguel | Segura, Pedro Perez | Nevanlinna, Heli | Aittomäki, Kristiina | van Os, Theo A.M. | Meijers-Heijboer, Hanne E.J. | van der Hout, Annemarie H. | Vreeswijk, Maaike P.G. | Hoogerbrugge, Nicoline | Ausems, Margreet G.E.M. | van Doorn, Helena C. | Collée, J. Margriet | Olah, Edith | Diez, Orland | Blanco, Ignacio | Lazaro, Conxi | Brunet, Joan | Feliubadalo, Lidia | Cybulski, Cezary | Gronwald, Jacek | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Sukiennicki, Grzegorz | Arason, Adalgeir | Chiquette, Jocelyne | Teixeira, Manuel R. | Olswold, Curtis | Couch, Fergus J. | Lindor, Noralane M. | Wang, Xianshu | Szabo, Csilla I. | Offit, Kenneth | Corines, Marina | Jacobs, Lauren | Robson, Mark E. | Zhang, Liying | Joseph, Vijai | Berger, Andreas | Singer, Christian F. | Rappaport, Christine | Kaulich, Daphne Geschwantler | Pfeiler, Georg | Tea, Muy-Kheng M. | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Rennert, Gad | Mulligan, Anna Marie | Glendon, Gord | Tchatchou, Sandrine | Andrulis, Irene L. | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Thomassen, Mads | Jensen, Uffe Birk | Laitman, Yael | Rantala, Johanna | von Wachenfeldt, Anna | Ehrencrona, Hans | Askmalm, Marie Stenmark | Borg, Åke | Kuchenbaecker, Karoline B. | McGuffog, Lesley | Barrowdale, Daniel | Healey, Sue | Lee, Andrew | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Friedman, Eitan
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 non-genetic 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 0.005-1.000. 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.
doi:10.1158/1055-9965.EPI-14-0532
PMCID: PMC4294951  PMID: 25336561
BRCA1 BRCA2 mutations; BRCA-mutation carriers, Breast cancer risk; Ovarian cancer risk; Candidate genetic risk modifiers
8.  Germline mutations in PALB2 in African-American breast cancer cases 
Purpose
Breast cancer incidence is lower in African Americans than in Caucasian Americans. However, African-American women have higher breast cancer mortality rates and tend to be diagnosed with earlier-onset disease. Identifying factors correlated to the racial/ethnic variation in the epidemiology of breast cancer may provide better understanding of the more aggressive disease at diagnosis. Truncating germline mutations in PALB2 have been identified in approximately 1% of early-onset and/or familial breast cancer cases. To date, PALB2 mutation testing has not been performed in African-American breast cancer cases.
Methods
We screened for germline mutations in PALB2 in 139 African-American breast cases by denaturing high-performance liquid chromatography and direct sequencing.
Results
Twelve variants were identified in these cases and none caused truncation of the protein. Three missense variants, including two rare variants (P8L and T300I) and one common variant (P210L), were predicted to be pathogenic, and were located in a coiled-coil domain of PALB2 required for RAD51- and BRCA1-binding. We investigated and found no significant association between the P210L variant and breast cancer risk in a small case-control study of African-American women.
Conclusions
This study adds to the literature that PALB2 mutations, although rare, appear to play a role in breast cancer in all populations investigated to date.
doi:10.1007/s10549-010-1271-7
PMCID: PMC3457798  PMID: 21113654
germline mutations; PALB2; missense variants; breast cancer; African Americans
9.  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
10.  An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers 
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 VO | 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 MW | Kets, Carolien M | Aalfs, Cora M | van Leeuwen, Flora E | Hogervorst, Frans BL | Meijers-Heijboer, Hanne EJ | Oosterwijk, Jan C | van Roozendaal, Kees EP | 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
Introduction
Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.
Methods
We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.
Results
We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.
Conclusions
This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0567-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0567-2
PMCID: PMC4478717  PMID: 25925750
11.  Genetic variation in IGFBP2 and IGFBP5 is associated with breast cancer in populations of African descent 
Human genetics  2008;123(3):247-255.
The insulin-like growth factor (IGF) signaling pathway is thought to play a major role in the etiology of breast cancer. Although incidence rates of breast cancer overall are lower in African Americans than in Caucasians, African-American women have a higher incidence under age 40 years, are diagnosed with more advanced disease, and have poorer prognosis. We investigated the association of breast cancer and genetic variants in genes in the IGF signaling pathway in a population-based case–control study of African-American women. We found significant associations at a locus encompassing parts of the IGFBP2 and IGFBP5 genes on chromosome 2q35, which we then replicated in a case–control study of Nigerian women. Based on those initial findings, we genotyped a total of 34 single nucleotide polymorphisms (SNPs) across the region in both study populations. Statistically significant associations with breast cancer were observed across approximately 50 kb of DNA sequence encompassing three exons in the 3′ end of IGFBP2 and three exons in the 3′ end of IGFBP5. SNPs were associated with breast cancer risk with P values as low as P = 0.0038 and P = 0.01 in African-Americans and Nigerians, respectively. This study is the first to report associations between genetic variants in IGFBP2 and IGFBP5 and breast cancer risk.
doi:10.1007/s00439-008-0468-x
PMCID: PMC4406274  PMID: 18210156
12.  BRCA1 Circos: a visualisation resource for functional analysis of missense variants 
Journal of Medical Genetics  2015;52(4):224-230.
Background
Inactivating germline mutations in the tumour suppressor gene BRCA1 are associated with a significantly increased risk of developing breast and ovarian cancer. A large number (>1500) of unique BRCA1 variants have been identified in the population and can be classified as pathogenic, non-pathogenic or as variants of unknown significance (VUS). Many VUS are rare missense variants leading to single amino acid changes. Their impact on protein function cannot be directly inferred from sequence information, precluding assessment of their pathogenicity. Thus, functional assays are critical to assess the impact of these VUS on protein activity. BRCA1 is a multifunctional protein and different assays have been used to assess the impact of variants on different biochemical activities and biological processes.
Methods and results
To facilitate VUS analysis, we have developed a visualisation resource that compiles and displays functional data on all documented BRCA1 missense variants. BRCA1 Circos is a web-based visualisation tool based on the freely available Circos software package. The BRCA1 Circos web tool (http://research.nhgri.nih.gov/bic/circos/) aggregates data from all published BRCA1 missense variants for functional studies, harmonises their results and presents various functionalities to search and interpret individual-level functional information for each BRCA1 missense variant.
Conclusions
This research visualisation tool will serve as a quick one-stop publically available reference for all the BRCA1 missense variants that have been functionally assessed. It will facilitate meta-analysis of functional data and improve assessment of pathogenicity of VUS.
doi:10.1136/jmedgenet-2014-102766
PMCID: PMC4392196  PMID: 25643705
Cancer: breast; Clinical genetics; Molecular genetics; BRCA1
13.  A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium 
Milne, Roger L. | Herranz, Jesús | Michailidou, Kyriaki | Dennis, Joe | Tyrer, Jonathan P. | Zamora, M. Pilar | Arias-Perez, José Ignacio | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Wang, Qin | Bolla, Manjeet K. | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Li, Jingmei | Anton-Culver, Hoda | Neuhausen, Susan L. | Ziogas, Argyrios | Clarke, Christina A. | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Chenevix-Trench, Georgia | Swerdlow, Anthony | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Dunning, Alison M. | Shah, Mitul | Guénel, Pascal | Truong, Thérèse | Sanchez, Marie | Mulot, Claire | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Hollestelle, Antoinette | Collée, J. Margriet | Jager, Agnes | Cox, Angela | Brock, Ian W. | Reed, Malcolm W.R. | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Dumont, Martine | Soucy, Penny | Dörk, Thilo | Bogdanova, Natalia V. | Hamann, Ute | Försti, Asta | Rüdiger, Thomas | Ulmer, Hans-Ulrich | Fasching, Peter A. | Häberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Peto, Julian | Radice, Paolo | Peterlongo, Paolo | Peissel, Bernard | Mariani, Paolo | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Marme, Federik | Burwinkel, Barbara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Lambrechts, Diether | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Schmidt, Marjanka K. | Broeks, Annegien | Verhoef, Senno | Rutgers, Emiel J. | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Pharoah, Paul D.P. | Hall, Per | Benítez, Javier | Malats, Núria | Easton, Douglas F.
Human Molecular Genetics  2013;23(7):1934-1946.
Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10−8. Results from the second analytic approach were consistent with those from the first (P > 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
doi:10.1093/hmg/ddt581
PMCID: PMC3943524  PMID: 24242184
14.  Assessing Associations between the AURKA-HMMR-TPX2-TUBG1 Functional Module and Breast Cancer Risk in BRCA1/2 Mutation Carriers 
Blanco, Ignacio | Kuchenbaecker, Karoline | Cuadras, Daniel | Wang, Xianshu | Barrowdale, Daniel | de Garibay, Gorka Ruiz | Librado, Pablo | Sánchez-Gracia, Alejandro | Rozas, Julio | Bonifaci, Núria | McGuffog, Lesley | Pankratz, Vernon S. | Islam, Abul | Mateo, Francesca | Berenguer, Antoni | Petit, Anna | Català, Isabel | Brunet, Joan | Feliubadaló, Lidia | Tornero, Eva | Benítez, Javier | Osorio, Ana | Cajal, Teresa Ramón y | Nevanlinna, Heli | Aittomäki, Kristiina | Arun, Banu K. | Toland, Amanda E. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | Greene, Mark H. | Mai, Phuong L. | Nussbaum, Robert L. | Andrulis, Irene L. | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Timothy R. | Barkardottir, Rosa B. | Jakubowska, Anna | Lubinski, Jan | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Claes, Kathleen | Van Maerken, Tom | Díez, Orland | Hansen, Thomas V. | Jønson, Lars | Gerdes, Anne-Marie | Ejlertsen, Bent | de la Hoya, Miguel | Caldés, Trinidad | Dunning, Alison M. | Oliver, Clare | Fineberg, Elena | Cook, Margaret | Peock, Susan | McCann, Emma | Murray, Alex | Jacobs, Chris | Pichert, Gabriella | Lalloo, Fiona | Chu, Carol | Dorkins, Huw | Paterson, Joan | Ong, Kai-Ren | Teixeira, Manuel R. | Hogervorst, Frans B. L. | van der Hout, Annemarie H. | Seynaeve, Caroline | van der Luijt, Rob B. | Ligtenberg, Marjolijn J. L. | Devilee, Peter | Wijnen, Juul T. | Rookus, Matti A. | Meijers-Heijboer, Hanne E. J. | Blok, Marinus J. | van den Ouweland, Ans M. W. | Aalfs, Cora M. | Rodriguez, Gustavo C. | Phillips, Kelly-Anne A. | Piedmonte, Marion | Nerenstone, Stacy R. | Bae-Jump, Victoria L. | O'Malley, David M. | Ratner, Elena S. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Rhiem, Kerstin | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hansjoerg J. | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Gehrig, Andrea | Bojesen, Anders | Pedersen, Inge Sokilde | Sunde, Lone | Jensen, Uffe Birk | Thomassen, Mads | Kruse, Torben A. | Foretova, Lenka | Peterlongo, Paolo | Bernard, Loris | Peissel, Bernard | Scuvera, Giulietta | Manoukian, Siranoush | Radice, Paolo | Ottini, Laura | Montagna, Marco | Agata, Simona | Maugard, Christine | Simard, Jacques | Soucy, Penny | Berger, Andreas | Fink-Retter, Anneliese | Singer, Christian F. | Rappaport, Christine | Geschwantler-Kaulich, Daphne | Tea, Muy-Kheng | Pfeiler, Georg | John, Esther M. | Miron, Alex | Neuhausen, Susan L. | Terry, Mary Beth | Chung, Wendy K. | Daly, Mary B. | Goldgar, David E. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elisabeth J. | Fostira, Florentia | Konstantopoulou, Irene | Garber, Judy | Godwin, Andrew K. | Olah, Edith | Narod, Steven A. | Rennert, Gad | Paluch, Shani Shimon | Laitman, Yael | Friedman, Eitan | Liljegren, Annelie | Rantala, Johanna | Stenmark-Askmalm, Marie | Loman, Niklas | Imyanitov, Evgeny N. | Hamann, Ute | Spurdle, Amanda B. | Healey, Sue | Weitzel, Jeffrey N. | Herzog, Josef | Margileth, David | Gorrini, Chiara | Esteller, Manel | Gómez, Antonio | Sayols, Sergi | Vidal, Enrique | Heyn, Holger | Stoppa-Lyonnet, Dominique | Léoné, Melanie | Barjhoux, Laure | Fassy-Colcombet, Marion | de Pauw, Antoine | Lasset, Christine | Ferrer, Sandra Fert | Castera, Laurent | Berthet, Pascaline | Cornelis, François | Bignon, Yves-Jean | Damiola, Francesca | Mazoyer, Sylvie | Sinilnikova, Olga M. | Maxwell, Christopher A. | Vijai, Joseph | Robson, Mark | Kauff, Noah | Corines, Marina J. | Villano, Danylko | Cunningham, Julie | Lee, Adam | Lindor, Noralane | Lázaro, Conxi | Easton, Douglas F. | Offit, Kenneth | Chenevix-Trench, Georgia | Couch, Fergus J. | Antoniou, Antonis C. | Pujana, Miguel Angel
PLoS ONE  2015;10(4):e0120020.
While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 – 1.15, p = 1.9 x 10−4 (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 – 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients’ survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.
doi:10.1371/journal.pone.0120020
PMCID: PMC4382299  PMID: 25830658
15.  Mitochondrial DNA G10398A variant is not associated with breast cancer in African-American women 
Cancer genetics and cytogenetics  2008;181(1):16-19.
Mitochondria play important roles in cellular energy production, free radical generation and apoptosis. In a previous report in Cancer Research, the mitochondrial DNA (mtDNA) G10398A (Thr → Ala) polymorphism was associated with breast cancer risk in African-American women. Here, we seek to replicate the association by genotyping the G10398A polymorphism in three established population-based case-control studies of breast cancer in African-American women. The 10398A allele was not significantly associated with risk in any of the studies [San Francisco study (542 cases, 282 controls, odds ratio (OR) = 1.73; 95% confidence interval (CI): 0.87, 3.47, P = 0.12); Multiethnic Cohort (391 cases, 460 controls, OR = 1.08; 95% CI: 0.62, 1.86, P = 0.79); CARE/LIFE study (524 cases, 236 controls, OR = 0.81; 95% CI: 0.43, 1.52, P = 0.50)]. When pooling the data across the three studies (1456 cases and 978 controls), no significant association was observed with the 10398A allele (OR = 1.14; 95% CI: 0.80, 1.62, P = 0.47, P heterogeneity=0.30). In analysis of advanced breast cancer cases (n=674), there also was no significant association (OR = 1.18; 95% CI: 0.76, 1.82, P = 0.46). Our results do not support the hypothesis that the mtDNA G10398A polymorphism is a marker of breast cancer risk in African Americans as previously reported.
doi:10.1016/j.cancergencyto.2007.10.019
PMCID: PMC3225405  PMID: 18262047
16.  Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2 
Orr, Nick | Dudbridge, Frank | Dryden, Nicola | Maguire, Sarah | Novo, Daniela | Perrakis, Eleni | Johnson, Nichola | Ghoussaini, Maya | Hopper, John L. | Southey, Melissa C. | Apicella, Carmel | Stone, Jennifer | Schmidt, Marjanka K. | Broeks, Annegien | Van't Veer, Laura J. | Hogervorst, Frans B. | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Gibson, Lorna | Aitken, Zoe | Warren, Helen | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Chistof | Guénel, Pascal | Truong, Thérèse | Cordina-Duverger, Emilie | Sanchez, Marie | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, Maria Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Anton-Culver, Hoda | Neuhausen, Susan L. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Hamann, Ute | Brauch, Hiltrud | Justenhoven, Christina | Brüning, Thomas | Ko, Yon-Dschun | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Bogdanova, Natalia | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Chenevix-Trench, Georgia | Beesley, Jonathan | Lambrechts, Diether | Moisse, Matthieu | Floris, Guiseppe | Beuselinck, Benoit | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Peissel, Bernard | Pensotti, Valeria | Couch, Fergus J. | Olson, Janet E. | Slettedahl, Seth | Vachon, Celine | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Kristensen, Vessela | Alnæs, Grethe Grenaker | Nord, Silje | Borresen-Dale, Anne-Lise | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha | Long, Jirong | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Devilee, Peter | Tollenaar, Robertus A. E. M. | Seynaeve, Caroline M. | Van Asperen, Christi J. | Garcia-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J. | Lissowska, Jolanta | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Klevebring, Daniel | Hooning, Maartje J. | Hollestelle, Antoinette | van Deurzen, Carolien H. M. | Kriege, Mieke | Hall, Per | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Pharoah, Paul D. P. | Dunning, Alison M. | Shah, Mitul | Perkins, Barbara J. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Ashworth, Alan | Swerdlow, Anthony | Jones, Michael | Schoemaker, Minouk J. | Meindl, Alfons | Schmutzler, Rita K. | Olswold, Curtis | Slager, Susan | Toland, Amanda E. | Yannoukakos, Drakoulis | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Matsuo, Keitaro | Ito, Hidema | Iwata, Hiroji | Ishiguro, Junko | Wu, Anna H. | Tseng, Chiu-chen | Van Den Berg, David | Stram, Daniel O. | Teo, Soo Hwang | Yip, Cheng Har | Kang, Peter | Ikram, Mohammad Kamran | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K. | Noh, Dong-Young | Hartman, Mikael | Miao, Hui | Lim, Wei Yen | Lee, Soo Chin | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | Mckay, James | Wu, Pei-Ei | Hou, Ming-Feng | Yu, Jyh-Cherng | Shen, Chen-Yang | Blot, William | Cai, Qiuyin | Signorello, Lisa B. | Luccarini, Craig | Bayes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Álvarez, Nuria | Herrero, Daniel | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Hunter, David J. | Lindstrom, Sara | Dennis, Joe | Michailidou, Kyriaki | Bolla, Manjeet K. | Easton, Douglas F. | dos Santos Silva, Isabel | Fletcher, Olivia | Peto, Julian
Human Molecular Genetics  2015;24(10):2966-2984.
We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; P-value = 1.58 × 10−25). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; P-value = 7.89 × 10−09) and rs13294895 (OR = 1.09 [1.06–1.12]; P-value = 2.97 × 10−11). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; P-value = 2.77 × 10−05). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
doi:10.1093/hmg/ddv035
PMCID: PMC4406292  PMID: 25652398
17.  Exome Sequencing of 75 Individuals from Multiply Affected Coeliac Families and Large Scale Resequencing Follow Up 
PLoS ONE  2015;10(1):e0116845.
Coeliac disease (CeD) is a highly heritable common autoimmune disease involving chronic small intestinal inflammation in response to dietary wheat. The human leukocyte antigen (HLA) region, and 40 newer regions identified by genome wide association studies (GWAS) and dense fine mapping, account for ∼40% of the disease heritability. We hypothesized that in pedigrees with multiple individuals with CeD rare [minor allele frequency (MAF) <0.5%] mutations of larger effect size (odds ratios of ∼ 2–5) might exist. We sequenced the exomes of 75 coeliac individuals of European ancestry from 55 multiply affected families. We selected interesting variants and genes for further follow up using a combination of: an assessment of shared variants between related subjects, a model-free linkage test, and gene burden tests for multiple, potentially causal, variants. We next performed highly multiplexed amplicon resequencing of all RefSeq exons from 24 candidate genes selected on the basis of the exome sequencing data in 2,248 unrelated coeliac cases and 2,230 controls. 1,335 variants with a 99.9% genotyping call rate were observed in 4,478 samples, of which 939 were present in coding regions of 24 genes (Ti/Tv 2.99). 91.7% of coding variants were rare (MAF <0.5%) and 60% were novel. Gene burden tests performed on rare functional variants identified no significant associations (p<1×10−3) in the resequenced candidate genes. Our strategy of sequencing multiply affected families with deep follow up of candidate genes has not identified any new CeD risk mutations.
doi:10.1371/journal.pone.0116845
PMCID: PMC4312029  PMID: 25635822
18.  Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers 
Kuchenbaecker, Karoline B | Neuhausen, Susan L | Robson, Mark | Barrowdale, Daniel | McGuffog, Lesley | Mulligan, Anna Marie | Andrulis, Irene L | Spurdle, Amanda B | Schmidt, Marjanka K | Schmutzler, Rita K | Engel, Christoph | Wappenschmidt, Barbara | Nevanlinna, Heli | Thomassen, Mads | Southey, Melissa | Radice, Paolo | Ramus, Susan J | Domchek, Susan M | Nathanson, Katherine L | Lee, Andrew | Healey, Sue | Nussbaum, Robert L | Rebbeck, Timothy R | Arun, Banu K | James, Paul | Karlan, Beth Y | Lester, Jenny | Cass, Ilana | Registry, Breast Cancer Family | Terry, Mary Beth | Daly, Mary B | Goldgar, David E | Buys, Saundra S | Janavicius, Ramunas | Tihomirova, Laima | Tung, Nadine | Dorfling, Cecilia M | van Rensburg, Elizabeth J | Steele, Linda | v O Hansen, Thomas | Ejlertsen, Bent | Gerdes, Anne-Marie | Nielsen, Finn C | Dennis, Joe | Cunningham, Julie | Hart, Steven | Slager, Susan | Osorio, Ana | Benitez, Javier | Duran, Mercedes | Weitzel, Jeffrey N | Tafur, Isaac | Hander, Mary | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Roversi, Gaia | Scuvera, Giulietta | Bonanni, Bernardo | Mariani, Paolo | Volorio, Sara | Dolcetti, Riccardo | Varesco, Liliana | Papi, Laura | Tibiletti, Maria Grazia | Giannini, Giuseppe | Fostira, Florentia | Konstantopoulou, Irene | Garber, Judy | Hamann, Ute | Donaldson, Alan | Brewer, Carole | Foo, Claire | Evans, D Gareth | Frost, Debra | Eccles, Diana | Douglas, Fiona | Brady, Angela | Cook, Jackie | Tischkowitz, Marc | Adlard, Julian | Barwell, Julian | Ong, Kai-ren | Walker, Lisa | Izatt, Louise | Side, Lucy E | Kennedy, M John | Rogers, Mark T | Porteous, Mary E | Morrison, Patrick J | Platte, Radka | Eeles, Ros | Davidson, Rosemarie | Hodgson, Shirley | Ellis, Steve | Godwin, Andrew K | Rhiem, Kerstin | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hansjoerg | Niederacher, Dieter | Sutter, Christian | Steinemann, Doris | Bogdanova-Markov, Nadja | Kast, Karin | Varon-Mateeva, Raymonda | Wang-Gohrke, Shan | Gehrig, Andrea | Markiefka, Birgid | Buecher, Bruno | Lefol, Cédrick | Stoppa-Lyonnet, Dominique | Rouleau, Etienne | Prieur, Fabienne | Damiola, Francesca | Barjhoux, Laure | Faivre, Laurence | Longy, Michel | Sevenet, Nicolas | Sinilnikova, Olga M | Mazoyer, Sylvie | Bonadona, Valérie | Caux-Moncoutier, Virginie | Isaacs, Claudine | Van Maerken, Tom | Claes, Kathleen | Piedmonte, Marion | Andrews, Lesley | Hays, John | Rodriguez, Gustavo C | Caldes, Trinidad | de la Hoya, Miguel | Khan, Sofia | Hogervorst, Frans BL | Aalfs, Cora M | de Lange, JL | Meijers-Heijboer, Hanne EJ | van der Hout, Annemarie H | Wijnen, Juul T | van Roozendaal, KEP | Mensenkamp, Arjen R | van den Ouweland, Ans MW | van Deurzen, Carolien HM | van der Luijt, Rob B | Olah, Edith | Diez, Orland | Lazaro, Conxi | Blanco, Ignacio | Teulé, Alex | Menendez, Mireia | Jakubowska, Anna | Lubinski, Jan | Cybulski, Cezary | Gronwald, Jacek | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Arason, Adalgeir | Maugard, Christine | Soucy, Penny | Montagna, Marco | Agata, Simona | Teixeira, Manuel R | Olswold, Curtis | Lindor, Noralane | Pankratz, Vernon S | Hallberg, Emily | Wang, Xianshu | Szabo, Csilla I | Vijai, Joseph | Jacobs, Lauren | Corines, Marina | Lincoln, Anne | Berger, Andreas | Fink-Retter, Anneliese | Singer, Christian F | Rappaport, Christine | Kaulich, Daphne Gschwantler | Pfeiler, Georg | Tea, Muy-Kheng | Phelan, Catherine M | Mai, Phuong L | Greene, Mark H | Rennert, Gad | Imyanitov, Evgeny N | Glendon, Gord | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Jensen, Uffe Birk | Caligo, Maria A | Friedman, Eitan | Berger, Raanan | Laitman, Yael | Rantala, Johanna | Arver, Brita | Loman, Niklas | Borg, Ake | Ehrencrona, Hans | Olopade, Olufunmilayo I | Simard, Jacques | Easton, Douglas F | Chenevix-Trench, Georgia | Offit, Kenneth | Couch, Fergus J | Antoniou, Antonis C
Breast Cancer Research : BCR  2014;16(6):3416.
Introduction
More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers.
Methods
We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement.
Results
The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10−6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement.
Conclusions
Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0492-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0492-9
PMCID: PMC4406179  PMID: 25919761
19.  Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia 
Spurdle, Amanda B | Couch, Fergus J | Parsons, Michael T | McGuffog, Lesley | Barrowdale, Daniel | Bolla, Manjeet K | Wang, Qin | Healey, Sue | Schmutzler, Rita Katharina | Wappenschmidt, Barbara | Rhiem, Kerstin | Hahnen, Eric | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hansjoerg | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Ellis, Steve | Frost, Debra | Platte, Radka | Perkins, Jo | Evans, D Gareth | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Scuvera, Giulietta | Manoukian, Siranoush | Bonanni, Bernardo | Mariette, Frederique | Fortuzzi, Stefano | Viel, Alessandra | Pasini, Barbara | Papi, Laura | Varesco, Liliana | Balleine, Rosemary | Nathanson, Katherine L | Domchek, Susan M | Offitt, Kenneth | Jakubowska, Anna | Lindor, Noralane | Thomassen, Mads | Jensen, Uffe Birk | Rantala, Johanna | Borg, Åke | Andrulis, Irene L | Miron, Alexander | Hansen, Thomas VO | Caldes, Trinidad | Neuhausen, Susan L | Toland, Amanda E | Nevanlinna, Heli | Montagna, Marco | Garber, Judy | Godwin, Andrew K | Osorio, Ana | Factor, Rachel E | Terry, Mary B | Rebbeck, Timothy R | Karlan, Beth Y | Southey, Melissa | Rashid, Muhammad Usman | Tung, Nadine | Pharoah, Paul DP | Blows, Fiona M | Dunning, Alison M | Provenzano, Elena | Hall, Per | Czene, Kamila | Schmidt, Marjanka K | Broeks, Annegien | Cornelissen, Sten | Verhoef, Senno | Fasching, Peter A | Beckmann, Matthias W | Ekici, Arif B | Slamon, Dennis J | Bojesen, Stig E | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Chang-Claude, Jenny | Flesch-Janys, Dieter | Rudolph, Anja | Seibold, Petra | Aittomäki, Kristiina | Muranen, Taru A | Heikkilä, Päivi | Blomqvist, Carl | Figueroa, Jonine | Chanock, Stephen J | Brinton, Louise | Lissowska, Jolanta | Olson, Janet E | Pankratz, Vernon S | John, Esther M | Whittemore, Alice S | West, Dee W | Hamann, Ute | Torres, Diana | Ulmer, Hans Ulrich | Rüdiger, Thomas | Devilee, Peter | Tollenaar, Robert AEM | Seynaeve, Caroline | Van Asperen, Christi J | Eccles, Diana M | Tapper, William J | Durcan, Lorraine | Jones, Louise | Peto, Julian | dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Dwek, Miriam | Swann, Ruth | Bane, Anita L | Glendon, Gord | Mulligan, Anna M | Giles, Graham G | Milne, Roger L | Baglietto, Laura | McLean, Catriona | Carpenter, Jane | Clarke, Christine | Scott, Rodney | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Cox, Angela | Cross, Simon S | Reed, Malcolm WR | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Gronwald, Jacek | Dörk, Thilo | Bogdanova, Natalia | Park-Simon, Tjoung-Won | Hillemanns, Peter | Haiman, Christopher A | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Burwinkel, Barbara | Marme, Frederik | Surovy, Harald | Yang, Rongxi | Anton-Culver, Hoda | Ziogas, Argyrios | Hooning, Maartje J | Collée, J Margriet | Martens, John WM | Tilanus-Linthorst, Madeleine MA | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volke | Stegmaier, Christa | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Lindblom, Annika | Margolin, Sara | Joseph, Vijai | Robson, Mark | Rau-Murthy, Rohini | González-Neira, Anna | Arias, José Ignacio | Zamora, Pilar | Benítez, Javier | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Peterlongo, Paolo | Zaffaroni, Daniela | Barile, Monica | Capra, Fabio | Radice, Paolo | Teo, Soo H | Easton, Douglas F | Antoniou, Antonis C | Chenevix-Trench, Georgia | Goldgar, David E
Breast Cancer Research : BCR  2014;16(6):3419.
Introduction
The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.
Methods
Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.
Results
ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)).
Conclusions
These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-014-0474-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-014-0474-y
PMCID: PMC4352262  PMID: 25857409
20.  Co-occurrence of celiac disease and other autoimmune diseases in celiacs and their first-degree relatives 
Journal of autoimmunity  2008;31(2):160-165.
The occurrence of other autoimmune diseases in celiac disease families has not been previously reported in a North American population. We investigated the familial aggregation of rheumatoid arthritis (RA), juvenile rheumatoid arthritis/juvenile idiopathic arthritis (JRA/JIA), hypothyroidism, insulin dependent diabetes mellitus (IDDM), and alopecia areata (AA) among individuals in families with celiac disease (CD). Family history information, obtained from questionnaires from the University of California Irvine Celiac Disease study, was reviewed for reports of RA, JRA/JIA, hypothyroidism, IDDM, and AA in celiac disease cases and their first-degree relatives. Reports of disease were compared with prevalence data from the literature and analyzed by calculating the standardized ratio (SR) with 95% confidence limits. We analyzed: 1) subjects with confirmed celiac disease or dermatitis herpetiformis (205 probands and 203 affected first-degree relatives) and 2) first-degree relatives of celiac disease cases (n=1,272). We found a significantly increased number of cases, relative to the expected number, of IDDM in both groups and hypothyroidism among subjects with celiac disease. JRA/JIA was increased among first-degree relatives of celiacs. These results indicate that the presence of IDDM within our celiac disease families may be due to shared genetic susceptibility predisposing to these diseases or autoimmune diseases in general.
doi:10.1016/j.jaut.2008.06.001
PMCID: PMC2630860  PMID: 18692362
autoimmune disease; celiac disease
21.  Reproductive Factors, Exogenous Hormones, and Pancreatic Cancer Risk in the CTS 
American Journal of Epidemiology  2013;178(9):1403-1413.
Female steroid hormones are hypothesized to play a protective role in pancreatic cancer risk. However, results from epidemiologic studies that examined hormone-related exposures have been inconsistent. The California Teachers Study is a cohort study of female public school professionals that was established in 1995–1996. Of the 118,164 eligible study participants, 323 women were diagnosed with incident invasive pancreatic cancer through December 31, 2009. Multivariable Cox proportional hazards regression methods were used to estimate hazard ratios and 95% confidence intervals for the association of pancreatic cancer risk with reproductive factors and exogenous hormone use. Current users of estrogen-only therapy at baseline (1995–1996) had a lower risk of pancreatic cancer than did participants who had never used hormone therapy (hazard ratio = 0.59, 95% confidence interval: 0.42, 0.84). Use of estrogen-plus-progestin therapy was not associated with the risk of pancreatic cancer. A longer duration of oral contraceptive use (≥10 years of use compared with never use) was associated with an increased risk of cancer (hazard ratio = 1.72, 95% confidence interval: 1.19, 2.49). Reproductive factors, including age at menarche, parity, breastfeeding, and age at menopause, were not associated with pancreatic cancer risk. Our results suggest that increased estrogen exposure through estrogen-only therapy may reduce pancreatic cancer risk in women.
doi:10.1093/aje/kwt154
PMCID: PMC3813312  PMID: 24008905
hormone therapy; oral contraceptives; pancreatic cancer
22.  The impact of pregnancy on breast cancer survival in women who carry a BRCA1 or BRCA2 mutation 
Physicians are often approached by young women with a BRCA mutation and a recent history of breast cancer who wish to have a baby. They wish to know if pregnancy impacts upon their future risks of cancer recurrence and survival. To date, there is little information on the survival experience of women who carry a mutation in one of the BRCA genes and who become pregnant. From an international multi-center cohort study of 12,084 women with a BRCA1 or BRCA2 mutation, we identified 128 case subjects who were diagnosed with breast cancer while pregnant or who became pregnant after a diagnosis of breast cancer. These women were age-matched to 269 mutation carriers with breast cancer who did not become pregnant (controls). Subjects were followed from the date of breast cancer diagnosis until the date of last follow-up or death from breast cancer. The Kaplan–Meier method was used to estimate 15-year survival rates. The hazard ratio for survival associated with pregnancy was calculated using a left-truncated Cox proportional hazard model, adjusting for other prognostic factors. Among women who were diagnosed with breast cancer when pregnant or who became pregnant thereafter, the 15-year survival rate was 91.5 %, compared to a survival of 88.6 % for women who did not become pregnant (adjusted hazard ratio = 0.76; 95 % CI 0.31–1.91; p = 0.56). Pregnancy concurrent with or after a diagnosis of breast cancer does not appear to adversely affect survival among BRCA1/2 mutation carriers.
doi:10.1007/s10549-013-2729-1
PMCID: PMC3940343  PMID: 24136669
BRCA1; BRCA2; Breast cancer; Pregnancy; Survival
23.  Genetic Susceptibility to Anthracycline-Related Congestive Heart Failure in Survivors of Haematopoietic Cell Transplantation 
British journal of haematology  2013;163(2):205-213.
Haematopoietic cell transplantation (HCT) survivors are at increased risk for developing congestive heart failure (CHF), primarily due to pre-HCT exposure to anthracyclines. We examined the association between the development of CHF after HCT and polymorphisms in 16 candidate genes involved in anthracycline metabolism, iron homeostasis, anti-oxidant defence, and myocardial remodelling. A nested case-control study design was used. Cases (post-HCT CHF) were identified from 2,950 patients who underwent HCT between 1988 and 2007 at City of Hope and had survived ≥1 year. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age, race/ethnicity, cumulative anthracycline exposure, stem cell source (allogeneic, autologous), and length of follow-up. Seventy-seven cases with pre-HCT germline DNA and 178 controls were genotyped. Multivariate analysis revealed that the odds of CHF was higher in females (Odds Ratio [OR]=2.9, p<0.01), individuals with pre-HCT chest radiation (OR=4.7, p=0.05), hypertension (OR=2.9, p=0.01), and with variants of genes coding for the NAD(P)H-oxidase subunit RAC2 (rs13058338, 7508T→A; OR=2.8, p<0.01), HFE (rs1799945, 63C→G; OR=2.5, p=0.05) or the doxorubicin efflux transporter ABCC2 (rs8187710, 1515G→A; OR=4.3, p<0.01). A combined (clinical and genetic) CHF predictive model performed better (area under the curve [AUC], 0.79) than the genetic (AUC=0.67) or the clinical (AUC=0.69) models alone.
doi:10.1111/bjh.12516
PMCID: PMC3795883  PMID: 23927520
Anthracyclines; congestive heart failure; genetic susceptibility; haematopoietic cell transplantation; late effects
24.  Detailed comparison of two popular variant calling packages for exome and targeted exon studies 
PeerJ  2014;2:e600.
The Genome Analysis Toolkit (GATK) is commonly used for variant calling of single nucleotide polymorphisms (SNPs) and small insertions and deletions (indels) from short-read sequencing data aligned against a reference genome. There have been a number of variant calling comparisons against GATK, but an equally comprehensive comparison for VarScan not yet been performed. More specifically, we compare (1) the effects of different pre-processing steps prior to variant calling with both GATK and VarScan, (2) VarScan variants called with increasingly conservative parameters, and (3) filtered and unfiltered GATK variant calls (for both the UnifiedGenotyper and the HaplotypeCaller). Variant calling was performed on three datasets (1 targeted exon dataset and 2 exome datasets), each with approximately a dozen subjects. In most cases, pre-processing steps (e.g., indel realignment and quality score base recalibration using GATK) had only a modest impact on the variant calls, but the importance of the pre-processing steps varied between datasets and variant callers. Based upon concordance statistics presented in this study, we recommend GATK users focus on “high-quality” GATK variants by filtering out variants flagged as low-quality. We also found that running VarScan with a conservative set of parameters (referred to as “VarScan-Cons”) resulted in a reproducible list of variants, with high concordance (>97%) to high-quality variants called by the GATK UnifiedGenotyper and HaplotypeCaller. These conservative parameters result in decreased sensitivity, but the VarScan-Cons variant list could still recover 84–88% of the high-quality GATK SNPs in the exome datasets. This study also provides limited evidence that VarScan-Cons has a decreased false positive rate among novel variants (relative to high-quality GATK SNPs) and that the GATK HaplotypeCaller has an increased false positive rate for indels (relative to VarScan-Cons and high-quality GATK UnifiedGenotyper indels). More broadly, we believe the metrics used for comparison in this study can be useful in assessing the quality of variant calls in the context of a specific experimental design. As an example, a limited number of variant calling comparisons are also performed on two additional variant callers.
doi:10.7717/peerj.600
PMCID: PMC4184249  PMID: 25289185
Variant calling; Exome; Targeted sequencing; GATK; VarScan; SNP; Small indel
25.  Genome-Wide Association Study of Celiac Disease in North America Confirms FRMD4B as New Celiac Locus 
PLoS ONE  2014;9(7):e101428.
We performed a genome-wide association study (GWAS) of 1550 North American celiac disease cases and 3084 controls. Twelve SNPs, distributed across four regions (3p21.31, 4q27, 6q15, 6q25), were significantly associated with disease (p-value <1.0×10−7), and a further seven SNPs, across four additional regions (1q24.3, 10p15.1, 6q22.31, 17q21.32) had suggestive evidence (1.0×10−7 < p-value < 1.0×10−6). This study replicated a previous suggestive association within FRMD4B (3p14.1), confirming it as a celiac disease locus. All four regions with significant associations and two regions with suggestive results (1q24.3, 10p15.1) were known disease loci. The 6q22.31 and 10p11.23 regions were not replicated. A total of 410 SNPs distributed across the eight significant and suggestive regions were tested for association with dermatitis herpetiformis and microscopic colitis. Preliminary, suggestive statistical evidence for association with the two traits was found at chromosomes 3p21.31, 6q15, 6q25, 1q24.3 and 10p11.23, with future studies being required to validate the reported associations.
doi:10.1371/journal.pone.0101428
PMCID: PMC4084811  PMID: 24999842

Results 1-25 (82)