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Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

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Abstract
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.
Keywords
GENOME-WIDE ASSOCIATION, OVARIAN-CANCER, MEDULLARY CARCINOMA, ESTROGEN-RECEPTOR, TUMOR SUBTYPES, VARIANTS, MODIFIERS, LOCI, INVESTIGATORS, CONSORTIUM

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Chicago
Kuchenbaecker, Karoline B, Susan L Neuhausen, Mark Robson, Daniel Barrowdale, Lesley McGuffog, Anna Marie Mulligan, Irene L Andrulis, et al. 2014. “Associations of Common Breast Cancer Susceptibility Alleles with Risk of Breast Cancer Subtypes in BRCA1 and BRCA2 Mutation Carriers.” Breast Cancer Research 16.
APA
Kuchenbaecker, K. B., Neuhausen, S. L., Robson, M., Barrowdale, D., McGuffog, L., Mulligan, A. M., Andrulis, I. L., et al. (2014). Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers. BREAST CANCER RESEARCH, 16.
Vancouver
1.
Kuchenbaecker KB, Neuhausen SL, Robson M, Barrowdale D, McGuffog L, Mulligan AM, et al. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers. BREAST CANCER RESEARCH. 2014;16.
MLA
Kuchenbaecker, Karoline B, Susan L Neuhausen, Mark Robson, et al. “Associations of Common Breast Cancer Susceptibility Alleles with Risk of Breast Cancer Subtypes in BRCA1 and BRCA2 Mutation Carriers.” BREAST CANCER RESEARCH 16 (2014): n. pag. Print.
@article{7180825,
  abstract     = {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 {\textlangle} 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.},
  articleno    = {3416},
  author       = {Kuchenbaecker, Karoline B and Neuhausen, Susan L and Robson, Mark and Barrowdale, Daniel and McGuffog, Lesley and Mulligan, Anna Marie and Andrulis, Irene L and Spurdle, Amanda B and Schmidt, Marjanka K and Schmutzler, Rita K and Engel, Christoph and Wappenschmidt, Barbara and Nevanlinna, Heli and Thomassen, Mads and Southey, Melissa and Radice, Paolo and Ramus, Susan J and Domchek, Susan M and Nathanson, Katherine L and Lee, Andrew and Healey, Sue and Nussbaum, Robert L and Rebbeck, Timothy R and Arun, Banu K and James, Paul and Karlan, Beth Y and Lester, Jenny and Cass, Ilana and Breast Cancer Family Registry, the and Terry, Mary Beth and Daly, Mary B and Goldgar, David E and Buys, Saundra S and Janavicius, Ramunas and Tihomirova, Laima and Tung, Nadine and Dorfling, Cecilia M and van Rensburg, Elizabeth J and Steele, Linda and v O Hansen, Thomas and Ejlertsen, Bent and Gerdes, Anne-Marie and Nielsen, Finn C and Dennis, Joe and Cunningham, Julie and Hart, Steven and Slager, Susan and Osorio, Ana and Benitez, Javier and Duran, Mercedes and Weitzel, Jeffrey N and Tafur, Isaac and Hander, Mary and Peterlongo, Paolo and Manoukian, Siranoush and Peissel, Bernard and Roversi, Gaia and Scuvera, Giulietta and Bonanni, Bernardo and Mariani, Paolo and Volorio, Sara and Dolcetti, Riccardo and Varesco, Liliana and Papi, Laura and Tibiletti, Maria Grazia and Giannini, Giuseppe and Fostira, Florentia and Konstantopoulou, Irene and Garber, Judy and Hamann, Ute and Donaldson, Alan and Brewer, Carole and Foo, Claire and Evans, D Gareth and Frost, Debra and Eccles, Diana and EMBRACE Study, the and Douglas, Fiona and Brady, Angela and Cook, Jackie and Tischkowitz, Marc and Adlard, Julian and Barwell, Julian and Ong, Kai-ren and Walker, Lisa and Izatt, Louise and Side, Lucy E and Kennedy, M John and Rogers, Mark T and Porteous, Mary E and Morrison, Patrick J and Platte, Radka and Eeles, Ros and Davidson, Rosemarie and Hodgson, Shirley and Ellis, Steve and Godwin, Andrew K and Rhiem, Kerstin and Meindl, Alfons and Ditsch, Nina and Arnold, Norbert and Plendl, Hansjoerg and Niederacher, Dieter and Sutter, Christian and Steinemann, Doris and Bogdanova-Markov, Nadja and Kast, Karin and Varon-Mateeva, Raymonda and Wang-Gohrke, Shan and Gehrig, Andrea and Markiefka, Birgid and Buecher, Bruno and Lefol, C{\'e}drick and Stoppa-Lyonnet, Dominique and Rouleau, Etienne and Prieur, Fabienne and Damiola, Francesca and GEMO Study Collaborators, the and Barjhoux, Laure and Faivre, Laurence and Longy, Michel and Sevenet, Nicolas and Sinilnikova, Olga M and Mazoyer, Sylvie and Bonadona, Val{\'e}rie and Caux-Moncoutier, Virginie and Isaacs, Claudine and Van Maerken, Tom and Claes, Kathleen and Piedmonte, Marion and Andrews, Lesley and Hays, John and Rodriguez, Gustavo C and Caldes, Trinidad and de la Hoya, Miguel and Khan, Sofia and Hogervorst, Frans BL and Aalfs, Cora M and de Lange, JL and Meijers-Heijboer, Hanne EJ and van der Hout, Annemarie H and Wijnen, Juul T and van Roozendaal, KEP and Mensenkamp, Arjen R and van den Ouweland, Ans MW and van Deurzen, Carolien HM and van der Luijt, Rob B and HEBON, .  and Olah, Edith and Diez, Orland and Lazaro, Conxi and Blanco, Ignacio and Teul{\'e}, Alex and Menendez, Mireia and Jakubowska, Anna and Lubinski, Jan and Cybulski, Cezary and Gronwald, Jacek and Jaworska-Bieniek, Katarzyna and Durda, Katarzyna and Arason, Adalgeir and Maugard, Christine and Soucy, Penny and Montagna, Marco and Agata, Simona and Teixeira, Manuel R and KConFab Investigators, the and Olswold, Curtis and Lindor, Noralane and Pankratz, Vernon S and Hallberg, Emily and Wang, Xianshu and Szabo, Csilla I and Vijai, Joseph and Jacobs, Lauren and Corines, Marina and Lincoln, Anne and Berger, Andreas and Fink-Retter, Anneliese and Singer, Christian F and Rappaport, Christine and Gschwantler Kaulich, Daphne and Pfeiler, Georg and Tea, Muy-Kheng and Phelan, Catherine M and Mai, Phuong L and Greene, Mark H and Rennert, Gad and Imyanitov, Evgeny N and Glendon, Gord and Toland, Amanda Ewart and Bojesen, Anders and Pedersen, Inge Sokilde and Jensen, Uffe Birk and Caligo, Maria A and Friedman, Eitan and Berger, Raanan and Laitman, Yael and Rantala, Johanna and Arver, Brita and Loman, Niklas and Borg, Ake and Ehrencrona, Hans and Olopade, Olufunmilayo I and Simard, Jacques and Easton, Douglas F and Chenevix-Trench, Georgia and Offit, Kenneth and Couch, Fergus J and Antoniou, Antonis C and CIMBA, on behalf of},
  issn         = {1465-542X},
  journal      = {BREAST CANCER RESEARCH},
  keyword      = {GENOME-WIDE ASSOCIATION,OVARIAN-CANCER,MEDULLARY CARCINOMA,ESTROGEN-RECEPTOR,TUMOR SUBTYPES,VARIANTS,MODIFIERS,LOCI,INVESTIGATORS,CONSORTIUM},
  language     = {eng},
  pages        = {27},
  title        = {Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers},
  url          = {http://dx.doi.org/10.1186/s13058-014-0492-9},
  volume       = {16},
  year         = {2014},
}

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