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1.  Large-scale genotyping identifies 41 new loci associated with breast cancer risk 
Michailidou, Kyriaki | Hall, Per | Gonzalez-Neira, Anna | Ghoussaini, Maya | Dennis, Joe | Milne, Roger L | Schmidt, Marjanka K | Chang-Claude, Jenny | Bojesen, Stig E | Bolla, Manjeet K | Wang, Qin | Dicks, Ed | Lee, Andrew | Turnbull, Clare | Rahman, Nazneen | Fletcher, Olivia | Peto, Julian | Gibson, Lorna | Silva, Isabel dos Santos | Nevanlinna, Heli | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel | van der Luijt, Rob B | Hein, Rebecca | Dahmen, Norbert | Beckman, Lars | Meindl, Alfons | Schmutzler, Rita K | Müller-Myhsok, Bertram | Lichtner, Peter | Hopper, John L | Southey, Melissa C | Makalic, Enes | Schmidt, Daniel F | Uitterlinden, Andre G | Hofman, Albert | Hunter, David J | Chanock, Stephen J | Vincent, Daniel | Bacot, François | Tessier, Daniel C | Canisius, Sander | Wessels, Lodewyk F A | Haiman, Christopher A | Shah, Mitul | Luben, Robert | Brown, Judith | Luccarini, Craig | Schoof, Nils | Humphreys, Keith | Li, Jingmei | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Couch, Fergus J | Wang, Xianshu | Vachon, Celine | Stevens, Kristen N | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Rudolph, Anja | Nickels, Stefan | Flesch-Janys, Dieter | Johnson, Nichola | Aitken, Zoe | Aaltonen, Kirsimari | Heikkinen, Tuomas | Broeks, Annegien | Van’t Veer, Laura J | van der Schoot, C Ellen | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Menegaux, Florence | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Zamora, M Pilar | Perez, Jose Ignacio Arias | Pita, Guillermo | Alonso, M Rosario | Cox, Angela | Brock, Ian W | Cross, Simon S | Reed, Malcolm W R | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Andrulis, Irene L | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J | Hollestelle, Antoinette | van den Ouweland, Ans M W | Jager, Agnes | Bui, Quang M | Stone, Jennifer | Dite, Gillian S | Apicella, Carmel | Tsimiklis, Helen | Giles, Graham G | Severi, Gianluca | Baglietto, Laura | Fasching, Peter A | Haeberle, Lothar | Ekici, Arif B | Beckmann, Matthias W | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Goldberg, Mark S | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Hamann, Ute | Brüning, Thomas | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Devilee, Peter | Tollenaar, Rob A E M | Seynaeve, Caroline | van Asperen, Christi J | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Bogdanova, Natalia V | Antonenkova, Natalia N | Dörk, Thilo | Kristensen, Vessela N | Anton-Culver, Hoda | Slager, Susan | Toland, Amanda E | Edge, Stephen | Fostira, Florentia | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Sueta, Aiko | Wu, Anna H | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Teo, Soo Hwang | Yip, Cheng Har | Phuah, Sze Yee | Cornes, Belinda K | Hartman, Mikael | Miao, Hui | Lim, Wei Yen | Sng, Jen-Hwei | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Ding, Shian-Ling | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Blot, William J | Signorello, Lisa B | Cai, Qiuyin | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha | Long, Jirong | Simard, Jacques | Garcia-Closas, Montse | Pharoah, Paul D P | Chenevix-Trench, Georgia | Dunning, Alison M | Benitez, Javier | Easton, Douglas F
Nature genetics  2013;45(4):353-361e2.
Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ~9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10−8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
doi:10.1038/ng.2563
PMCID: PMC3771688  PMID: 23535729
4.  BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk 
Journal of medical genetics  2012;49(8):10.1136/jmedgenet-2012-101037.
Background
Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p. Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer.
Methods
Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X).
Results
Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G>A p.Arg1699Gln variant carriers had family histories that were less ‘BRCA1-like’ than BRCA1 c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more ‘BRCA1-like’ than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G >A p. Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%.
Conclusions
Our results provide substantial evidence that the BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.
doi:10.1136/jmedgenet-2012-101037
PMCID: PMC3810416  PMID: 22889855
5.  Genome-wide association analysis identifies three new breast cancer susceptibility loci 
Ghoussaini, Maya | Fletcher, Olivia | Michailidou, Kyriaki | Turnbull, Clare | Schmidt, Marjanka K | Dicks, Ed | Dennis, Joe | Wang, Qin | Humphreys, Manjeet K | Luccarini, Craig | Baynes, Caroline | Conroy, Don | Maranian, Melanie | Ahmed, Shahana | Driver, Kristy | Johnson, Nichola | Orr, Nicholas | Silva, Isabel dos Santos | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Uitterlinden, Andre G. | Rivadeneira, Fernando | Hall, Per | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Meindl, Alfons | Schmutzler, Rita K | Müller-Myhsok, Bertram | Lichtner, Peter | Chang-Claude, Jenny | Hein, Rebecca | Nickels, Stefan | Flesch-Janys, Dieter | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel | Bui, Minh | Hopper, John L | Apicella, Carmel | Park, Daniel J | Southey, Melissa | Hunter, David J | Chanock, Stephen J | Broeks, Annegien | Verhoef, Senno | Hogervorst, Frans BL | Fasching, Peter A. | Lux, Michael P. | Beckmann, Matthias W. | Ekici, Arif B. | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Guénel, Pascal | Truong, Thérèse | Cordina-Duverger, Emilie | Menegaux, Florence | Bojesen, Stig E | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Milne, Roger L. | Alonso, M. Rosario | González-Neira, Anna | Benítez, Javier | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Dur, Christina Clarke | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Justenhoven, Christina | Brauch, Hiltrud | Brüning, Thomas | Wang-Gohrke, Shan | Eilber, Ursula | Dörk, Thilo | Schürmann, Peter | Bremer, Michael | Hillemanns, Peter | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Rogov, Yuri I. | Karstens, Johann H. | Bermisheva, Marina | Prokofieva, Darya | Khusnutdinova, Elza | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Lambrechts, Diether | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Manoukian, Siranoush | Bonanni, Bernardo | Fortuzzi, Stefano | Peterlongo, Paolo | Couch, Fergus J | Wang, Xianshu | Stevens, Kristen | Lee, Adam | Giles, Graham G. | Baglietto, Laura | Severi, Gianluca | McLean, Catriona | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børrensen-Dale, Anne-Lise | John, Esther M. | Miron, Alexander | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Andrulis, Irene L. | Glendon, Gord | Mulligan, Anna Marie | Devilee, Peter | van Asperen, Christie J. | Tollenaar, Rob A.E.M. | Seynaeve, Caroline | Figueroa, Jonine D | Garcia-Closas, Montserrat | Brinton, Louise | Lissowska, Jolanta | Hooning, Maartje J. | Hollestelle, Antoinette | Oldenburg, Rogier A. | van den Ouweland, Ans M.W. | Cox, Angela | Reed, Malcolm WR | Shah, Mitul | Jakubowska, Ania | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Jones, Michael | Schoemaker, Minouk | Ashworth, Alan | Swerdlow, Anthony | Beesley, Jonathan | Chen, Xiaoqing | Muir, Kenneth R | Lophatananon, Artitaya | Rattanamongkongul, Suthee | Chaiwerawattana, Arkom | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Shen, Chen-Yang | Yu, Jyh-Cherng | Wu, Pei-Ei | Hsiung, Chia-Ni | Perkins, Annie | Swann, Ruth | Velentzis, Louiza | Eccles, Diana M | Tapper, Will J | Gerty, Susan M | Graham, Nikki J | Ponder, Bruce A. J. | Chenevix-Trench, Georgia | Pharoah, Paul D.P. | Lathrop, Mark | Dunning, Alison M. | Rahman, Nazneen | Peto, Julian | Easton, Douglas F
Nature genetics  2012;44(3):312-318.
Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ~ 8% of the heritability of the disease. We followed up 72 promising associations from two independent Genome Wide Association Studies (GWAS) in ~70,000 cases and ~68,000 controls from 41 case-control studies and nine breast cancer GWAS. We identified three new breast cancer risk loci on 12p11 (rs10771399; P=2.7 × 10−35), 12q24 (rs1292011; P=4.3×10−19) and 21q21 (rs2823093; P=1.1×10−12). SNP rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) plays a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, while NRIP1 (21q21) encodes an ER co-factor and has a role in the regulation of breast cancer cell growth.
doi:10.1038/ng.1049
PMCID: PMC3653403  PMID: 22267197
6.  Downregulation of Serine Protease HTRA1 Is Associated with Poor Survival in Breast Cancer 
PLoS ONE  2013;8(4):e60359.
HTRA1 is a highly conserved serine protease which has been implicated in suppression of epithelial-to-mesenchymal-transition (EMT) and cell motility in breast cancer. Its prognostic relevance for breast cancer is unclear so far. Therefore, we evaluated the impact of HTRA1 mRNA expression on patient outcome using a cohort of 131 breast cancer patients as well as a validation cohort including 2809 publically available data sets. Additionally, we aimed at investigating for the presence of promoter hypermethylation as a mechanism for silencing the HTRA1 gene in breast tumors. HTRA1 downregulation was detected in more than 50% of the breast cancer specimens and was associated with higher tumor stage (p = 0.025). By applying Cox proportional hazard models, we observed favorable overall (OS) and disease-free survival (DFS) related to high HTRA1 expression (HR = 0.45 [CI 0.23–0.90], p = 0.023; HR = 0.55 [CI 0.32–0.94], p = 0.028, respectively), with even more pronounced impact in node-positive patients (HR = 0.21 [CI 0.07–0.63], p = 0.006; HR = 0.29 [CI 0.13–0.65], p = 0.002, respectively). Moreover, HTRA1 remained a statistically significant factor predicting DFS among established clinical parameters in the multivariable analysis. Its impact on patient outcome was independently confirmed in the validation set (for relapse-free survival (n = 2809): HR = 0.79 [CI 0.7–0.9], log-rank p = 0.0003; for OS (n = 971): HR = 0.63 [CI 0.48–0.83], log-rank p = 0.0009). In promoter analyses, we in fact detected methylation of HTRA1 in a small subset of breast cancer specimens (two out of a series of 12), and in MCF-7 breast cancer cells which exhibited 22-fold lower HTRA1 mRNA expression levels compared to unmethylated MDA-MB-231 cells. In conclusion, we show that downregulation of HTRA1 is associated with shorter patient survival, particularly in node-positive breast cancer. Since HTRA1 loss was demonstrated to induce EMT and cancer cell invasion, these patients might benefit from demethylating agents or histone deacetylase inhibitors previously reported to lead to HTRA1 upregulation, or from novel small-molecule inhibitors targeting EMT-related processes.
doi:10.1371/journal.pone.0060359
PMCID: PMC3620283  PMID: 23580433
7.  Analysis of 30 Putative BRCA1 Splicing Mutations in Hereditary Breast and Ovarian Cancer Families Identifies Exonic Splice Site Mutations That Escape In Silico Prediction 
PLoS ONE  2012;7(12):e50800.
Screening for pathogenic mutations in breast and ovarian cancer genes such as BRCA1/2, CHEK2 and RAD51C is common practice for individuals from high-risk families. However, test results may be ambiguous due to the presence of unclassified variants (UCV) in the concurrent absence of clearly cancer-predisposing mutations. Especially the presence of intronic or exonic variants within these genes that possibly affect proper pre-mRNA processing poses a challenge as their functional implications are not immediately apparent. Therefore, it appears necessary to characterize potential splicing UCV and to develop appropriate classification tools. We investigated 30 distinct BRCA1 variants, both intronic and exonic, regarding their spliceogenic potential by commonly used in silico prediction algorithms (HSF, MaxEntScan) along with in vitro transcript analyses. A total of 25 variants were identified spliceogenic, either causing/enhancing exon skipping or activation of cryptic splice sites, or both. Except from a single intronic variant causing minor effects on BRCA1 pre-mRNA processing in our analyses, 23 out of 24 intronic variants were correctly predicted by MaxEntScan, while HSF was less accurate in this cohort. Among the 6 exonic variants analyzed, 4 severely impair correct pre-mRNA processing, while the remaining two have partial effects. In contrast to the intronic alterations investigated, only half of the spliceogenic exonic variants were correctly predicted by HSF and/or MaxEntScan. These data support the idea that exonic splicing mutations are commonly disease-causing and concurrently prone to escape in silico prediction, hence necessitating experimental in vitro splicing analysis.
doi:10.1371/journal.pone.0050800
PMCID: PMC3519833  PMID: 23239986
8.  19p13.1 is a triple negative-specific breast cancer susceptibility locus 
Stevens, Kristen N. | Fredericksen, Zachary | Vachon, Celine M. | Wang, Xianshu | Margolin, Sara | Lindblom, Annika | Nevanlinna, Heli | Greco, Dario | Aittomäki, Kristiina | Blomqvist, Carl | Chang-Claude, Jenny | Vrieling, Alina | Flesch-Janys, Dieter | Sinn, Hans-Peter | Wang-Gohrke, Shan | Nickels, Stefan | Brauch, Hiltrud | Ko, Yon-Dschun | Fischer, Hans-Peter | Schmutzler, Rita K. | Meindl, Alfons | Bartram, Claus R. | Schott, Sarah | Engel, Christof | Godwin, Andrew K. | Weaver, JoEllen | Pathak, Harsh B. | Sharma, Priyanka | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Miron, Penelope | Yannoukakos, Drakoulis | Stavropoulou, Alexandra | Fountzilas, George | Gogas, Helen J. | Swann, Ruth | Dwek, Miriam | Perkins, Annie | Milne, Roger L. | Benítez, Javier | Zamora, M Pilar | Pérez, José Ignacio Arias | Bojesen, Stig E. | Nielsen, Sune F. | Nordestgaard, Børge G | Flyger, Henrik | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Cordina-Duverger, Emilie | Burwinkel, Barbara | Marmé, Frederick | Schneeweiss, Andreas | Sohn, Christof | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael J. | Peto, Julian | Johnson, Nichola | Fletcher, Olivia | Silva, Isabel dos Santos | Fasching, Peter A. | Beckmann, Matthias W. | Hartmann, Arndt | Ekici, Arif B. | Lophatananon, Artitaya | Muir, Kenneth | Puttawibul, Puttisak | Wiangnon, Surapon | Schmidt, Marjanka K | Broeks, Annegien | Braaf, Linde M | Rosenberg, Efraim H | Hopper, John L. | Apicella, Carmel | Park, Daniel J. | Southey, Melissa C. | Swerdlow, Anthony J. | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk J. | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Dur, Christina Clarke | Shen, Chen-Yang | Yu, Jyh-Cherng | Hsu, Huan-Ming | Hsiung, Chia-Ni | Hamann, Ute | Dünnebier, Thomas | Rüdiger, Thomas | Ulmer, Hans Ulrich | Pharoah, Paul P. | Dunning, Alison M | Humphreys, Manjeet K. | Wang, Qin | Cox, Angela | Cross, Simon S. | Reed, Malcom W. | Hall, Per | Czene, Kamila | Ambrosone, Christine B. | Ademuyiwa, Foluso | Hwang, Helena | Eccles, Diana M. | Garcia-Closas, Montserrat | Figueroa, Jonine D. | Sherman, Mark E. | Lissowska, Jolanta | Devilee, Peter | Seynaeve, Caroline | Tollenaar, R.A.E.M. | Hooning, Maartje J. | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | John, Esther M. | Miron, Alexander | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | Giles, Graham G. | Baglietto, Laura | McLean, Catriona A | Severi, Gianluca | Kosel, Matthew L. | Pankratz, V.S. | Slager, Susan | Olson, Janet E. | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Lambrechts, Diether | Hatse, Sigrid | Dieudonne, Anne-Sophie | Christiaens, Marie-Rose | Chenevix-Trench, Georgia | Beesley, Jonathan | Chen, Xiaoqing | Mannermaa, Arto | Kosma, Veli-Matti | Hartikainen, Jaana M. | Soini, Ylermi | Easton, Douglas F. | Couch, Fergus J.
Cancer Research  2012;72(7):1795-1803.
The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with risk of ovarian cancer. Here we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 Odds Ratio (OR)=1.10, 95% Confidence Interval (CI) 1.05 – 1.15, p=3.49 × 10-5] and triple negative (TN) (ER, PR and HER2 negative) breast cancer [rs8170 OR=1.22, 95% CI 1.13 – 1.31, p=2.22 × 10-7]. However, rs8170 was no longer associated with ER-negative breast cancer risk when TN cases were excluded [OR=0.98, 95% CI 0.89 – 1.07, p=0.62]. In addition, a combined analysis of TN cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC) (n=3,566) identified a genome-wide significant association between rs8170 and TN breast cancer risk [OR=1.25, 95% CI 1.18 – 1.33, p=3.31 × 10-13]. Thus, 19p13.1 is the first triple negative-specific breast cancer risk locus and the first locus specific to a histological subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple negative tumors and other subtypes likely arise through distinct etiologic pathways.
doi:10.1158/0008-5472.CAN-11-3364
PMCID: PMC3319792  PMID: 22331459
genetic susceptibility; association study; subtype; neoplasms; common variant
9.  Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2 
Kirchhoff, Tomas | Gaudet, Mia M. | Antoniou, Antonis C. | McGuffog, Lesley | Humphreys, Manjeet K. | Dunning, Alison M. | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Dork, Thilo | Schürmann, Peter | Karstens, Johann H. | Hillemanns, Peter | Couch, Fergus J. | Olson, Janet | Vachon, Celine | Wang, Xianshu | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W.R. | Burwinkel, Barbara | Meindl, Alfons | Brauch, Hiltrud | Hamann, Ute | Ko, Yon-Dschun | Broeks, Annegien | Schmidt, Marjanka K. | Van ‘t Veer, Laura J. | Braaf, Linde M. | Johnson, Nichola | Fletcher, Olivia | Gibson, Lorna | Peto, Julian | Turnbull, Clare | Seal, Sheila | Renwick, Anthony | Rahman, Nazneen | Wu, Pei-Ei | Yu, Jyh-Cherng | Hsiung, Chia-Ni | Shen, Chen-Yang | Southey, Melissa C. | Hopper, John L. | Hammet, Fleur | Van Dorpe, Thijs | Dieudonne, Anne-Sophie | Hatse, Sigrid | Lambrechts, Diether | Andrulis, Irene L. | Bogdanova, Natalia | Antonenkova, Natalia | Rogov, Juri I. | Prokofieva, Daria | Bermisheva, Marina | Khusnutdinova, Elza | van Asperen, Christi J. | Tollenaar, Robert A.E.M. | Hooning, Maartje J. | Devilee, Peter | Margolin, Sara | Lindblom, Annika | Milne, Roger L. | Arias, José Ignacio | Zamora, M. Pilar | Benítez, Javier | Severi, Gianluca | Baglietto, Laura | Giles, Graham G. | kConFab,  | Group, AOCS Study | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Holland, Helene | Healey, Sue | Wang-Gohrke, Shan | Chang-Claude, Jenny | Mannermaa, Arto | Kosma, Veli-Matti | Kauppinen, Jaana | Kataja, Vesa | Agnarsson, Bjarni A. | Caligo, Maria A. | Godwin, Andrew K. | Nevanlinna, Heli | Heikkinen, Tuomas | Fredericksen, Zachary | Lindor, Noralane | Nathanson, Katherine L. | Domchek, Susan M. | SWE-BRCA,  | Loman, Niklas | Karlsson, Per | Askmalm, Marie Stenmark | Melin, Beatrice | von Wachenfeldt, Anna | HEBON,  | Hogervorst, Frans B. L. | Verheus, Martijn | Rookus, Matti A. | Seynaeve, Caroline | Oldenburg, Rogier A. | Ligtenberg, Marjolijn J. | Ausems, Margreet G.E.M. | Aalfs, Cora M. | Gille, Hans J.P. | Wijnen, Juul T. | Gómez García, Encarna B. | EMBRACE,  | Peock, Susan | Cook, Margaret | Oliver, Clare T. | Frost, Debra | Luccarini, Craig | Pichert, Gabriella | Davidson, Rosemarie | Chu, Carol | Eccles, Diana | Ong, Kai-Ren | Cook, Jackie | Douglas, Fiona | Hodgson, Shirley | Evans, D. Gareth | Eeles, Rosalind | Gold, Bert | Pharoah, Paul D.P. | Offit, Kenneth | Chenevix-Trench, Georgia | Easton, Douglas F. | Prokunina-Olsson, Ludmila
PLoS ONE  2012;7(6):e35706.
Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00–1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I2 = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80–1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
doi:10.1371/journal.pone.0035706
PMCID: PMC3387216  PMID: 22768030
10.  Association of the Variants CASP8 D302H and CASP10 V410I with Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers 
Background
The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population.
Methods
To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIM-BA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).
Results
The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76–0.97; Ptrend = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53–0.89; Ptrend = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers.
Conclusions
CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers.
Impact
The combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers.
doi:10.1158/1055-9965.EPI-10-0517
PMCID: PMC3077716  PMID: 20978178
11.  Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers 
Human Molecular Genetics  2010;19(14):2886-2897.
Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 × 10−3) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (Ptrend < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69–0.90, Ptrend = 3.6 × 10−4 and HR = 1.25, 95% CI: 1.10–1.41, Ptrend = 4.2 × 10−4), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25–1.92, Ptrend = 6 × 10−5 and HR = 1.37, 95% CI: 1.16–1.62, Ptrend = 1.7 × 10−4). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.
doi:10.1093/hmg/ddq174
PMCID: PMC2893806  PMID: 20418484
12.  Full-Length L1CAM and Not Its Δ2Δ27 Splice Variant Promotes Metastasis through Induction of Gelatinase Expression 
PLoS ONE  2011;6(4):e18989.
Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression.
doi:10.1371/journal.pone.0018989
PMCID: PMC3081839  PMID: 21541352
13.  Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls 
Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Orr, Nick | Ashworth, Alan | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Burwinkel, Barbara | Bartram, Claus R. | Meindl, Alfons | Schmutzler, Rita K. | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W. R. | Southey, Melissa C. | Smith, Letitia | Spurdle, Amanda B. | Hopper, John L. | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Schürmann, Peter | Waltes, Regina | Bremer, Michael | Dörk, Thilo | Devilee, Peter | van Asperen, Christie J. | Tollenaar, Rob A.E.M. | Seynaeve, Caroline | Hall, Per | Czene, Kamila | Humphreys, Keith | Liu, Jianjun | Ahmed, Shahana | Dunning, Alison M. | Maranian, Melanie | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Beesley, Jonathan | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Zalutsky, Iosif V. | Anton-Culver, Hoda | Ziogas, Argyrios | Brauch, Hiltrud | Ko, Yon-Dschun | Hamann, Ute | Fasching, Peter A. | Strick, Reiner | Ekici, Arif B. | Beckmann, Matthias W. | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | English, Dallas R. | Milne, Roger L. | Benítez, Javier | Arias, José Ignacio | Pita, Guillermo | Nordestgaard, Børge G. | Bojesen, Stig E. | Flyger, Henrik | Kang, Daehee | Yoo, Keun-Young | Noh, Dong Young | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | García-Closas, Montserrat | Chanock, Stephen | Lissowska, Jolanta | Brinton, Louise A. | Chang-Claude, Jenny | Wang- Gohrke, Shan | Broeks, Annegien | Schmidt, Marjanka K | van Leeuwen, Flora E | Van 't Veer, Laura J | Margolin, Sara | Lindblom, Annika | Humphreys, Manjeet K. | Morrison, Jonathan | Platte, Radka | Easton, Douglas F. | Peto, Julian
Background
Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious.
Methods
We have genotyped five polymorphic (MAF 0.9% to 2.6%) missense single nucleotide polymorphisms (SNPs) in ATM (S49C, S707P, F858L, P1054R, L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium (BCAC).
Results
Combining data from all five SNPs, the OR was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR=1.06 (Ptrend=0.04). The trend OR among bilateral and familial cases was 1.12 (95% CI 1.02-1.23; Ptrend=0.02).
Conclusions
In this large combined analysis, these 5 missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer.
Impact
Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.
doi:10.1158/1055-9965.EPI-10-0374
PMCID: PMC2938473  PMID: 20826828
14.  Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls 
Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Orr, Nick | Ashworth, Alan | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Burwinkel, Barbara | Bartram, Claus R. | Meindl, Alfons | Schmutzler, Rita K. | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W. R. | Southey, Melissa C. | Smith, Letitia | Spurdle, Amanda B. | Hopper, John L. | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Schürmann, Peter | Waltes, Regina | Bremer, Michael | Dörk, Thilo | Devilee, Peter | van Asperen, Christie J. | Tollenaar, Rob A.E.M. | Seynaeve, Caroline | Hall, Per | Czene, Kamila | Humphreys, Keith | Liu, Jianjun | Ahmed, Shahana | Dunning, Alison M. | Maranian, Melanie | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Beesley, Jonathan | Investigators, kConFab | Group, AOCS | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Zalutsky, Iosif V. | Anton-Culver, Hoda | Ziogas, Argyrios | Brauch, Hiltrud | Ko, Yon-Dschun | Hamann, Ute | Fasching, Peter A. | Strick, Reiner | Ekici, Arif B. | Beckmann, Matthias W. | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | English, Dallas R. | Milne, Roger L. | Benítez, Javier | Arias, José Ignacio | Pita, Guillermo | Nordestgaard, Børge G. | Bojesen, Stig E. | Flyger, Henrik | Kang, Daehee | Yoo, Keun-Young | Noh, Dong Young | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | García-Closas, Montserrat | Chanock, Stephen | Lissowska, Jolanta | Brinton, Louise A. | Chang-Claude, Jenny | Wang- Gohrke, Shan | Broeks, Annegien | Schmidt, Marjanka K | van Leeuwen, Flora E | Van ‘t Veer, Laura J | Margolin, Sara | Lindblom, Annika | Humphreys, Manjeet K. | Morrison, Jonathan | Platte, Radka | Easton, Douglas F. | Peto, Julian
Background
Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious.
Methods
We have genotyped five polymorphic (MAF 0.9% to 2.6%) missense single nucleotide polymorphisms (SNPs) in ATM (S49C, S707P, F858L, P1054R, L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium (BCAC).
Results
Combining data from all five SNPs, the OR was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR=1.06 (Ptrend=0.04). The trend OR among bilateral and familial cases was 1.12 (95% CI 1.02-1.23; Ptrend=0.02).
Conclusions
In this large combined analysis, these 5 missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer.
Impact
Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.
doi:10.1158/1055-9965.EPI-10-0374
PMCID: PMC2938473  PMID: 20826828
15.  Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers 
Walker, Logan C | Fredericksen, Zachary S | Wang, Xianshu | Tarrell, Robert | Pankratz, Vernon S | Lindor, Noralane M | Beesley, Jonathan | Healey, Sue | Chen, Xiaoqing | Stoppa-Lyonnet, Dominique | Tirapo, Carole | Giraud, Sophie | Mazoyer, Sylvie | Muller, Danièle | Fricker, Jean-Pierre | Delnatte, Capucine | Schmutzler, Rita K | Wappenschmidt, Barbara | Engel, Christoph | Schönbuchner, Ines | Deissler, Helmut | Meindl, Alfons | Hogervorst, Frans B | Verheus, Martijn | Hooning, Maartje J | van den Ouweland, Ans MW | Nelen, Marcel R | Ausems, Margreet GEM | Aalfs, Cora M | van Asperen, Christi J | Devilee, Peter | Gerrits, Monique M | Waisfisz, Quinten | Szabo, Csilla I | Easton, Douglas F | Peock, Susan | Cook, Margaret | Oliver, Clare T | Frost, Debra | Harrington, Patricia | Evans, D Gareth | Lalloo, Fiona | Eeles, Ros | Izatt, Louise | Chu, Carol | Davidson, Rosemarie | Eccles, Diana | Ong, Kai-Ren | Cook, Jackie | Rebbeck, Tim | Nathanson, Katherine L | Domchek, Susan M | Singer, Christian F | Gschwantler-Kaulich, Daphne | Dressler, Anne-Catharina | Pfeiler, Georg | Godwin, Andrew K | Heikkinen, Tuomas | Nevanlinna, Heli | Agnarsson, Bjarni A | Caligo, Maria Adelaide | Olsson, Håkan | Kristoffersson, Ulf | Liljegren, Annelie | Arver, Brita | Karlsson, Per | Melin, Beatrice | Sinilnikova, Olga M | McGuffog, Lesley | Antoniou, Antonis C | Chenevix-Trench, Georgia | Spurdle, Amanda B | Couch, Fergus J
Breast Cancer Research : BCR  2010;12(6):R102.
Introduction
Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.
Methods
We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers.
Results
SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r2 = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, Ptrend = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, Ptrend = 0.018).
Conclusions
This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.
doi:10.1186/bcr2785
PMCID: PMC3046447  PMID: 21114847
16.  Risk of Estrogen Receptor–Positive and –Negative Breast Cancer and Single–Nucleotide Polymorphism 2q35-rs13387042 
Milne, Roger L. | Benítez, Javier | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Arias, José Ignacio | Zamora, M. Pilar | Burwinkel, Barbara | Bartram, Claus R. | Meindl, Alfons | Schmutzler, Rita K. | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W. R. | Southey, Melissa C. | Smith, Letitia | Spurdle, Amanda B. | Hopper, John L. | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Schürmann, Peter | Bremer, Michael | Hillemanns, Peter | Dörk, Thilo | Devilee, Peter | van Asperen, Christie J. | Tollenaar, Rob A. E. M. | Seynaeve, Caroline | Hall, Per | Czene, Kamila | Liu, Jianjun | Li, Yuqing | Ahmed, Shahana | Dunning, Alison M. | Maranian, Melanie | Pharoah, Paul D. P. | Chenevix-Trench, Georgia | Beesley, Jonathan | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Zalutsky, Iosif V. | Anton-Culver, Hoda | Ziogas, Argyrios | Brauch, Hiltrud | Justenhoven, Christina | Ko, Yon-Dschun | Haas, Susanne | Fasching, Peter A. | Strick, Reiner | Ekici, Arif B. | Beckmann, Matthias W. | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | English, Dallas R. | Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Peto, Julian | Turnbull, Clare | Hines, Sarah | Renwick, Anthony | Rahman, Nazneen | Nordestgaard, Børge G. | Bojesen, Stig E. | Flyger, Henrik | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | García-Closas, Montserrat | Chanock, Stephen | Lissowska, Jolanta | Brinton, Louise A. | Chang-Claude, Jenny | Wang-Gohrke, Shan | Shen, Chen-Yang | Wang, Hui-Chun | Yu, Jyh-Cherng | Chen, Sou-Tong | Bermisheva, Marina | Nikolaeva, Tatjana | Khusnutdinova, Elza | Humphreys, Manjeet K. | Morrison, Jonathan | Platte, Radka | Easton, Douglas F.
Background
A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)–positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium.
Methods
2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided.
Results
We found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; Ptrend = 1.0 × 10−19). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P ≥ .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P  =  .02). An association was observed for both ER-positive (OR  =  1.14, 95% CI  =  1.10 to 1.17; P = 10−15) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)–positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 × 10−14) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002).
Conclusion
The rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.
doi:10.1093/jnci/djp167
PMCID: PMC2724850  PMID: 19567422
17.  No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study 
Background
The transforming growth factor β-1 gene (TGFB1) is a plausible candidate for breast cancer susceptibility. The L10P variant of TGFB1 is associated with higher circulating levels and secretion of TGF-β, and recent large-scale studies suggest strongly that this variant is associated with breast cancer risk in the general population.
Methods
To evaluate whether TGFB1 L10P also modifies the risk of breast cancer in BRCA1 or BRCA2 mutation carriers, we undertook a multi-center study of 3,442 BRCA1 and 2,095 BRCA2 mutation carriers.
Results
We found no evidence of association between TGFB1 L10P and breast cancer risk in either BRCA1 or BRCA2 mutation carriers. The per-allele HR for the L10P variant was 1.01 (95%CI: 0.92–1.11) in BRCA1 carriers and 0.92 (95%CI: 0.81–1.04) in BRCA2 mutation carriers.
Conclusions
These results do not support the hypothesis that TGFB1 L10P genotypes modify the risk of breast cancer in BRCA1 or BRCA2 mutation carriers.
doi:10.1007/s10549-008-0064-8
PMCID: PMC2700286  PMID: 18523885
BRCA1; BRCA2; Risk modifiers; Hereditary cancer
18.  Identification of Novel Susceptibility Genes for Breast Cancer – Genome-Wide Association Studies or Evaluation of Candidate Genes? 
Breast Care  2009;4(2):93-99.
Summary
To determine the genetic components that constitute polygenic traits in familial or sporadic breast cancer, low-risk variants on the one hand and mutations conferring moderate penetrance on the other hand have to be identified. While members of the latter group were found by comprehensive screening of candidate genes which are, like the 2 highly penetrant genes BRCA1/BRCA2, located in the DNA repair pathway, the development of novel techniques was urgently needed to identify low-risk variants. The hybridization of chips which contain several hundred thousand single nucleotide polymorphisms (SNPs) with several thousand DNAs from either sporadic breast cancer cases or healthy controls (genome-wide association study, GWAS) has already led to the detection of at least 8 low-risk variants, conferring odds ratios of 1.06–1.64. As they are common in the population, it is likely that extended GWAS will develop a genetic pattern that is able to discriminate women suitable or not for population screening programs.
doi:10.1159/000211991
PMCID: PMC2931067  PMID: 21049069
Breast cancer; Genome-wide association studies; Polygenic inheritance; Genetic counselling
19.  A breast cancer risk haplotype in the caspase-8 gene 
Cancer research  2009;69(7):2724-2728.
Recent large-scale studies have been successful in identifying common, low penetrance variants associated with common cancers. One such variant in the caspase-8 (CASP8) gene, D302H (rs1045485), has been confirmed to be associated with breast cancer risk, although the functional impact of this polymorphism (if any) is not yet clear. In order to further map the CASP8 gene with respect to breast cancer susceptibility, we performed extensive haplotype analyses using single nucleotide polymorphisms (SNPs) chosen to tag all common variation in the gene (tSNPs). We used a staged study design based on 3200 breast cancer and 3324 control subjects from the UK, Utah and Germany. Using a haplotype-mining algorithm in the UK cohort, we identified a 4-SNP haplotype that was significantly associated with breast cancer and superior to any other single or multi-locus combination (P=8.0×10−5), with a per allele odds ratio and 95% confidence interval [OR (95% CI)] of 1.30 (1.12, 1.49). The result remained significant after adjustment for the multiple testing inherent in mining techniques (false discovery rate (FDR), q=0.044). As expected, this haplotype includes the D302H locus. Multi-center analyses on a subset of the tSNPs yielded consistent results. This risk haplotype is likely to carry one or more underlying breast cancer susceptibility alleles, making it an excellent candidate for re-sequencing in homozygous individuals. An understanding of the mode of action of these alleles will aid risk assessment and may lead to the identification of novel treatment targets in breast cancer.
doi:10.1158/0008-5472.CAN-08-4266
PMCID: PMC2730164  PMID: 19318553
Polymorphism; breast cancer; apoptosis; haplotype; association
20.  Nuclear receptor coregulator SNP discovery and impact on breast cancer risk 
BMC Cancer  2009;9:438.
Background
Coregulator proteins are "master regulators", directing transcriptional and posttranscriptional regulation of many target genes, and are critical in many normal physiological processes, but also in hormone driven diseases, such as breast cancer. Little is known on how genetic changes in these genes impact disease development and progression. Thus, we set out to identify novel single nucleotide polymorphisms (SNPs) within SRC-1 (NCoA1), SRC-3 (NCoA3, AIB1), NCoR (NCoR1), and SMRT (NCoR2), and test the most promising SNPs for associations with breast cancer risk.
Methods
The identification of novel SNPs was accomplished by sequencing the coding regions of these genes in 96 apparently normal individuals (48 Caucasian Americans, 48 African Americans). To assess their association with breast cancer risk, five SNPs were genotyped in 1218 familial BRCA1/2-mutation negative breast cancer cases and 1509 controls (rs1804645, rs6094752, rs2230782, rs2076546, rs2229840).
Results
Through our resequencing effort, we identified 74 novel SNPs (30 in NCoR, 32 in SMRT, 10 in SRC-3, and 2 in SRC-1). Of these, 8 were found with minor allele frequency (MAF) >5% illustrating the large amount of genetic diversity yet to be discovered. The previously shown protective effect of rs2230782 in SRC-3 was strengthened (OR = 0.45 [0.21-0.98], p = 0.04). No significant associations were found with the other SNPs genotyped.
Conclusions
This data illustrates the importance of coregulators, especially SRC-3, in breast cancer development and suggests that more focused studies, including functional analyses, should be conducted.
doi:10.1186/1471-2407-9-438
PMCID: PMC2804710  PMID: 20003447
21.  AURKA F31I Polymorphism and Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers: A CIMBA study 
Couch, Fergus J. | Sinilnikova, Olga | Vierkant, Robert A | Pankratz, V. Shane | Fredericksen, Zachary S. | Stoppa-Lyonnet, Dominique | Coupier, Isabelle | Hughes, David | Hardouin, Agnès | Berthet, Pascaline | Peock, Susan | Cook, Margaret | Baynes, Caroline | Hodgson, Shirley | Morrison, Patrick J. | Porteous, Mary E. | Jakubowska, Anna | Lubinski, Jan | Gronwald, Jacek | Spurdle, Amanda B. | Schmutzler, Rita | Versmold, Beatrix | Engel, Christoph | Meindl, Alfons | Sutter, Christian | Horst, Jurgen | Schaefer, Dieter | Offit, Kenneth | Kirchhoff, Tomas | Andrulis, Irene L. | Ilyushik, Eduard | Glendon, Gordon | Devilee, Peter | Vreeswijk, Maaike P.G. | Vasen, Hans F.A. | Borg, Ake | Backenhorn, Katja | Struewing, Jeffery P. | Greene, Mark H. | Neuhausen, Susan L. | Rebbeck, Timothy R. | Nathanson, Katherine | Domchek, Susan | Wagner, Theresa | Garber, Judy E. | Szabo, Csilla | Zikan, Michal | Foretova, Lenka | Olson, Janet E. | Sellers, Thomas A. | Lindor, Noralane | Nevanlinna, Heli | Tommiska, Johanna | Aittomaki, Kristiina | Hamann, Ute | Rashid, Muhammad U. | Torres, Diana | Simard, Jacques | Durocher, Francine | Guenard, Frederic | Lynch, Henry T. | Isaacs, Claudine | Weitzel, Jeffrey | Olopade, Olufunmilayo I. | Narod, Steven | Daly, Mary B. | Godwin, Andrew K. | Tomlinson, Gail | Easton, Douglas F. | Chenevix-Trench, Georgia | Antoniouon, Antonis C.
The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 co-operate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). CIMBA was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4935 BRCA1 and 2241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations were genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined (HR = 0.91; 95% CI 0.77-1.06). Similarly, no significant association was seen in BRCA1 (HR = 0.90; 95% CI 0.75-1.08) or BRCA2 carriers (HR = 0.93; 95% CI 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers.
doi:10.1158/1055-9965.EPI-07-0129
PMCID: PMC2775799  PMID: 17627006
BRCA1; BRCA2; AURKA; CIMBA; Breast cancer risk
22.  Breast cancer susceptibility: current knowledge and implications for genetic counselling 
Breast cancer is the most common malignancy in women in the Western world. Except for the high breast cancer risk in BRCA1 and BRCA2 mutation carriers as well as the risk for breast cancer in certain rare syndromes caused by mutations in TP53, STK11, PTEN, CDH1, NF1 or NBN, familial clustering of breast cancer remains largely unexplained. Despite significant efforts, BRCA3 could not be identified, but several reports have recently been published on genes involved in DNA repair and single nucleotide polymorphisms (SNPs) associated with an increased breast cancer risk. Although candidate gene approaches demonstrated moderately increased breast cancer risks for rare mutations in genes involved in DNA repair (ATM, CHEK2, BRIP1, PALB2 and RAD50), genome-wide association studies identified several SNPs as low-penetrance breast cancer susceptibility polymorphisms within genes as well as in chromosomal loci with no known genes (FGFR2, TOX3, LSP1, MAP3K1, TGFB1, 2q35 and 8q). Some of these low-penetrance breast cancer susceptibility polymorphisms also act as modifier genes in BRCA1/BRCA2 mutation carriers. This review not only outlines the recent key developments and potential clinical benefit for preventive management and therapy but also discusses the current limitations of genetic testing of variants associated with intermediate and low breast cancer risk.
doi:10.1038/ejhg.2008.212
PMCID: PMC2947107  PMID: 19092773
hereditary breast and ovarian cancer; breast cancer susceptibility; low penetrance genes; modifier genes; genetic counselling; single nucleotide polymorphisms (SNPs)
23.  Girls homozygous for an IL-2–inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation 
The Journal of Clinical Investigation  2009;119(5):1350-1358.
The fatal immune dysregulation that sometimes follows EBV infection in boys has been linked to mutations in two X chromosome–encoded genes, SLAM-associated protein (SAP) and X-linked inhibitor of apoptosis (XIAP). In this study we describe 2 girls from a consanguineous Turkish family who died after developing severe immune dysregulation and therapy-resistant EBV-positive B cell proliferation following EBV infection. SNP array–based genome-wide linkage analysis revealed IL-2–inducible T cell kinase (ITK) as a candidate gene for this immunodeficiency syndrome. Both girls harbored a homozygous missense mutation that led to substitution of a highly conserved residue (R335W) in the SH2 domain of ITK. Characteristics of ITK deficiency in mouse models, such as absence of NKT cells and high levels of eomesodermin in CD8+ cells, were seen in either one or both of the girls. Two lines of evidence suggested that R335W caused instability of the ITK protein. First, in silico modeling of the mutant protein predicted destabilization of the SH2 domain. Additionally, Western blot analysis revealed that, unlike wild-type ITK, the R335W mutant was nearly undetectable when expressed in 293 T cells. Our results suggest that ITK deficiency causes what we believe to be a novel immunodeficiency syndrome that leads to a fatal inadequate immune response to EBV. Because ITK deficiency resembles EBV-associated lymphoproliferative disorders in boys, we suggest that this molecular cause should be considered during diagnosis and treatment.
doi:10.1172/JCI37901
PMCID: PMC2673872  PMID: 19425169
24.  Strong Association of a Common Dihydropyrimidine Dehydrogenase Gene Polymorphism with Fluoropyrimidine-Related Toxicity in Cancer Patients 
PLoS ONE  2008;3(12):e4003.
Background
Cancer patients carrying mutations in the dihydropyrimidine dehydrogenase gene (DPYD) have a high risk to experience severe drug-adverse effects following chemotherapy with fluoropyrimidine drugs such as 5-fluorouracil (5-FU) or capecitabine. The pretreatment detection of this impairment of pyrimidine catabolism could prevent serious, potentially lethal side effects. As known deleterious mutations explain only a limited proportion of the drug-adverse events, we systematically searched for additional DPYD variations associated with enhanced drug toxicity.
Methodology/Principal Findings
We performed a whole gene approach covering the entire coding region and compared DPYD genotype frequencies between cancer patients with good (n = 89) and with poor (n = 39) tolerance of a fluoropyrimidine-based chemotherapy regimen. Applying logistic regression analysis and sliding window approaches we identified the strongest association with fluoropyrimidine-related grade III and IV toxicity for the non-synonymous polymorphism c.496A>G (p.Met166Val). We then confirmed our initial results using an independent sample of 53 individuals suffering from drug-adverse-effects. The combined odds ratio calculated for 92 toxicity cases was 4.42 [95% CI 2.12–9.23]; p (trend)<0.001; p (corrected) = 0.001; the attributable risk was 56.9%. Comparing tumor-type matched sets of samples, correlation of c.496A>G with toxicity was particularly present in patients with gastroesophageal and breast cancer, but did not reach significance in patients with colorectal malignancies.
Conclusion
Our results show compelling evidence that, at least in distinct tumor types, a common DPYD polymorphism strongly contributes to the occurrence of fluoropyrimidine-related drug adverse effects. Carriers of this variant could benefit from individual dose adjustment of the fluoropyrimidine drug or alternate therapies.
doi:10.1371/journal.pone.0004003
PMCID: PMC2602733  PMID: 19104657
25.  BRIP1 (BACH1) variants and familial breast cancer risk: a case-control study 
BMC Cancer  2007;7:83.
Background
Inactivating and truncating mutations of the nuclear BRCA1-interacting protein 1 (BRIP1) have been shown to be the major cause of Fanconi anaemia and, due to subsequent alterations of BRCA1 function, predispose to breast cancer (BC).
Methods
We investigated the effect of BRIP1 -64G>A and Pro919Ser on familial BC risk by means of TaqMan allelic discrimination, analysing BRCA1/BRCA2 mutation-negative index patients of 571 German BC families and 712 control individuals.
Results
No significant differences in genotype frequencies between BC cases and controls for BRIP1 -64G>A and Pro919Ser were observed.
Conclusion
We found no effect of the putatively functional BRIP1 variants -64G>A and Pro919Ser on the risk of familial BC.
doi:10.1186/1471-2407-7-83
PMCID: PMC1887536  PMID: 17504528

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