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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
2.  A Comparison of Tumor Biology in Primary Ductal Carcinoma In Situ Recurring as Invasive Carcinoma versus a New In Situ 
Introduction. About half of all new ipsilateral events after a primary ductal carcinoma in situ (DCIS) are invasive carcinoma. We studied tumor markers in the primary DCIS in relation to type of event (invasive versus in situ). Methods. Two hundred and sixty-six women with a primary DCIS from two source populations, all with a known ipsilateral event, were included. All new events were regarded as recurrences. Patient and primary tumor characteristics (estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR, and Ki67) were evaluated. Logistic regression was used to calculate odd ratios and 95% confidence intervals in univariate and multivariate analyses. Results. One hundred and thirty-six of the recurrences were invasive carcinoma and 130 were in situ. The recurrence was more often invasive if the primary DCIS was ER+ (OR 2.5, 95% CI 1.2–5.1). Primary DCIS being HER2+ (OR 0.5, 95% CI 0.3–0.9), EGFR+ (OR 0.4, 95% CI 0.2–0.9), and ER95−/HER2+ (OR 0.2, 95% CI 0.1–0.6) had a lower risk of a recurrence being invasive. Conclusions. In this study, comparing type of recurrence after a DCIS showed that the ER−/HER2+ tumors were related to a recurrence being a new DCIS. And surprisingly, tumors being ER+, HER2−, and EGFR− were related to a recurrence being invasive cancer.
doi:10.1155/2013/582134
PMCID: PMC3893751  PMID: 24490077
3.  A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11 
Siddiq, Afshan | Couch, Fergus J. | Chen, Gary K. | Lindström, Sara | Eccles, Diana | Millikan, Robert C. | Michailidou, Kyriaki | Stram, Daniel O. | Beckmann, Lars | Rhie, Suhn Kyong | Ambrosone, Christine B. | Aittomäki, Kristiina | Amiano, Pilar | Apicella, Carmel | Baglietto, Laura | Bandera, Elisa V. | Beckmann, Matthias W. | Berg, Christine D. | Bernstein, Leslie | Blomqvist, Carl | Brauch, Hiltrud | Brinton, Louise | Bui, Quang M. | Buring, Julie E. | Buys, Saundra S. | Campa, Daniele | Carpenter, Jane E. | Chasman, Daniel I. | Chang-Claude, Jenny | Chen, Constance | Clavel-Chapelon, Françoise | Cox, Angela | Cross, Simon S. | Czene, Kamila | Deming, Sandra L. | Diasio, Robert B. | Diver, W. Ryan | Dunning, Alison M. | Durcan, Lorraine | Ekici, Arif B. | Fasching, Peter A. | Feigelson, Heather Spencer | Fejerman, Laura | Figueroa, Jonine D. | Fletcher, Olivia | Flesch-Janys, Dieter | Gaudet, Mia M. | Gerty, Susan M. | Rodriguez-Gil, Jorge L. | Giles, Graham G. | van Gils, Carla H. | Godwin, Andrew K. | Graham, Nikki | Greco, Dario | Hall, Per | Hankinson, Susan E. | Hartmann, Arndt | Hein, Rebecca | Heinz, Judith | Hoover, Robert N. | Hopper, John L. | Hu, Jennifer J. | Huntsman, Scott | Ingles, Sue A. | Irwanto, Astrid | Isaacs, Claudine | Jacobs, Kevin B. | John, Esther M. | Justenhoven, Christina | Kaaks, Rudolf | Kolonel, Laurence N. | Coetzee, Gerhard A. | Lathrop, Mark | Le Marchand, Loic | Lee, Adam M. | Lee, I-Min | Lesnick, Timothy | Lichtner, Peter | Liu, Jianjun | Lund, Eiliv | Makalic, Enes | Martin, Nicholas G. | McLean, Catriona A. | Meijers-Heijboer, Hanne | Meindl, Alfons | Miron, Penelope | Monroe, Kristine R. | Montgomery, Grant W. | Müller-Myhsok, Bertram | Nickels, Stefan | Nyante, Sarah J. | Olswold, Curtis | Overvad, Kim | Palli, Domenico | Park, Daniel J. | Palmer, Julie R. | Pathak, Harsh | Peto, Julian | Pharoah, Paul | Rahman, Nazneen | Rivadeneira, Fernando | Schmidt, Daniel F. | Schmutzler, Rita K. | Slager, Susan | Southey, Melissa C. | Stevens, Kristen N. | Sinn, Hans-Peter | Press, Michael F. | Ross, Eric | Riboli, Elio | Ridker, Paul M. | Schumacher, Fredrick R. | Severi, Gianluca | dos Santos Silva, Isabel | Stone, Jennifer | Sund, Malin | Tapper, William J. | Thun, Michael J. | Travis, Ruth C. | Turnbull, Clare | Uitterlinden, Andre G. | Waisfisz, Quinten | Wang, Xianshu | Wang, Zhaoming | Weaver, JoEllen | Schulz-Wendtland, Rüdiger | Wilkens, Lynne R. | Van Den Berg, David | Zheng, Wei | Ziegler, Regina G. | Ziv, Elad | Nevanlinna, Heli | Easton, Douglas F. | Hunter, David J. | Henderson, Brian E. | Chanock, Stephen J. | Garcia-Closas, Montserrat | Kraft, Peter | Haiman, Christopher A. | Vachon, Celine M.
Human Molecular Genetics  2012;21(24):5373-5384.
Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10-5 in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10−8) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10–6) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10−9), and with both ER-positive (OR = 1.09; P = 1.5 × 10−5) and ER-negative (OR = 1.16, P = 2.5 × 10−7) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
doi:10.1093/hmg/dds381
PMCID: PMC3510753  PMID: 22976474
4.  Identification of inherited genetic variations influencing prognosis in early onset breast cancer 
Cancer research  2013;73(6):1883-1891.
Genome Wide Association Studies (GWAs) have begun to investigate associations between inherited genetic variations and breast cancer prognosis. Here we report our findings from a GWAs conducted in 536 early onset breast cancer patients aged 40 or less at diagnosis and with a mean follow-up period of 4.1 years (S.D=1.96). Patients were selected from the POSH (Prospective study of Outcomes in Sporadic versus Hereditary breast cancer). A Bonferroni correction for multiple testing determined that a p-value of 1.0 × 10−7 was a statistically significant association signal. Following QC we identified 487496 SNPs for association tests in stage-1. In stage 2, 35 SNPs with the most significant associations were genotyped in 1516 independent cases from the same early onset cohort. In stage-2, 11 SNPs remained associated in the same direction (p{less than or equal to}0.05). Fixed effects meta-analysis models identified one SNP associated at close to genome wide level of significance 556 kb upstream of the ARRDC3 locus HR=1.61 (1.33-1.96, p=9.5 × 10-7). Four further associations at or close to the PBX1, RORα, NTN1 and SYT6 loci also came close to genome wide significance levels (p=10-6). In the first ever GWAS for identification of SNPs associated with prognosis in early onset breast cancer patients we report a SNP upstream of the ARRDC3 locus as potentially associated with prognosis (Median follow-up time for genotypes CC=4 years, CT=3 years and TT=2.7 years, Wilcoxon rank sum test CC vs. CT, p=4 × 10-4 and CT vs. TT, P=0.76). Four further loci might also be associated with prognosis
doi:10.1158/0008-5472.CAN-12-3377
PMCID: PMC3601979  PMID: 23319801
Early onset; Breast cancer; Prognosis; Survival analysis and GWAs
5.  The role of genetic breast cancer susceptibility variants as prognostic factors 
Fasching, Peter A. | Pharoah, Paul D.P. | Cox, Angela | Nevanlinna, Heli | Bojesen, Stig E. | Karn, Thomas | Broeks, Annegien | van Leeuwen, Flora E. | van 't Veer, Laura J. | Udo, Renate | Dunning, Alison M. | Greco, Dario | Aittomäki, Kristiina | Blomqvist, Carl | Shah, Mitul | Nordestgaard, Børge G. | Flyger, Henrik | Hopper, John L. | Southey, Melissa C. | Apicella, Carmel | Garcia-Closas, Montserrat | Sherman, Mark | Lissowska, Jolanta | Seynaeve, Caroline | Huijts, Petra E.A. | Tollenaar, Rob A.E.M. | Ziogas, Argyrios | Ekici, Arif B. | Rauh, Claudia | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Andrulis, Irene L. | Ozcelik, Hilmi | Mulligan, Anna-Marie | Glendon, Gord | Hall, Per | Czene, Kamila | Liu, Jianjun | Chang-Claude, Jenny | Wang-Gohrke, Shan | Eilber, Ursula | Nickels, Stefan | Dörk, Thilo | Schiekel, Maria | Bremer, Michael | Park-Simon, Tjoung-Won | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Hooning, Maartje J. | Martens, John W.M. | Jager, Agnes | Kriege, Mieke | Lindblom, Annika | Margolin, Sara | Couch, Fergus J. | Stevens, Kristen N. | Olson, Janet E. | Kosel, Matthew | Cross, Simon S. | Balasubramanian, Sabapathy P. | Reed, Malcolm W.R. | Miron, Alexander | John, Esther M. | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Chenevix-Trench, Georgia | Lambrechts, Diether | Dieudonne, Anne-Sophie | Hatse, Sigrid | van Limbergen, Erik | Benitez, Javier | Milne, Roger L. | Zamora, M. Pilar | Pérez, José Ignacio Arias | Bonanni, Bernardo | Peissel, Bernard | Loris, Bernard | Peterlongo, Paolo | Rajaraman, Preetha | Schonfeld, Sara J. | Anton-Culver, Hoda | Devilee, Peter | Beckmann, Matthias W. | Slamon, Dennis J. | Phillips, Kelly-Anne | Figueroa, Jonine D. | Humphreys, Manjeet K. | Easton, Douglas F. | Schmidt, Marjanka K.
Human Molecular Genetics  2012;21(17):3926-3939.
Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09–1.35, P=0.0002 and HR=1.29; 95% CI: 1.12–1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.
doi:10.1093/hmg/dds159
PMCID: PMC3412377  PMID: 22532573
6.  Identification of genetic markers with synergistic survival effect in cancer 
BMC Systems Biology  2013;7(Suppl 1):S2.
Background
Cancers are complex diseases arising from accumulated genetic mutations that disrupt intracellular signaling networks. While several predisposing genetic mutations have been found, these individual mutations account only for a small fraction of cancer incidence and mortality. With large-scale measurement technologies, such as single nucleotide polymorphism (SNP) microarrays, it is now possible to identify combinatorial effects that have significant impact on cancer patient survival.
Results
The identification of synergetic functioning SNPs on genome-scale is a computationally daunting task and requires advanced algorithms. We introduce a novel algorithm, Geninter, to identify SNPs that have synergetic effect on survival of cancer patients. Using a large breast cancer cohort we generate a simulator that allows assessing reliability and accuracy of Geninter and logrank test, which is a standard statistical method to integrate genetic and survival data.
Conclusions
Our results show that Geninter outperforms the logrank test and is able to identify SNP-pairs with synergetic impact on survival.
doi:10.1186/1752-0509-7-S1-S2
PMCID: PMC3750540  PMID: 24267921
7.  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
8.  A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer 
Haiman, Christopher A | Chen, Gary K | Vachon, Celine M | Canzian, Federico | Dunning, Alison | Millikan, Robert C | Wang, Xianshu | Ademuyiwa, Foluso | Ahmed, Shahana | Ambrosone, Christine B | Baglietto, Laura | Balleine, Rosemary | Bandera, Elisa V | Beckmann, Matthias W | Berg, Christine D | Bernstein, Leslie | Blomqvist, Carl | Blot, William J | Brauch, Hiltrud | Buring, Julie E | Carey, Lisa A | Carpenter, Jane E | Chang-Claude, Jenny | Chanock, Stephen J | Chasman, Daniel I | Clarke, Christine L | Cox, Angela | Cross, Simon S | Deming, Sandra L | Diasio, Robert B | Dimopoulos, Athanasios M | Driver, W Ryan | Dünnebier, Thomas | Durcan, Lorraine | Eccles, Diana | Edlund, Christopher K | Ekici, Arif B | Fasching, Peter A | Feigelson, Heather S | Flesch-Janys, Dieter | Fostira, Florentia | Försti, Asta | Fountzilas, George | Gerty, Susan M | Giles, Graham G | Godwin, Andrew K | Goodfellow, Paul | Graham, Nikki | Greco, Dario | Hamann, Ute | Hankinson, Susan E | Hartmann, Arndt | Hein, Rebecca | Heinz, Judith | Holbrook, Andrea | Hoover, Robert N | Hu, Jennifer J | Hunter, David J | Ingles, Sue A | Irwanto, Astrid | Ivanovich, Jennifer | John, Esther M | Johnson, Nicola | Jukkola-Vuorinen, Arja | Kaaks, Rudolf | Ko, Yon-Dschun | Kolonel, Laurence N | Konstantopoulou, Irene | Kosma, Veli-Matti | Kulkarni, Swati | Lambrechts, Diether | Lee, Adam M | Le Marchand, Loïc | Lesnick, Timothy | Liu, Jianjun | Lindstrom, Sara | Mannermaa, Arto | Margolin, Sara | Martin, Nicholas G | Miron, Penelope | Montgomery, Grant W | Nevanlinna, Heli | Nickels, Stephan | Nyante, Sarah | Olswold, Curtis | Palmer, Julie | Pathak, Harsh | Pectasides, Dimitrios | Perou, Charles M | Peto, Julian | Pharoah, Paul D P | Pooler, Loreall C | Press, Michael F | Pylkäs, Katri | Rebbeck, Timothy R | Rodriguez-Gil, Jorge L | Rosenberg, Lynn | Ross, Eric | Rüdiger, Thomas | Silva, Isabel dos Santos | Sawyer, Elinor | Schmidt, Marjanka K | Schulz-Wendtland, Rüdiger | Schumacher, Fredrick | Severi, Gianluca | Sheng, Xin | Signorello, Lisa B | Sinn, Hans-Peter | Stevens, Kristen N | Southey, Melissa C | Tapper, William J | Tomlinson, Ian | Hogervorst, Frans B L | Wauters, Els | Weaver, JoEllen | Wildiers, Hans | Winqvist, Robert | Van Den Berg, David | Wan, Peggy | Xia, Lucy Y | Yannoukakos, Drakoulis | Zheng, Wei | Ziegler, Regina G | Siddiq, Afshan | Slager, Susan L | Stram, Daniel O | Easton, Douglas | Kraft, Peter | Henderson, Brian E | Couch, Fergus J
Nature Genetics  2011;43(12):1210-1214.
Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10−10). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10−9), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10−9). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
doi:10.1038/ng.985
PMCID: PMC3279120  PMID: 22037553
9.  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
10.  ARLTS1 germline variants and the risk for breast, prostate, and colorectal cancer 
Recently, a nonsense alteration Trp149Stop in the ARLTS1 gene was found more frequently in familial cancer cases vs. sporadic cancer patients and healthy controls. Here, the role of Trp149Stop or any other ARLTS1 germline variant was evaluated on breast, prostate, and colorectal cancer risk. The whole gene was screened for germline alterations in 855 familial cancer patients. The five observed variants were further screened in 1169 non-familial cancer patients as well as in 809 healthy population controls. The Trp149Stop was found at low frequencies (0.5–1.2%) in all patient subgroups vs. 1.6% in controls, and the mutant allele did not co-segregate with disease status in families with multiple affected individuals. The CC genotype in the Cys148Arg variant was slightly more common among both familial and sporadic breast (OR=1.48, 95% CI 1.16–1.87, p=0.001) and prostate cancer patients (OR 1.50, 95% CI 1.13–1.99, p=0.005) when compared to controls. A novel ARLTS1 variant Gly65Val was found at higher frequency among familial prostate cancer patients (8/164, 4.9%) than in controls (13/809, 1.6%; OR 3.14, 95% CI 1.28–7.70, p=0.016). However, after adjusting for multiple testing, none of these results were still significant. No association was found with any of the variants and colorectal cancer risk. Our results suggest that Trp149Stop is not a predisposition allele in breast, prostate, or colorectal cancer in the Finnish population, and, while the Gly65Val variant may increase familial prostate cancer risk and the Cys148Arg change may affect both breast and prostate cancer risk, the evidence is not strong in these data.
doi:10.1038/ejhg.2008.43
PMCID: PMC3404127  PMID: 18337727
ARLTS1; ARL11; prostate cancer; breast cancer; colorectal cancer
11.  7q21-rs6964587 and breast cancer risk: an extended case–control study by the Breast Cancer Association Consortium 
Milne, Roger L | Lorenzo-Bermejo, Justo | Burwinkel, Barbara | Malats, Núria | Arias, Jose Ignacio | Zamora, M Pilar | Benítez, Javier | Humphreys, Manjeet K | García-Closas, Montserrat | Chanock, Stephen J | Lissowska, Jolanta | Sherman, Mark E | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Anton-Culver, Hoda | Ziogas, Argyrios | Devilee, Peter | van Asperen, Christie J | Tollenaar, Rob A E M | Seynaeve, Caroline | Hall, Per | Czene, Kamila | Liu, Jianjun | Irwanto, Astrid K | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Couch, Fergus J | Olson, Janet E | Wang, Xianshu | Fredericksen, Zachary | Nordestgaard, Børge G | Bojesen, Stig E | Flyger, Henrik | Margolin, Sara | Lindblom, Annika | Fasching, Peter A | Schulz-Wendtland, Ruediger | Ekici, Arif B | Beckmann, Matthias W | Wang-Gohrke, Shan | Shen, Chen-Yang | Yu, Jyh-Cherng | Hsu, Huan-Ming | Wu, Pei-Ei | Giles, Graham G | Severi, Gianluca | Baglietto, Laura | English, Dallas R | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W R | Beesley, Jonathan | Chen, Xiaoqing | Fletcher, Olivia | Gibson, Lorna | Silva, Isabel dos Santos | Peto, Julian | Frank, Bernd | Heil, Joerg | Meindl, Alfons | Chang-Claude, Jenny | Hein, Rebecca | Vrieling, Alina | Flesch-Janys, Dieter | Southey, Melissa C | Smith, Letitia | Apicella, Carmel | Hopper, John L | Dunning, Alison M | Pooley, Karen A | Pharoah, Paul D P | Hamann, Ute | Pesch, Beate | Ko, Yon-Dschun | Easton, Douglas F | Chenevix-Trench, Georgia
Journal of Medical Genetics  2011;48(10):698-702.
Background
Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case–control studies.
Methods
The authors genotyped 14 843 invasive case patients and 19 852 control subjects with white European ancestry and 2595 invasive case patients and 2192 control subjects with Asian ancestry. ORs were estimated by logistic regression, adjusted for study. Heterogeneity in ORs was assessed by fitting interaction terms or by subclassifying case patients and applying polytomous logistic regression.
Results
For white European women, the minor T allele of 7q21-rs6964587 was associated with breast cancer risk under a recessive model (OR 1.07, 95% CI 1.00 to 1.13, p = 0.04). Results were inconclusive for Asian women. From a combined analysis of 24 154 case patients and 33 376 control subjects of white European ancestry from the present and previous series, the best-fitting model was recessive, with an estimated OR of 1.08 (95% CI 1.03 to 1.13, p = 0.001). The OR was greater at younger ages (p trend = 0.01).
Conclusion
This may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance.
doi:10.1136/jmedgenet-2011-100303
PMCID: PMC3371608  PMID: 21931171
12.  Effect of image compression and scaling on automated scoring of immunohistochemical stainings and segmentation of tumor epithelium 
Diagnostic Pathology  2012;7:29.
Background
Digital whole-slide scanning of tissue specimens produces large images demanding increasing storing capacity. To reduce the need of extensive data storage systems image files can be compressed and scaled down. The aim of this article is to study the effect of different levels of image compression and scaling on automated image analysis of immunohistochemical (IHC) stainings and automated tumor segmentation.
Methods
Two tissue microarray (TMA) slides containing 800 samples of breast cancer tissue immunostained against Ki-67 protein and two TMA slides containing 144 samples of colorectal cancer immunostained against EGFR were digitized with a whole-slide scanner. The TMA images were JPEG2000 wavelet compressed with four compression ratios: lossless, and 1:12, 1:25 and 1:50 lossy compression. Each of the compressed breast cancer images was furthermore scaled down either to 1:1, 1:2, 1:4, 1:8, 1:16, 1:32, 1:64 or 1:128. Breast cancer images were analyzed using an algorithm that quantitates the extent of staining in Ki-67 immunostained images, and EGFR immunostained colorectal cancer images were analyzed with an automated tumor segmentation algorithm. The automated tools were validated by comparing the results from losslessly compressed and non-scaled images with results from conventional visual assessments. Percentage agreement and kappa statistics were calculated between results from compressed and scaled images and results from lossless and non-scaled images.
Results
Both of the studied image analysis methods showed good agreement between visual and automated results. In the automated IHC quantification, an agreement of over 98% and a kappa value of over 0.96 was observed between losslessly compressed and non-scaled images and combined compression ratios up to 1:50 and scaling down to 1:8. In automated tumor segmentation, an agreement of over 97% and a kappa value of over 0.93 was observed between losslessly compressed images and compression ratios up to 1:25.
Conclusions
The results of this study suggest that images stored for assessment of the extent of immunohistochemical staining can be compressed and scaled significantly, and images of tumors to be segmented can be compressed without compromising computer-assisted analysis results using studied methods.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2442925476534995
doi:10.1186/1746-1596-7-29
PMCID: PMC3375185  PMID: 22436596
Breast cancer; Colorectal cancer; Immunohistochemistry; Texture analysis; Image processing; Computer-Assisted; Image compression; Image scaling
13.  Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies 
Yang, Xiaohong R. | Chang-Claude, Jenny | Goode, Ellen L. | Couch, Fergus J. | Nevanlinna, Heli | Milne, Roger L. | Gaudet, Mia | Schmidt, Marjanka K. | Broeks, Annegien | Cox, Angela | Fasching, Peter A. | Hein, Rebecca | Spurdle, Amanda B. | Blows, Fiona | Driver, Kristy | Flesch-Janys, Dieter | Heinz, Judith | Sinn, Peter | Vrieling, Alina | Heikkinen, Tuomas | Aittomäki, Kristiina | Heikkilä, Päivi | Blomqvist, Carl | Lissowska, Jolanta | Peplonska, Beata | Chanock, Stephen | Figueroa, Jonine | Brinton, Louise | Hall, Per | Czene, Kamila | Humphreys, Keith | Darabi, Hatef | Liu, Jianjun | Van ‘t Veer, Laura J. | van Leeuwen, Flora E. | Andrulis, Irene L. | Glendon, Gord | Knight, Julia A. | Mulligan, Anna Marie | O’Malley, Frances P. | Weerasooriya, Nayana | John, Esther M. | Beckmann, Matthias W. | Hartmann, Arndt | Weihbrecht, Sebastian B. | Wachter, David L. | Jud, Sebastian M. | Loehberg, Christian R. | Baglietto, Laura | English, Dallas R. | Giles, Graham G. | McLean, Catriona A. | Severi, Gianluca | Lambrechts, Diether | Vandorpe, Thijs | Weltens, Caroline | Paridaens, Robert | Smeets, Ann | Neven, Patrick | Wildiers, Hans | Wang, Xianshu | Olson, Janet E. | Cafourek, Victoria | Fredericksen, Zachary | Kosel, Matthew | Vachon, Celine | Cramp, Helen E. | Connley, Daniel | Cross, Simon S. | Balasubramanian, Sabapathy P. | Reed, Malcolm W. R. | Dörk, Thilo | Bremer, Michael | Meyer, Andreas | Karstens, Johann H. | Ay, Aysun | Park-Simon, Tjoung-Won | Hillemanns, Peter | Arias Pérez, Jose Ignacio | Rodríguez, Primitiva Menéndez | Zamora, Pilar | Benítez, Javier | Ko, Yon-Dschun | Fischer, Hans-Peter | Hamann, Ute | Pesch, Beate | Brüning, Thomas | Justenhoven, Christina | Brauch, Hiltrud | Eccles, Diana M. | Tapper, William J. | Gerty, Sue M. | Sawyer, Elinor J. | Tomlinson, Ian P. | Jones, Angela | Kerin, Michael | Miller, Nicola | McInerney, Niall | Anton-Culver, Hoda | Ziogas, Argyrios | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Yang, Show-Lin | Yu, Jyh-Cherng | Chen, Shou-Tung | Hsu, Giu-Cheng | Haiman, Christopher A. | Henderson, Brian E. | Le Marchand, Loic | Kolonel, Laurence N. | Lindblom, Annika | Margolin, Sara | Jakubowska, Anna | Lubiński, Jan | Huzarski, Tomasz | Byrski, Tomasz | Górski, Bohdan | Gronwald, Jacek | Hooning, Maartje J. | Hollestelle, Antoinette | van den Ouweland, Ans M. W. | Jager, Agnes | Kriege, Mieke | Tilanus-Linthorst, Madeleine M. A. | Collée, Margriet | Wang-Gohrke, Shan | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Mononen, Kari | Grip, Mervi | Hirvikoski, Pasi | Winqvist, Robert | Mannermaa, Arto | Kosma, Veli-Matti | Kauppinen, Jaana | Kataja, Vesa | Auvinen, Päivi | Soini, Ylermi | Sironen, Reijo | Bojesen, Stig E. | Dynnes Ørsted, David | Kaur-Knudsen, Diljit | Flyger, Henrik | Nordestgaard, Børge G. | Holland, Helene | Chenevix-Trench, Georgia | Manoukian, Siranoush | Barile, Monica | Radice, Paolo | Hankinson, Susan E. | Hunter, David J. | Tamimi, Rulla | Sangrajrang, Suleeporn | Brennan, Paul | McKay, James | Odefrey, Fabrice | Gaborieau, Valerie | Devilee, Peter | Huijts, P.E.A. | Tollenaar, RAEM. | Seynaeve, C. | Dite, Gillian S. | Apicella, Carmel | Hopper, John L. | Hammet, Fleur | Tsimiklis, Helen | Smith, Letitia D. | Southey, Melissa C. | Humphreys, Manjeet K. | Easton, Douglas | Pharoah, Paul | Sherman, Mark E. | Garcia-Closas, Montserrat
Background
Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.
Methods
We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case–case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case–control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.
Results
In case–case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR− than PR+ tumors (P = .001). Nulliparity (P = 3 × 10−6) and increasing age at first birth (P = 2 × 10−9) were less frequent in ER− than in ER+ tumors. Obesity (body mass index [BMI] ≥ 30 kg/m2) in younger women (≤50 years) was more frequent in ER−/PR− than in ER+/PR+ tumors (P = 1 × 10−7), whereas obesity in older women (>50 years) was less frequent in PR− than in PR+ tumors (P = 6 × 10−4). The triple-negative (ER−/PR−/HER2−) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6+ and/or epidermal growth factor receptor [EGFR]+) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case–control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER+ or PR+ tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.
Conclusions
This study shows that reproductive factors and BMI are most clearly associated with hormone receptor–positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
doi:10.1093/jnci/djq526
PMCID: PMC3107570  PMID: 21191117
14.  Variants on the promoter region of PTEN affect breast cancer progression and patient survival 
Breast Cancer Research : BCR  2011;13(6):R130.
Introduction
The PTEN gene, a regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt oncogenic pathway, is mutated in various cancers and its expression has been associated with tumor progression in a dose-dependent fashion. We investigated the effect of germline variation in the promoter region of the PTEN gene on clinical characteristics and survival in breast cancer.
Methods
We screened the promoter region of the PTEN gene for germline variation in 330 familial breast cancer cases and further determined the genotypes of three detected PTEN promoter polymorphisms -903GA, -975GC, and -1026CA in a total of 2,412 breast cancer patients to evaluate the effects of the variants on tumor characteristics and disease outcome. We compared the gene expression profiles in breast cancers of 10 variant carriers and 10 matched non-carriers and performed further survival analyses based on the differentially expressed genes.
Results
All three promoter variants associated with worse prognosis. The Cox's regression hazard ratio for 10-year breast cancer specific survival in multivariate analysis was 2.01 (95% CI 1.17 to 3.46) P = 0.0119, and for 5-year breast cancer death or distant metastasis free survival 1.79 (95% CI 1.03 to 3.11) P = 0.0381 for the variant carriers, indicating PTEN promoter variants as an independent prognostic factor. The breast tumors from the promoter variant carriers exhibited a similar gene expression signature of 160 differentially expressed genes compared to matched non-carrier tumors. The signature further stratified patients into two groups with different recurrence free survival in independent breast cancer gene expression data sets.
Conclusions
Inherited variation in the PTEN promoter region affects the tumor progression and gene expression profile in breast cancer. Further studies are warranted to establish PTEN promoter variants as clinical markers for prognosis in breast cancer.
doi:10.1186/bcr3076
PMCID: PMC3326572  PMID: 22171747
15.  MiR-34a Expression Has an Effect for Lower Risk of Metastasis and Associates with Expression Patterns Predicting Clinical Outcome in Breast Cancer 
PLoS ONE  2011;6(11):e26122.
MiR-34a acts as a candidate tumour suppressor gene, and its expression is reduced in several cancer types. We aimed to study miR-34a expression in breast cancer and its correlation with tumour characteristics and clinical outcome, and regulatory links with other genes. We analysed miR-34a expression in 1,172 breast tumours on TMAs. 25% of the tumours showed high, 43% medium and 32% low expression of miR-34a. High miR-34a expression associated with poor prognostic factors for breast cancer: positive nodal status (p = 0.006), high tumour grade (p<0.0001), ER-negativity (p = 0.0002), HER2-positivity (p = 0.0002), high proliferation rate (p<0.0001), p53-positivity (p<0.0001), high cyclin E (p<0.0001) and γH2AX (p<0.0001). However, multivariate analysis adjusting for conventional prognostic factors indicated that high miR-34a expression in fact associated with a lower risk of recurrence or death from breast cancer (HR = 0.63, 95% CI = 0.41–0.96, p = 0.031). Gene expression analysis by differential miR-34a expression revealed an expression signature with an effect on both the 5-year and 10-year survival of the patients (p<0.001). Functional genomic analysis highlighted a novel regulatory role of the transcription factor MAZ, apart from the known control by p53, on the expression of miR-34a and a number of miR-34a targets. Our findings suggest that while miR-34a expression activation is a marker of aggressive breast tumour phenotype it exerts an independent effect for a lower risk of recurrence or death from breast cancer. We also present an expression signature of 190 genes associated with miR-34a expression. Our analysis for regulatory loops suggest that MAZ and p53 transcription factors co-operate in modulating miR-34a, as well as miR-34a targets involved in several cellular pathways. Taken together, these results suggest that the network of genes co-regulated with and targeted by miR-34a form a group of down-stream effectors that maybe of use in predicting clinical outcome, and that highlight novel regulatory mechanisms in breast cancer.
doi:10.1371/journal.pone.0026122
PMCID: PMC3213093  PMID: 22102859
16.  Breast tumors from CHEK2 1100delC-mutation carriers: genomic landscape and clinical implications 
Introduction
Checkpoint kinase 2 (CHEK2) is a moderate penetrance breast cancer risk gene, whose truncating mutation 1100delC increases the risk about twofold. We investigated gene copy-number aberrations and gene-expression profiles that are typical for breast tumors of CHEK2 1100delC-mutation carriers.
Methods
In total, 126 breast tumor tissue specimens including 32 samples from patients carrying CHEK2 1100delC were studied in array-comparative genomic hybridization (aCGH) and gene-expression (GEX) experiments. After dimensionality reduction with CGHregions R package, CHEK2 1100delC-associated regions in the aCGH data were detected by the Wilcoxon rank-sum test. The linear model was fitted to GEX data with R package limma. Genes whose expression levels were associated with CHEK2 1100delC mutation were detected by the bayesian method.
Results
We discovered four lost and three gained CHEK2 1100delC-related loci. These include losses of 1p13.3-31.3, 8p21.1-2, 8p23.1-2, and 17p12-13.1 as well as gains of 12q13.11-3, 16p13.3, and 19p13.3. Twenty-eight genes located on these regions showed differential expression between CHEK2 1100delC and other tumors, nominating them as candidates for CHEK2 1100delC-associated tumor-progression drivers. These included CLCA1 on 1p22 as well as CALCOCO1, SBEM, and LRP1 on 12q13. Altogether, 188 genes were differentially expressed between CHEK2 1100delC and other tumors. Of these, 144 had elevated and 44, reduced expression levels.
Our results suggest the WNT pathway as a driver of tumorigenesis in breast tumors of CHEK2 1100delC-mutation carriers and a role for the olfactory receptor protein family in cancer progression. Differences in the expression of the 188 CHEK2 1100delC-associated genes divided breast tumor samples from three independent datasets into two groups that differed in their relapse-free survival time.
Conclusions
We have shown that copy-number aberrations of certain genomic regions are associated with CHEK2 mutation 1100delC. On these regions, we identified potential drivers of CHEK2 1100delC-associated tumorigenesis, whose role in cancer progression is worth investigating. Furthermore, poorer survival related to the CHEK2 1100delC gene-expression signature highlights pathways that are likely to have a role in the development of metastatic disease in carriers of the CHEK2 1100delC mutation.
doi:10.1186/bcr3015
PMCID: PMC3262202  PMID: 21542898
17.  Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor–Negative Breast Cancer Survival 
Background
Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival.
Methods
We evaluated possible associations between overall survival after a breast cancer diagnosis and 10 621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26 978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14 096 patients with invasive breast cancer (including 2303 deaths and 70 019 person-years at risk) from 15 international case–control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided.
Results
In the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor–negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10−5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10−4).
Conclusion
The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor–negative breast cancer.
doi:10.1093/jnci/djq057
PMCID: PMC2864289  PMID: 20308648
18.  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
19.  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
20.  Genetic variation of ESR1 and its co-activator PPARGC1B is synergistic in augmenting the risk of estrogen receptor-positive breast cancer 
Introduction
Given the role of estrogen in breast carcinogenesis and the modification of estrogen receptor (ER) activity by its biochemical cofactors, we hypothesize that genetic variation within ER cofactor genes alters cellular response to estrogen exposure and consequently modifies the risk for ER-positive breast cancer.
Methods
We genotyped 790 tagging SNPs within 60 ER cofactor genes in 1,257 cases and 1,464 controls from Sweden and in 2,215 cases and 1,265 controls from Finland, and tested their associations with either ER-positive or ER-negative breast cancer.
Results
Seven SNPs showed consistent association with ER-positive breast cancer in the two independent samples, and six of them were located within PPARGC1B, encoding an ER co-activator, with the strongest association at rs741581 (odds ratio = 1.41, P = 4.84 × 10-5) that survived Bonferroni correction for multiple testing in the combined ER-positive breast cancer sample (Pcorrected = 0.03). Moreover, we also observed significant synergistic interaction (Pinteraction = 0.008) between the genetic polymorphisms within PPARGC1B and ESR1 in ER-positive breast cancer. By contrast, no consistent association was observed in ER-negative breast cancer. Furthermore, we found that administration of estrogen in the MCF-7 cell line induced PPARGC1B expression and enhanced occupancies of ER and RNA polymerase II within the region of SNP association, suggesting the upregulation of PPARGC1B expression by ESR1 activation.
Conclusions
Our study revealed that DNA polymorphisms of PPARGC1B, coding a bona fide ER co-activator, are associated with ER-positive breast cancer risk. The feed-forward transcriptional regulatory loop between PPARGC1B and ESR1 further augments their protein interaction, which provides a plausible mechanistic explanation for the synergistic genetic interaction between PPARGC1B and ESR1 in ER-positive breast cancer. Our study also highlights that biochemically and genomically informed candidate gene studies can enhance the discovery of interactive disease susceptibility genes.
doi:10.1186/bcr2817
PMCID: PMC3109578  PMID: 21269472
21.  Germ-line variation at a functional p53 binding site increases susceptibility to breast cancer development 
The HUGO Journal  2010;3(1-4):31-40.
Multiple lines of evidence suggest regulatory variation to play an important role in phenotypic evolution and disease development, but few regulatory polymorphisms have been characterized genetically and molecularly. Recent technological advances have made it possible to identify bona fide regulatory sequences experimentally on a genome-wide scale and opened the window for the biological interrogation of germ-line polymorphisms within these sequences. In this study, through a forward genetic analysis of bona fide p53 binding sites identified by a genome-wide chromatin immunoprecipitation and sequence analysis, we discovered a SNP (rs1860746) within the motif sequence of a p53 binding site where p53 can function as a regulator of transcription. We found that the minor allele (T) binds p53 poorly and has low transcriptional regulation activity as compared to the major allele (G). Significantly, the homozygosity of the minor allele was found to be associated with an increased risk of ER negative breast cancer (OR = 1.47, P = 0.038) from the analysis of five independent breast cancer samples of European origin consisting of 6,127 breast cancer patients and 5,197 controls. rs1860746 resides in the third intron of the PRKAG2 gene that encodes the γ subunit of the AMPK protein, a major sensor of metabolic stress and a modulator of p53 action. However, this gene does not appear to be regulated by p53 in lymphoblastoid cell lines nor in a cancer cell line. These results suggest that either the rs1860746 locus regulates another gene through distant interactions, or that this locus is in linkage disequilibrium with a second causal mutation. This study shows the feasibility of using genomic scale molecular data to uncover disease associated SNPs, but underscores the complexity of determining the function of regulatory variants in human populations.
Electronic supplementary material
The online version of this article (doi:10.1007/s11568-010-9138-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s11568-010-9138-x
PMCID: PMC2882646  PMID: 21119756
p53 binding sites; PRKAG2 gene; Polymorphism; ER negative tumors; Breast cancer susceptibility
22.  53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers 
Germ-line mutations in BRCA1 predispose to breast and ovarian cancer. BRCA1-mutated tumors show genomic instability, mainly as a consequence of impaired recombinatorial DNA repair. Here we identify 53BP1 as an essential factor for sustaining the growth arrest induced by Brca1 deletion. Depletion of 53BP1 abrogates the ATM-dependent checkpoint response and G2 cell cycle arrest triggered by the accumulation of DNA breaks in Brca1-deleted cells. This effect of 53BP1 is specific to BRCA1 function, as 53BP1 depletion did not alleviate proliferation arrest or checkpoint responses in Brca2-deleted cells. Importantly, loss of 53BP1 partially restores the homologous recombination defect of Brca1-deleted cells and reverts their hypersensitivity to DNA-damaging agents. We find reduced 53BP1 expression in subsets of sporadic triple-negative and BRCA-associated breast cancers, indicating the potential clinical implications of our findings.
doi:10.1038/nsmb.1831
PMCID: PMC2912507  PMID: 20453858
23.  Long-term survival of women with basal-like ductal carcinoma in situ of the breast: a population-based cohort study 
BMC Cancer  2010;10:653.
Background
Microarray gene-profiling of invasive breast cancer has identified different subtypes including luminal A, luminal B, HER2-overexpressing and basal-like groups. Basal-like invasive breast cancer is associated with a worse prognosis. However, the prognosis of basal-like ductal carcinoma in situ (DCIS) is still unknown. Our aim was to study the prognosis of basal-like DCIS in a large population-based cohort.
Methods
All 458 women with a primary DCIS diagnosed between 1986 and 2004, in Uppland and Västmanland, Sweden were included. TMA blocks were constructed. To classify the DCIS tumors, we used immunohistochemical (IHC) markers (estrogen-, progesterone-, HER2, cytokeratin 5/6 and epidermal growth factor receptor) as a surrogate for the gene expression profiling. The association with prognosis was examined for basal-like DCIS and other subtypes using Kaplan-Meier survival analyses and Cox proportional hazards regression models.
Results
IHC data were complete for 392 women. Thirty-two were basal-like (8.2%), 351 were luminal or HER2-positive (89.5%) and 9 unclassified (2.3%). Seventy-six women had a local recurrence of which 34 were invasive. Another 3 women had general metastases as first event. Basal-like DCIS showed a higher risk of local recurrence and invasive recurrence 1.8 (Confidence interval (CI) 95%, 0.8-4.2) and 1.9 (0.7-5.1), respectively. However, the difference was not statistically significant. Also, no statistically significant increased risk was seen for triple-negative or high grade DCIS.
Conclusions
Basal-like DCIS showed about a doubled, however not statistically significant risk for local recurrence and developing invasive cancer compared with the other molecular subtypes. Molecular subtyping was a better prognostic parameter than histopathological grade.
doi:10.1186/1471-2407-10-653
PMCID: PMC3001723  PMID: 21118480
24.  A genome-wide association scan on estrogen receptor-negative breast cancer 
Introduction
Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk.
Methods
We conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases.
Results
Association with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer shares a polygenic basis to disease with ER-positive breast cancer.
Conclusions
ER-negative breast cancer is a distinct breast cancer subtype that merits independent analyses. Given the clinical importance of this phenotype and the likelihood that genetic effect sizes are small, greater sample sizes and further studies are required to understand the etiology of ER-negative breast cancers.
doi:10.1186/bcr2772
PMCID: PMC3046434  PMID: 21062454
25.  No evidence that GATA3 rs570613 SNP modifies breast cancer risk 
GATA-binding protein 3 (GATA3) is a transcription factor that is crucial to mammary gland morphogenesis and differentiation of progenitor cells, and has been suggested to have a tumor suppressor function. The rs570613 single nucleotide polymorphism (SNP) in intron 4 of GATA3 was previously found to be associated with a reduction in breast cancer risk in the Cancer Genetic Markers of Susceptibility project and in pooled analysis of two case-control studies from Norway and Poland (Ptrend =0.004), with some evidence for a stronger association with estrogen receptor (ER) negative tumours [1]. We genotyped GATA3 rs570613 in 6,388 cases and 4,995 controls from the Breast Cancer Association Consortium (BCAC) and 5,617 BRCA1 and BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). We found no association between this SNP and breast cancer risk in BCAC cases overall (ORper-allele = 1.00, 95% CI 0.94 − 1.05), in ER negative BCAC cases (ORper-allele = 1.02, 95% CI 0.91−1.13), in BRCA1 mutation carriers RRper-allele = 0.99, 95% CI 0.90−1.09) or BRCA2 mutation carriers (RRper-allele = 0.93, 95% CI 0.80−1.07). We conclude that there is no evidence that either GATA3 rs570613, or any variant in strong linkage disequilibrium with it, is associated with breast cancer risk in women.
doi:10.1007/s10549-008-0257-1
PMCID: PMC2728174  PMID: 19082709
GATA3; breast cancer; polymorphism; BRCA1 and BRCA2; risk

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