Florey Department of Neuroscience and Mental Health - Research Publications

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    Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer
    Shi, J ; Zhang, Y ; Zheng, W ; Michailidou, K ; Ghoussaini, M ; Bolla, MK ; Wang, Q ; Dennis, J ; Lush, M ; Milne, RL ; Shu, X-O ; Beesley, J ; Kar, S ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Beckmann, MW ; Zhao, Z ; Guo, X ; Benitez, J ; Beeghly-Fadiel, A ; Blot, W ; Bogdanova, NV ; Bojesen, SE ; Brauch, H ; Brenner, H ; Brinton, L ; Broeks, A ; Bruening, T ; Burwinkel, B ; Cai, H ; Canisius, S ; Chang-Claude, J ; Choi, J-Y ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Darabi, H ; Devilee, P ; Droit, A ; Dork, T ; Fasching, PA ; Fletcher, O ; Flyger, H ; Fostira, F ; Gaborieau, V ; Garcia-Closas, M ; Giles, GG ; Grip, M ; Guenel, P ; Haiman, CA ; Hamann, U ; Hartman, M ; Miao, H ; Hollestelle, A ; Hopper, JL ; Hsiung, C-N ; Investigators, K ; Ito, H ; Jakubowska, A ; Johnson, N ; Torres, D ; Kabisch, M ; Kang, D ; Khan, S ; Knight, JA ; Kosma, V-M ; Lambrechts, D ; Li, J ; Lindblom, A ; Lophatananon, A ; Lubinski, J ; Mannermaa, A ; Manoukian, S ; Le Marchand, L ; Margolin, S ; Marme, F ; Matsuo, K ; McLean, C ; Meindl, A ; Muir, K ; Neuhausen, SL ; Nevanlinna, H ; Nord, S ; Borresen-Dale, A-L ; Olson, JE ; Orr, N ; van den Ouweland, AMW ; Peterlongo, P ; Putti, TC ; Rudolph, A ; Sangrajrang, S ; Sawyer, EJ ; Schmidt, MK ; Schmutzler, RK ; Shen, C-Y ; Hou, M-F ; Shrubsole, MJ ; Southey, MC ; Swerdlow, A ; Teo, SH ; Thienpont, B ; Toland, AE ; Tollenaar, RAEM ; Tomlinson, I ; Truong, T ; Tseng, C-C ; Wen, W ; Winqvist, R ; Wu, AH ; Yip, CH ; Zamora, PM ; Zheng, Y ; Floris, G ; Cheng, C-Y ; Hooning, MJ ; Martens, JWM ; Seynaeve, C ; Kristensen, VN ; Hall, P ; Pharoah, PDP ; Simard, J ; Chenevix-Trench, G ; Dunning, AM ; Antoniou, AC ; Easton, DF ; Cai, Q ; Long, J (WILEY, 2016-09-15)
    Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2)  = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.
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    Body mass index and breast cancer survival: a Mendelian randomization analysis
    Guo, Q ; Burgess, S ; Turman, C ; Bolla, MK ; Wang, Q ; Lush, M ; Abraham, J ; Aittomaki, K ; Andrulis, IL ; Apicella, C ; Arndt, V ; Barrdahl, M ; Benitez, J ; Berg, CD ; Blomqvist, C ; Bojesen, SE ; Bonanni, B ; Brand, JS ; Brenner, H ; Broeks, A ; Burwinkel, B ; Caldas, C ; Campa, D ; Canzian, F ; Chang-Claude, J ; Chanock, SJ ; Chin, S-F ; Couch, FJ ; Cox, A ; Cross, SS ; Cybulski, C ; Czene, K ; Darabi, H ; Devilee, P ; Diver, WR ; Dunning, AM ; Earl, HM ; Eccles, DM ; Ekici, AB ; Eriksson, M ; Evans, DG ; Fasching, PA ; Figueroa, J ; Flesch-Janys, D ; Flyger, H ; Gapstur, SM ; Gaudet, MM ; Giles, GG ; Glendon, G ; Grip, M ; Gronwald, J ; Haeberle, L ; Haiman, CA ; Hall, P ; Hamann, U ; Hankinson, S ; Hartikainen, JM ; Hein, A ; Hiller, L ; Hogervorst, FB ; Holleczek, B ; Hooning, MJ ; Hoover, RN ; Humphreys, K ; Hunter, DJ ; Husing, A ; Jakubowska, A ; Jukkola-Vuorinen, A ; Kaaks, R ; Kabisch, M ; Kataja, V ; Knight, JA ; Koppert, LB ; Kosma, V-M ; Kristensen, VN ; Lambrechts, D ; Le Marchand, L ; Li, J ; Lindblom, A ; Lindstrom, S ; Lissowska, J ; Lubinski, J ; Machiela, MJ ; Mannermaa, A ; Manoukian, S ; Margolin, S ; Marme, F ; Martens, JWM ; McLean, C ; Menendez, P ; Milne, RL ; Mulligan, AM ; Muranen, TA ; Nevanlinna, H ; Neven, P ; Nielsen, SF ; Nordestgaard, BG ; Olson, JE ; Perez, JIA ; Peterlongo, P ; Phillips, K-A ; Poole, CJ ; Pylkas, K ; Radice, P ; Rahman, N ; Rudiger, T ; Rudolph, A ; Sawyer, EJ ; Schumacher, F ; Seibold, P ; Seynaeve, C ; Shah, M ; Smeets, A ; Southey, MC ; Tollenaar, RAEM ; Tomlinson, I ; Tsimiklis, H ; Ulmer, H-U ; Vachon, C ; van den Ouweland, AMW ; Van't Veer, LJ ; Wildiers, H ; Willett, W ; Winqvist, R ; Zamora, MP ; Chenevix-Trench, G ; Dork, T ; Easton, DF ; Garcia-Closas, M ; Kraft, P ; Hopper, JL ; Zheng, W ; Schmidt, MK ; Pharoah, PDP (OXFORD UNIV PRESS, 2017-12-01)
    BACKGROUND: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer. METHODS: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis. RESULTS: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95). CONCLUSIONS: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.
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    Genome-wide association analysis identifies three new breast cancer susceptibility loci
    Ghoussaini, M ; Fletcher, O ; Michailidou, K ; Turnbull, C ; Schmidt, MK ; Dicks, E ; Dennis, J ; Wang, Q ; Humphreys, MK ; Luccarini, C ; Baynes, C ; Conroy, D ; Maranian, M ; Ahmed, S ; Driver, K ; Johnson, N ; Orr, N ; Silva, IDS ; Waisfisz, Q ; Meijers-Heijboer, H ; Uitterlinden, AG ; Rivadeneira, F ; Hall, P ; Czene, K ; Irwanto, A ; Liu, J ; Nevanlinna, H ; Aittomaki, K ; Blomqvist, C ; Meindl, A ; Schmutzler, RK ; Mueller-Myhsok, B ; Lichtner, P ; Chang-Claude, J ; Hein, R ; Nickels, S ; Flesch-Janys, D ; Tsimiklis, H ; Makalic, E ; Schmidt, D ; Bui, M ; Hopper, JL ; Apicella, C ; Park, DJ ; Southey, M ; Hunter, DJ ; Chanock, SJ ; Broeks, A ; Verhoef, S ; Hogervorst, FBL ; Fasching, PA ; Lux, MP ; Beckmann, MW ; Ekici, AB ; Sawyer, E ; Tomlinson, I ; Kerin, M ; Marme, F ; Schneeweiss, A ; Sohn, C ; Burwinkel, B ; Guenel, P ; Truong, T ; Cordina-Duverger, E ; Menegaux, F ; Bojesen, SE ; Nordestgaard, BG ; Nielsen, SF ; Flyger, H ; Milne, RL ; Rosario Alonso, M ; Gonzalez-Neira, A ; Benitez, J ; Anton-Culver, H ; Ziogas, A ; Bernstein, L ; Dur, CC ; Brenner, H ; Mueller, H ; Arndt, V ; Stegmaier, C ; Justenhoven, C ; Brauch, H ; Bruening, T ; Wang-Gohrke, S ; Eilber, U ; Doerk, T ; Schuermann, P ; Bremer, M ; Hillemanns, P ; Bogdanova, NV ; Antonenkova, NN ; Rogov, YI ; Karstens, JH ; Bermisheva, M ; Prokofieva, D ; Khusnutdinova, E ; Lindblom, A ; Margolin, S ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, JM ; Lambrechts, D ; Yesilyurt, BT ; Floris, G ; Leunen, K ; Manoukian, S ; Bonanni, B ; Fortuzzi, S ; Peterlongo, P ; Couch, FJ ; Wang, X ; Stevens, K ; Lee, A ; Giles, GG ; Baglietto, L ; Severi, G ; McLean, C ; Alnaes, GG ; Kristensen, V ; Borrensen-Dale, A-L ; John, EM ; Miron, A ; Winqvist, R ; Pylkas, K ; Jukkola-Vuorinen, A ; Kauppila, S ; Andrulis, IL ; Glendon, G ; Mulligan, AM ; Devilee, P ; van Asperen, CJ ; Tollenaar, RAEM ; Seynaeve, C ; Figueroa, JD ; Garcia-Closas, M ; Brinton, L ; Lissowska, J ; Hooning, MJ ; Hollestelle, A ; Oldenburg, RA ; van den Ouweland, AMW ; Cox, A ; Reed, MWR ; Shah, M ; Jakubowska, A ; Lubinski, J ; Jaworska, K ; Durda, K ; Jones, M ; Schoemaker, M ; Ashworth, A ; Swerdlow, A ; Beesley, J ; Chen, X ; Muir, KR ; Lophatananon, A ; Rattanamongkongul, S ; Chaiwerawattana, A ; Kang, D ; Yoo, K-Y ; Noh, D-Y ; Shen, C-Y ; Yu, J-C ; Wu, P-E ; Hsiung, C-N ; Perkins, A ; Swann, R ; Velentzis, L ; Eccles, DM ; Tapper, WJ ; Gerty, SM ; Graham, NJ ; Ponder, BAJ ; Chenevix-Trench, G ; Pharoah, PDP ; Lathrop, M ; Dunning, AM ; Rahman, N ; Peto, J ; Easton, DF (NATURE PUBLISHING GROUP, 2012-03-01)
    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 attempted to replicate 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 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). 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) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
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    Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk
    Stevens, KN ; Garcia-Closas, M ; Fredericksen, Z ; Kosel, M ; Pankratz, VS ; Hopper, JL ; Dite, GS ; Apicella, C ; Southey, MC ; Schmidt, MK ; Broeks, A ; Van 't Veer, LJ ; Tollenaar, RAEM ; Fasching, PA ; Beckmann, MW ; Hein, A ; Ekici, AB ; Johnson, N ; Peto, J ; Silva, IDS ; Gibson, L ; Sawyer, E ; Tomlinson, I ; Kerin, MJ ; Chanock, S ; Lissowska, J ; Hunter, DJ ; Hoover, RN ; Thomas, GD ; Milne, RL ; Perez, JIA ; Gonzalez-Neira, A ; Benitez, J ; Burwinkel, B ; Meindl, A ; Schmutzler, RK ; Bartrar, CR ; Hamann, U ; Ko, YD ; Bruening, T ; Chang-Claude, J ; Hein, R ; Wang-Gohrke, S ; Doerk, T ; Schuermann, P ; Bremer, M ; Hillemanns, P ; Bogdanova, N ; Zalutsky, JV ; Rogov, YI ; Antonenkova, N ; Lindblom, A ; Margolin, S ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, J ; Chenevix-Trench, G ; Chen, X ; Peterlongo, P ; Bonanni, B ; Bernard, L ; Manoukian, S ; Wang, X ; Cerhan, J ; Vachon, CM ; Olson, J ; Giles, GG ; Baglietto, L ; McLean, CA ; Severi, G ; John, EM ; Miron, A ; Winqvist, R ; Pylkaes, K ; Jukkola-Vuorinen, A ; Grip, M ; Andrulis, I ; Knight, JA ; Glendon, G ; Mulligan, AM ; Cox, A ; Brock, IW ; Elliott, G ; Cross, SS ; Pharoah, PP ; Dunning, AM ; Pooley, KA ; Humphreys, MK ; Wang, J ; Kang, D ; Yoo, K-Y ; Noh, D-Y ; Sangrajrang, S ; Gabrieau, V ; Brennan, P ; Mckay, J ; Anton-Culver, H ; Ziogas, A ; Couch, FJ ; Easton, DF (NATURE PUBLISHING GROUP, 2011-12-06)
    BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.
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    Subtyping of Breast Cancer by Immunohistochemistry to Investigate a Relationship between Subtype and Short and Long Term Survival: A Collaborative Analysis of Data for 10,159 Cases from 12 Studies
    Blows, FM ; Driver, KE ; Schmidt, MK ; Broeks, A ; van Leeuwen, FE ; Wesseling, J ; Cheang, MC ; Gelmon, K ; Nielsen, TO ; Blomqvist, C ; Heikkila, P ; Heikkinen, T ; Nevanlinna, H ; Akslen, LA ; Begin, LR ; Foulkes, WD ; Couch, FJ ; Wang, X ; Cafourek, V ; Olson, JE ; Baglietto, L ; Giles, GG ; Severi, G ; McLean, CA ; Southey, MC ; Rakha, E ; Green, AR ; Ellis, IO ; Sherman, ME ; Lissowska, J ; Anderson, WF ; Cox, A ; Cross, SS ; Reed, MWR ; Provenzano, E ; Dawson, S-J ; Dunning, AM ; Humphreys, M ; Easton, DF ; Garcia-Closas, M ; Caldas, C ; Pharoah, PD ; Huntsman, D ; Marincola, FM (PUBLIC LIBRARY SCIENCE, 2010-05-01)
    BACKGROUND: Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate mortality for patients with the major subtypes of breast cancer as classified using five immunohistochemical markers, to investigate patterns of mortality over time, and to test for heterogeneity by subtype. METHODS AND FINDINGS: We pooled data from more than 10,000 cases of invasive breast cancer from 12 studies that had collected information on hormone receptor status, human epidermal growth factor receptor-2 (HER2) status, and at least one basal marker (cytokeratin [CK]5/6 or epidermal growth factor receptor [EGFR]) together with survival time data. Tumours were classified as luminal and nonluminal tumours according to hormone receptor expression. These two groups were further subdivided according to expression of HER2, and finally, the luminal and nonluminal HER2-negative tumours were categorised according to expression of basal markers. Changes in mortality rates over time differed by subtype. In women with luminal HER2-negative subtypes, mortality rates were constant over time, whereas mortality rates associated with the luminal HER2-positive and nonluminal subtypes tended to peak within 5 y of diagnosis and then decline over time. In the first 5 y after diagnosis the nonluminal tumours were associated with a poorer prognosis, but over longer follow-up times the prognosis was poorer in the luminal subtypes, with the worst prognosis at 15 y being in the luminal HER2-positive tumours. Basal marker expression distinguished the HER2-negative luminal and nonluminal tumours into different subtypes. These patterns were independent of any systemic adjuvant therapy. CONCLUSIONS: The six subtypes of breast cancer defined by expression of five markers show distinct behaviours with important differences in short term and long term prognosis. Application of these markers in the clinical setting could have the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit. The different patterns of mortality over time also suggest important biological differences between the subtypes that may result in differences in response to specific therapies, and that stratification of breast cancers by clinically relevant subtypes in clinical trials is urgently required.
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    Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia
    Spurdle, AB ; Couch, FJ ; Parsons, MT ; McGuffog, L ; Barrowdale, D ; Bolla, MK ; Wang, Q ; Healey, S ; Schmutzler, RK ; Wappenschmidt, B ; Rhiem, K ; Hahnen, E ; Engel, C ; Meindl, A ; Ditsch, N ; Arnold, N ; Plendl, H ; Niederacher, D ; Sutter, C ; Wang-Gohrke, S ; Steinemann, D ; Preisler-Adams, S ; Kast, K ; Varon-Mateeva, R ; Ellis, S ; Frost, D ; Platte, R ; Perkins, J ; Evans, DG ; Izatt, L ; Eeles, R ; Adlard, J ; Davidson, R ; Cole, T ; Scuvera, G ; Manoukian, S ; Bonanni, B ; Mariette, F ; Fortuzzi, S ; Viel, A ; Pasini, B ; Papi, L ; Varesco, L ; Balleine, R ; Nathanson, KL ; Domchek, SM ; Offitt, K ; Jakubowska, A ; Lindor, N ; Thomassen, M ; Jensen, UB ; Rantala, J ; Borg, A ; Andrulis, IL ; Miron, A ; Hansen, TVO ; Caldes, T ; Neuhausen, SL ; Toland, AE ; Nevanlinna, H ; Montagna, M ; Garber, J ; Godwin, AK ; Osorio, A ; Factor, RE ; Terry, MB ; Rebbeck, TR ; Karlan, BY ; Southey, M ; Rashid, MU ; Tung, N ; Pharoah, PDP ; Blows, FM ; Dunning, AM ; Provenzano, E ; Hall, P ; Czene, K ; Schmidt, MK ; Broeks, A ; Cornelissen, S ; Verhoef, S ; Fasching, PA ; Beckmann, MW ; Ekici, AB ; Slamon, DJ ; Bojesen, SE ; Nordestgaard, BG ; Nielsen, SF ; Flyger, H ; Chang-Claude, J ; Flesch-Janys, D ; Rudolph, A ; Seibold, P ; Aittomaki, K ; Muranen, TA ; Heikkila, P ; Blomqvist, C ; Figueroa, J ; Chanock, SJ ; Brinton, L ; Lissowska, J ; Olson, JE ; Pankratz, VS ; John, EM ; Whittemore, AS ; West, DW ; Hamann, U ; Torres, D ; Ulmer, HU ; Rudiger, T ; Devilee, P ; Tollenaar, RAEM ; Seynaeve, C ; Van Asperen, CJ ; Eccles, DM ; Tapper, WJ ; Durcan, L ; Jones, L ; Peto, J ; dos-Santos-Silva, I ; Fletcher, O ; Johnson, N ; Dwek, M ; Swann, R ; Bane, AL ; Glendon, G ; Mulligan, AM ; Giles, GG ; Milne, RL ; Baglietto, L ; McLean, C ; Carpenter, J ; Clarke, C ; Scott, R ; Brauch, H ; Bruning, T ; Ko, Y-D ; Cox, A ; Cross, SS ; Reed, MWR ; Lubinski, J ; Jaworska-Bieniek, K ; Durda, K ; Gronwald, J ; Dork, T ; Bogdanova, N ; Park-Simon, T-W ; Hillemanns, P ; Haiman, CA ; Henderson, BE ; Schumacher, F ; Le Marchand, L ; Burwinkel, B ; Marme, F ; Surovy, H ; Yang, R ; Anton-Culver, H ; Ziogas, A ; Hooning, MJ ; Collee, JM ; Martens, JWM ; Tilanus-Linthorst, MMA ; Brenner, H ; Dieffenbach, AK ; Arndt, V ; Stegmaier, C ; Winqvist, R ; Pylkas, K ; Jukkola-Vuorinen, A ; Grip, M ; Lindblom, A ; Margolin, S ; Joseph, V ; Robson, M ; Rau-Murthy, R ; Gonzalez-Neira, A ; Arias, JI ; Zamora, P ; Benitez, J ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, JM ; Peterlongo, P ; Zaffaroni, D ; Barile, M ; Capra, F ; Radice, P ; Teo, SH ; Easton, DF ; Antoniou, AC ; Chenevix-Trench, G ; Goldgar, DE (BMC, 2014-01-01)
    INTRODUCTION: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. METHODS: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. RESULTS: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). CONCLUSIONS: These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
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    SNP-SNP interaction analysis of NF-kappa B signaling pathway on breast cancer survival
    Jamshidi, M ; Fagerholm, R ; Khan, S ; Aittomaki, K ; Czene, K ; Darabi, H ; Li, J ; Andrulis, IL ; Chang-Claude, J ; Devilee, P ; Fasching, PA ; Michailidou, K ; Bolla, MK ; Dennis, J ; Wang, Q ; Guo, Q ; Rhenius, V ; Cornelissen, S ; Rudolph, A ; Knight, JA ; Loehberg, CR ; Burwinkel, B ; Marme, F ; Hopper, JL ; Southey, MC ; Bojesen, SE ; Flyger, H ; Brenner, H ; Holleczek, B ; Margolin, S ; Mannermaa, A ; Kosma, V-M ; Van Dyck, L ; Nevelsteen, I ; Couch, FJ ; Olson, JE ; Giles, GG ; McLean, C ; Haiman, CA ; Henderson, BE ; Winqvist, R ; Pylkas, K ; Tollenaar, RAEM ; Garcia-Closas, M ; Figueroa, J ; Hooning, MJ ; Martens, JWM ; Cox, A ; Cross, SS ; Simard, J ; Dunning, AM ; Easton, DF ; Pharoah, PDP ; Hall, P ; Blomqvist, C ; Schmidt, MK ; Nevanlinna, H (IMPACT JOURNALS LLC, 2015-11-10)
    In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox' regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P=1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.
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    Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants
    Mavaddat, N ; Pharoah, PDP ; Michailidou, K ; Tyrer, J ; Brook, MN ; Bolla, MK ; Wang, Q ; Dennis, J ; Dunning, AM ; Shah, M ; Luben, R ; Brown, J ; Bojesen, SE ; Nordestgaard, BG ; Nielsen, SF ; Flyger, H ; Czene, K ; Darabi, H ; Eriksson, M ; Peto, J ; dos-Santos-Silva, I ; Dudbridge, F ; Johnson, N ; Schmidt, MK ; Broeks, A ; Verhoef, S ; Rutgers, EJ ; Swerdlow, A ; Ashworth, A ; Orr, N ; Schoemaker, MJ ; Figueroa, J ; Chanock, SJ ; Brinton, L ; Lissowska, J ; Couch, FJ ; Olson, JE ; Vachon, C ; Pankratz, VS ; Lambrechts, D ; Wildiers, H ; Van Ongeval, C ; Van Limbergen, E ; Kristensen, V ; Alnaes, GG ; Nord, S ; Borresen-Dale, A-L ; Nevanlinna, H ; Muranen, TA ; Aittomaeki, K ; Blomqvist, C ; Chang-Claude, J ; Rudolph, A ; Seibold, P ; Flesch-Janys, D ; Fasching, PA ; Haeberle, L ; Ekici, AB ; Beckmann, MW ; Burwinkel, B ; Marme, F ; Schneeweiss, A ; Sohn, C ; Trentham-Dietz, A ; Newcomb, P ; Titus, L ; Egan, KM ; Hunter, DJ ; Lindstrom, S ; Tamimi, RM ; Kraft, P ; Rahman, N ; Turnbull, C ; Renwick, A ; Seal, S ; Li, J ; Liu, J ; Humphreys, K ; Benitez, J ; Zamora, MP ; Perez, JIA ; Menendez, P ; Jakubowska, A ; Lubinski, J ; Jaworska-Bieniek, K ; Durda, K ; Bogdanova, NV ; Antonenkova, NN ; Doerk, T ; Anton-Culver, H ; Neuhausen, SL ; Ziogas, A ; Bernstein, L ; Devilee, P ; Tollenaar, RAEM ; Seynaeve, C ; van Asperen, CJ ; Cox, A ; Cross, SS ; Reed, MWR ; Khusnutdinova, E ; Bermisheva, M ; Prokofyeva, D ; Takhirova, Z ; Meindl, A ; Schmutzler, RK ; Sutter, C ; Yang, R ; Schuermann, P ; Bremer, M ; Christiansen, H ; Park-Simon, T-W ; Hillemanns, P ; Guenel, P ; Truong, T ; Menegaux, F ; Sanchez, M ; Radice, P ; Peterlongo, P ; Manoukian, S ; Pensotti, V ; Hopper, JL ; Tsimiklis, H ; Apicella, C ; Southey, MC ; Brauch, H ; Bruening, T ; Ko, Y-D ; Sigurdson, AJ ; Doody, MM ; Hamann, U ; Torres, D ; Ulmer, H-U ; Foersti, A ; Sawyer, EJ ; Tomlinson, I ; Kerin, MJ ; Miller, N ; Andrulis, IL ; Knight, JA ; Glendon, G ; Mulligan, AM ; Chenevix-Trench, G ; Balleine, R ; Giles, GG ; Milne, RL ; McLean, C ; Lindblom, A ; Margolin, S ; Haiman, CA ; Henderson, BE ; Schumacher, F ; Le Marchand, L ; Eilber, U ; Wang-Gohrke, S ; Hooning, MJ ; Hollestelle, A ; van den Ouweland, AMW ; Koppert, LB ; Carpenter, J ; Clarke, C ; Scott, R ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, JM ; Brenner, H ; Arndt, V ; Stegmaier, C ; Dieffenbach, AK ; Winqvist, R ; Pylkaes, K ; Jukkola-Vuorinen, A ; Grip, M ; Offit, K ; Vijai, J ; Robson, M ; Rau-Murthy, R ; Dwek, M ; Swann, R ; Perkins, KA ; Goldberg, MS ; Labreche, F ; Dumont, M ; Eccles, DM ; Tapper, WJ ; Rafiq, S ; John, EM ; Whittemore, AS ; Slager, S ; Yannoukakos, D ; Toland, AE ; Yao, S ; Zheng, W ; Halverson, SL ; Gonzalez-Neira, A ; Pita, G ; Alonso, MR ; Alvarez, N ; Herrero, D ; Tessier, DC ; Vincent, D ; Bacot, F ; Luccarini, C ; Baynes, C ; Ahmed, S ; Maranian, M ; Healey, CS ; Simard, J ; Hall, P ; Easton, DF ; Garcia-Closas, M (OXFORD UNIV PRESS INC, 2015-05-01)
    BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. METHODS: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. RESULTS: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. CONCLUSIONS: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
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    Common germline polymorphisms associated with breast cancer-specific survival
    Pirie, A ; Guo, Q ; Kraft, P ; Canisius, S ; Eccles, DM ; Rahman, N ; Nevanlinna, H ; Chen, C ; Khan, S ; Tyrer, J ; Bolla, MK ; Wang, Q ; Dennis, J ; Michailidou, K ; Lush, M ; Dunning, AM ; Shah, M ; Czene, K ; Darabi, H ; Eriksson, M ; Lambrechts, D ; Weltens, C ; Leunen, K ; van Ongeval, C ; Nordestgaard, BG ; Nielsen, SF ; Flyger, H ; Rudolph, A ; Seibold, P ; Flesch-Janys, D ; Blomqvist, C ; Aittomaki, K ; Fagerholm, R ; Muranen, TA ; Olsen, JE ; Hallberg, E ; Vachon, C ; Knight, JA ; Glendon, G ; Mulligan, AM ; Broeks, A ; Cornelissen, S ; Haiman, CA ; Henderson, BE ; Schumacher, F ; Le Marchand, L ; Hopper, JL ; Tsimiklis, H ; Apicella, C ; Southey, MC ; Cross, SS ; Reed, MWR ; Giles, GG ; Milne, RL ; McLean, C ; Winqvist, R ; Pylkas, K ; Jukkola-Vuorinen, A ; Grip, M ; Hooning, MJ ; Hollestelle, A ; Martens, JWM ; van den Ouweland, AMW ; Marme, F ; Schneeweiss, A ; Yang, R ; Burwinkel, B ; Figueroa, J ; Chanock, SJ ; Lissowska, J ; Sawyer, EJ ; Tomlinson, I ; Kerin, MJ ; Miller, N ; Brenner, H ; Butterbach, K ; Holleczek, B ; Kataja, V ; Kosma, V-M ; Hartikainen, JM ; Li, J ; Brand, JS ; Humphreys, K ; Devilee, P ; Tollenaar, RAEM ; Seynaeve, C ; Radice, P ; Peterlongo, P ; Manoukian, S ; Ficarazzi, F ; Beckmann, MW ; Hein, A ; Ekici, AB ; Balleine, R ; Phillips, K-A ; Benitez, J ; Zamora, MP ; Perez, JIA ; Menendez, P ; Jakubowska, A ; Lubinski, J ; Gronwald, J ; Durda, K ; Hamann, U ; Kabisch, M ; Ulmer, HU ; Ruediger, T ; Margolin, S ; Kristensen, V ; Nord, S ; Evans, DG ; Abraham, J ; Earl, H ; Poole, CJ ; Hiller, L ; Dunn, JA ; Bowden, S ; Yang, R ; Campa, D ; Diver, WR ; Gapstur, SM ; Gaudet, MM ; Hankinson, S ; Hoover, RN ; Husing, A ; Kaaks, R ; Machiela, MJ ; Willett, W ; Barrdahl, M ; Canzian, F ; Chin, S-F ; Caldas, C ; Hunter, DJ ; Lindstrom, S ; Garcia-Closas, M ; Couch, FJ ; Chenevix-Trench, G ; Mannermaa, A ; Andrulis, IL ; Hall, P ; Chang-Claude, J ; Easton, DF ; Bojesen, SE ; Cox, A ; Fasching, PA ; Pharoah, PDP ; Schmidt, MK (BMC, 2015-04-22)
    INTRODUCTION: Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. METHODS: A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect. RESULTS: Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease. CONCLUSIONS: Although no variants reached genome-wide significance (P <5 x 10(-8)), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.
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    Identification of Novel Genetic Markers of Breast Cancer Survival
    Guo, Q ; Schmidt, MK ; Kraft, P ; Canisius, S ; Chen, C ; Khan, S ; Tyrer, J ; Bolla, MK ; Wang, Q ; Dennis, J ; Michailidou, K ; Lush, M ; Kar, S ; Beesley, J ; Dunning, AM ; Shah, M ; Czene, K ; Darabi, H ; Eriksson, M ; Lambrechts, D ; Weltens, C ; Leunen, K ; Bojesen, SE ; Nordestgaard, BG ; Nielsen, SF ; Flyger, H ; Chang-Claude, J ; Rudolph, A ; Seibold, P ; Flesch-Janys, D ; Blomqvist, C ; Aittomaeki, K ; Fagerholm, R ; Muranen, TA ; Couch, FJ ; Olson, JE ; Vachon, C ; Andrulis, IL ; Knight, JA ; Glendon, G ; Mulligan, AM ; Broeks, A ; Hogervorst, FB ; Haiman, CA ; Henderson, BE ; Schumacher, F ; Le Marchand, L ; Hopper, JL ; Tsimiklis, H ; Apicella, C ; Southey, MC ; Cox, A ; Cross, SS ; Reed, MWR ; Giles, GG ; Milne, RL ; McLean, C ; Winqvist, R ; Pylkaes, K ; Jukkola-Vuorinen, A ; Grip, M ; Hooning, MJ ; Hollestelle, A ; Martens, JWM ; Van den Ouweland, AMW ; Marme, F ; Schneeweiss, A ; Yang, R ; Burwinkel, B ; Figueroa, J ; Chanock, SJ ; Lissowska, J ; Sawyer, EJ ; Tomlinson, I ; Kerin, MJ ; Miller, N ; Brenner, H ; Dieffenbach, AK ; Arndt, V ; Holleczek, B ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, JM ; Li, J ; Brand, JS ; Humphreys, K ; Devilee, P ; Tollenaar, RAEM ; Seynaeve, C ; Radice, P ; Peterlongo, P ; Bonanni, B ; Mariani, P ; Fasching, PA ; Beckmann, MW ; Hein, A ; Ekici, AB ; Chenevix-Trench, G ; Balleine, R ; Phillips, K-A ; Benitez, J ; Zamora, MP ; Perez, JIA ; Menendez, P ; Jakubowska, A ; Lubinski, J ; Jaworska-Bieniek, K ; Durda, K ; Hamann, U ; Kabisch, M ; Ulmer, HU ; Ruediger, T ; Margolin, S ; Kristensen, V ; Nord, S ; Evans, DG ; Abraham, JE ; Earl, HM ; Hiller, L ; Dunn, JA ; Bowden, S ; Berg, C ; Campa, D ; Diver, WR ; Gapstur, SM ; Gaudet, MM ; Hankinson, SE ; Hoover, RN ; Huesing, A ; Kaaks, R ; Machiela, MJ ; Willett, W ; Barrdahl, M ; Canzian, F ; Chin, S-F ; Caldas, C ; Hunter, DJ ; Lindstrom, S ; Garcia-Closas, M ; Hall, P ; Easton, DF ; Eccles, DM ; Rahman, N ; Nevanlinna, H ; Pharoah, PDP (OXFORD UNIV PRESS INC, 2015-05-01)
    BACKGROUND: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. METHODS: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. RESULTS: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. CONCLUSIONS: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.