Florey Department of Neuroscience and Mental Health - Research Publications

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    Common variants in breast cancer risk loci predispose to distinct tumor subtypes
    Ahearn, TU ; Zhang, H ; Michailidou, K ; Milne, RL ; Bolla, MK ; Dennis, J ; Dunning, AM ; Lush, M ; Wang, Q ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Aronson, KJ ; Auer, PL ; Augustinsson, A ; Baten, A ; Becher, H ; Behrens, S ; Benitez, J ; Bermisheva, M ; Blomqvist, C ; Bojesen, SE ; Bonanni, B ; Borresen-Dale, A-L ; Brauch, H ; Brenner, H ; Brooks-Wilson, A ; Bruening, T ; Burwinkel, B ; Buys, SS ; Canzian, F ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Collee, JM ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Dork, T ; Dwek, M ; Eccles, DM ; Evans, DG ; Fasching, PA ; Figueroa, J ; Floris, G ; Gago-Dominguez, M ; Gapstur, SM ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Goldberg, MS ; Gonzalez-Neira, A ; Alnaes, GIG ; Grip, M ; Guenel, P ; Haiman, CA ; Hall, P ; Hamann, U ; Harkness, EF ; Heemskerk-Gerritsen, BAM ; Holleczek, B ; Hollestelle, A ; Hooning, MJ ; Hoover, RN ; Hopper, JL ; Howell, A ; Jakimovska, M ; Jakubowska, A ; John, EM ; Jones, ME ; Jung, A ; Kaaks, R ; Kauppila, S ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Ko, Y-D ; Koutros, S ; Kristensen, VN ; Kruger, U ; Kubelka-Sabit, K ; Kurian, AW ; Kyriacou, K ; Lambrechts, D ; Lee, DG ; Lindblom, A ; Linet, M ; Lissowska, J ; Llaneza, A ; Lo, W-Y ; MacInnis, RJ ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; Martinez, ME ; McLean, C ; Meindl, A ; Menon, U ; Nevanlinna, H ; Newman, WG ; Nodora, J ; Offit, K ; Olsson, H ; Orr, N ; Park-Simon, T-W ; Patel, A ; Peto, J ; Pita, G ; Plaseska-Karanfilska, D ; Prentice, R ; Punie, K ; Pylkas, K ; Radice, P ; Rennert, G ; Romero, A ; Ruediger, T ; Saloustros, E ; Sampson, S ; Sandler, DP ; Sawyer, EJ ; Schmutzler, RK ; Schoemaker, MJ ; Schottker, B ; Sherman, ME ; Shu, X-O ; Smichkoska, S ; Southey, MC ; Spinelli, JJ ; Swerdlow, AJ ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Teras, LR ; Terry, MB ; Torres, D ; Troester, MA ; Vachon, CM ; van Deurzen, CHM ; van Veen, EM ; Wagner, P ; Weinberg, CR ; Wendt, C ; Wesseling, J ; Winqvist, R ; Wolk, A ; Yang, XR ; Zheng, W ; Couch, FJ ; Simard, J ; Kraft, P ; Easton, DF ; Pharoah, PDP ; Schmidt, MK ; Garcia-Closas, M ; Chatterjee, N (BMC, 2022-01-04)
    BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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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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    Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses
    Zhan, H ; Ahearn, TU ; Lecarpentier, J ; Barnes, D ; Beesley, J ; Qi, G ; Jiang, X ; O'Mara, TA ; Zhao, N ; Bolla, MK ; Dunning, AM ; Dennis, J ; Wang, Q ; Abu Ful, Z ; Aittomaki, K ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Aronson, KJ ; Arun, BK ; Auer, PL ; Azzollini, J ; Barrowdale, D ; Becher, H ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bialkowska, K ; Blanco, A ; Blomqvist, C ; Bogdanova, N ; Bojesen, SE ; Bonanni, B ; Bondavalli, D ; Borg, A ; Brauch, H ; Brenner, H ; Briceno, I ; Broeks, A ; Brucker, SY ; Bruening, T ; Burwinkel, B ; Buys, SS ; Byers, H ; Caldes, T ; Caligo, MA ; Calvello, M ; Campa, D ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Christiaens, M ; Christiansen, H ; Chung, WK ; Claes, KBM ; Clarke, CL ; Cornelissen, S ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Diez, O ; Domchek, SM ; Doerk, T ; Dwek, M ; Eccles, DM ; Ekici, AB ; Evans, DG ; Fasching, PA ; Figueroa, J ; Foretova, L ; Fostira, F ; Friedman, E ; Frost, D ; Gago-Dominguez, M ; Gapstur, SM ; Garber, J ; Garcia-Saenz, JA ; Gaudet, MM ; Gayther, SA ; Giles, GG ; Godwin, AK ; Goldberg, MS ; Goldgar, DE ; Gonzalez-Neira, A ; Greene, MH ; Gronwald, J ; Guenel, P ; Haeberle, L ; Hahnen, E ; Haiman, CA ; Hake, CR ; Hall, P ; Hamann, U ; Harkness, EF ; Heemskerk-Gerritsen, BAM ; Hillemanns, P ; Hogervorst, FBL ; Holleczek, B ; Hollestelle, A ; Hooning, MJ ; Hoover, RN ; Hopper, JL ; Howell, A ; Huebner, H ; Hulick, PJ ; Imyanitov, EN ; Isaacs, C ; Izatt, L ; Jager, A ; Jakimovska, M ; Jakubowska, A ; James, P ; Janavicius, R ; Janni, W ; John, EM ; Jones, ME ; Jung, A ; Kaaks, R ; Kapoor, PM ; Karlan, BY ; Keeman, R ; Khan, S ; Khusnutdinova, E ; Kitahara, CM ; Ko, Y-D ; Konstantopoulou, I ; Koppert, LB ; Koutros, S ; Kristensen, VN ; Laenkholm, A-V ; Lambrechts, D ; Larsson, SC ; Laurent-Puig, P ; Lazaro, C ; Lazarova, E ; Lejbkowicz, F ; Leslie, G ; Lesueur, F ; Lindblom, A ; Lissowska, J ; Lo, W-Y ; Loud, JT ; Lubinski, J ; Lukomska, A ; MacInnis, RJ ; Mannermaa, A ; Manoochehri, M ; Manoukian, S ; Margolin, S ; Martinez, ME ; Matricardi, L ; McGuffog, L ; McLean, C ; Mebirouk, N ; Meindl, A ; Menon, U ; Miller, A ; Mingazheva, E ; Montagna, M ; Mulligan, AM ; Mulot, C ; Muranen, TA ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Neven, P ; Newman, WG ; Nielsens, FC ; Nikitina-Zake, L ; Nodora, J ; Offit, K ; Olah, E ; Olopade, O ; Olsson, H ; Orr, N ; Papi, L ; Papp, J ; Park-Simon, T-W ; Parsons, MT ; Peissel, B ; Peixoto, A ; Peshkin, B ; Peterlongo, P ; Peto, J ; Phillips, K-A ; Piedmonte, M ; Plaseska-Karanfilska, D ; Prajzendanc, K ; Prentice, R ; Prokofyeva, D ; Rack, B ; Radice, P ; Ramus, SJ ; Rantala, J ; Rashid, MU ; Rennert, G ; Rennert, HS ; Risch, HA ; Romero, A ; Rookus, MA ; Ruebner, M ; Ruediger, T ; Saloustros, E ; Sampson, S ; Sandler, DP ; Sawyer, EJ ; Scheuner, MT ; Schmutzler, RK ; Schneeweiss, A ; Schoemaker, MJ ; Schoettker, B ; Schuermann, P ; Senter, L ; Sharma, P ; Sherman, ME ; Shu, X-O ; Singer, CF ; Smichkoska, S ; Soucy, P ; Southey, MC ; Spinelli, JJ ; Stone, J ; Stoppa-Lyonnet, D ; Swerdlow, AJ ; Szabo, C ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Teixeira, MR ; Terry, M ; Thomassen, M ; Thull, DL ; Tischkowitz, M ; Toland, AE ; Tollenaar, RAEM ; Tomlinson, I ; Torres, D ; Troester, MA ; Truong, T ; Tung, N ; Untch, M ; Vachon, CM ; van den Ouweland, AMW ; van der Kolk, LE ; van Veen, EM ; vanRensburg, EJ ; Vega, A ; Wappenschmidt, B ; Weinberg, CR ; Weitzel, JN ; Wildiers, H ; Winqvist, R ; Wolk, A ; Yang, XR ; Yannoukakos, D ; Zheng, W ; Zorn, KK ; Milne, RL ; Kraft, P ; Simard, J ; Pharoah, PDP ; Michailidou, K ; Antoniou, AC ; Schmidt, MK ; Chenevix-Trench, G ; Easton, DF ; Chatterjee, N ; Garcia-Closas, M (NATURE RESEARCH, 2020-05-18)
    Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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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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    Dietary patterns and risk of breast cancer
    Baglietto, L ; Krishnan, K ; Severi, G ; Hodge, A ; Brinkman, M ; English, DR ; McLean, C ; Hopper, JL ; Giles, GG (SPRINGERNATURE, 2011-02-01)
    BACKGROUND: Evidence is emerging that prudent/healthy dietary patterns might be associated with a reduced risk of breast cancer. METHODS: Using data from the prospective Melbourne Collaborative Cohort Study, we applied principal factor analysis to 124 foods and beverages to identify dietary patterns and estimated their association with breast cancer risk overall and by tumour characteristics using Cox regression. RESULTS: During an average of 14.1 years of follow-up of 20 967 women participants, 815 invasive breast cancers were diagnosed. Among the four dietary factors that we identified, only that characterised by high consumption of fruit and salad was associated with a reduced risk, with stronger associations observed for tumours not expressing oestrogen (ER) and progesterone receptors (PR). Compared with women in the lowest quintile of the factor score, the hazard ratio for women in the highest quintile was 0.92 (95% confidence interval (CI)=0.70-1.21; test for trend, P=0.5) for ER-positive or PR-positive tumours and 0.48 (95% CI=0.26-0.86; test for trend, P=0.002) for ER-negative and PR-negative tumours (test for homogeneity, P=0.01). CONCLUSION: Our study provides additional support for the hypothesis that a dietary pattern rich in fruit and salad might protect against invasive breast cancer and that the effect might be stronger for ER- and PR-negative tumours.
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    BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received
    Dawson, S-J ; Makretsov, N ; Blows, FM ; Driver, KE ; Provenzano, E ; Le Quesne, J ; Baglietto, L ; Severi, G ; Giles, GG ; McLean, CA ; Callagy, G ; Green, AR ; Ellis, I ; Gelmon, K ; Turashvili, G ; Leung, S ; Aparicio, S ; Huntsman, D ; Caldas, C ; Pharoah, P (NATURE PUBLISHING GROUP, 2010-08-24)
    BACKGROUND: Breast cancer is heterogeneous and the existing prognostic classifiers are limited in accuracy, leading to unnecessary treatment of numerous women. B-cell lymphoma 2 (BCL2), an antiapoptotic protein, has been proposed as a prognostic marker, but this effect is considered to relate to oestrogen receptor (ER) status. This study aimed to test the clinical validity of BCL2 as an independent prognostic marker. METHODS: Five studies of 11 212 women with early-stage breast cancer were analysed. Individual patient data included tumour size, grade, lymph node status, endocrine therapy, chemotherapy and mortality. BCL2, ER, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) levels were determined in all tumours. A Cox model incorporating the time-dependent effects of each variable was used to explore the prognostic significance of BCL2. RESULTS: In univariate analysis, ER, PR and BCL2 positivity was associated with improved survival and HER2 positivity with inferior survival. For ER and PR this effect was time dependent, whereas for BCL2 and HER2 the effect persisted over time. In multivariate analysis, BCL2 positivity retained independent prognostic significance (hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.66-0.88, P<0.001). BCL2 was a powerful prognostic marker in ER- (HR 0.63, 95% CI 0.54-0.74, P<0.001) and ER+ disease (HR 0.56, 95% CI 0.48-0.65, P<0.001), and in HER2- (HR 0.55, 95% CI 0.49-0.61, P<0.001) and HER2+ disease (HR 0.70, 95% CI 0.57-0.85, P<0.001), irrespective of the type of adjuvant therapy received. Addition of BCL2 to the Adjuvant! Online prognostic model, for a subset of cases with a 10-year follow-up, improved the survival prediction (P=0.0039). CONCLUSIONS: BCL2 is an independent indicator of favourable prognosis for all types of early-stage breast cancer. This study establishes the rationale for introduction of BCL2 immunohistochemistry to improve prognostic stratification. Further work is now needed to ascertain the exact way to apply BCL2 testing for risk stratification and to standardise BCL2 immunohistochemistry for this application.
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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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    Second to fourth digit ratio (2D: 4D), breast cancer risk factors, and breast cancer risk: a prospective cohort study
    Muller, DC ; Baglietto, L ; Manning, JT ; McLean, C ; Hopper, JL ; English, DR ; Giles, GG ; Severi, G (NATURE PUBLISHING GROUP, 2012-10-23)
    BACKGROUND: We aimed to assess whether 2D:4D measures are associated with breast cancer risk. METHODS: We derived the ratio of the lengths of the index and ring fingers (2D:4D), and right minus left 2D:4D (Δ(r-l)) from digit lengths measured from photocopies of participants' hands collected during a recent follow-up of the Melbourne Collaborative Cohort Study, a prospective study including 24 469 women. Of the 9044 women with available data, we identified 573 incident breast cancer cases. Hazard ratios (HR) and 95% confidence intervals (CI) for a one standard deviation difference in 2D:4D measures were obtained from Weibull survival models, and linear regression models were used to examine potential associations between 2D:4D measures and age at menarche and menopause. RESULTS: We found a direct association between left 2D:4D and breast cancer risk, an inverse association between Δ(r-l) and risk of breast cancer, but no association between right 2D:4D and breast cancer risk. Among breast cancer cases, both right 2D:4D and Δ(r-l) were inversely associated with age at diagnosis. We also observed associations between both right 2D:4D and Δ(r-l) and age at menopause, with increasing digit ratio measures related to earlier mean age at menopause. CONCLUSION: Digit ratio measures might be associated with breast cancer risk and age at onset of breast cancer. If confirmed in other studies, this suggests that lower exposure or sensitivity to prenatal testosterone might be associated with lower risk of breast cancer.