Melbourne School of Population and Global Health - Research Publications

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    Identification of new breast cancer predisposition genes via whole exome sequencing
    Southey, MC ; Park, DJ ; Lesueur, F ; Odefrey, F ; Nguyen-Dumont, T ; Hammet, F ; Neuhausen, SL ; John, EM ; Andrulis, IL ; Chenevix-Trench, G ; Baglietto, L ; Le Calvez-Kelm, F ; Pertesi, M ; Lonie, A ; Pope, B ; Sinilnikova, O ; Tsimiklis, H ; Giles, GG ; Hopper, JL ; Tavtigian, SV ; Goldgar, DE (Springer Science and Business Media LLC, 2012-01)
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    Meta-Analysis Combining New and Existing Data Sets Confirms that the TERT-CLPTM1L Locus Influences Melanoma Risk
    Law, MH ; Montgomery, GW ; Brown, KM ; Martin, NG ; Mann, GJ ; Hayward, NK ; MacGregor, S (NATURE PUBLISHING GROUP, 2012-02-01)
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    Detectable clonal mosaicism and its relationship to aging and cancer
    Jacobs, KB ; Yeager, M ; Zhou, W ; Wacholder, S ; Wang, Z ; Rodriguez-Santiago, B ; Hutchinson, A ; Deng, X ; Liu, C ; Horner, M-J ; Cullen, M ; Epstein, CG ; Burdett, L ; Dean, MC ; Chatterjee, N ; Sampson, J ; Chung, CC ; Kovaks, J ; Gapstur, SM ; Stevens, VL ; Teras, LT ; Gaudet, MM ; Albanes, D ; Weinstein, SJ ; Virtamo, J ; Taylor, PR ; Freedman, ND ; Abnet, CC ; Goldstein, AM ; Hu, N ; Yu, K ; Yuan, J-M ; Liao, L ; Ding, T ; Qiao, Y-L ; Gao, Y-T ; Koh, W-P ; Xiang, Y-B ; Tang, Z-Z ; Fan, J-H ; Aldrich, MC ; Amos, C ; Blot, WJ ; Bock, CH ; Gillanders, EM ; Harris, CC ; Haiman, CA ; Henderson, BE ; Kolonel, LN ; Le Marchand, L ; McNeill, LH ; Rybicki, BA ; Schwartz, AG ; Signorello, LB ; Spitz, MR ; Wiencke, JK ; Wrensch, M ; Wu, X ; Zanetti, KA ; Ziegler, RG ; Figueroa, JD ; Garcia-Closas, M ; Malats, N ; Marenne, G ; Prokunina-Olsson, L ; Baris, D ; Schwenn, M ; Johnson, A ; Landi, MT ; Goldin, L ; Consonni, D ; Bertazzi, PA ; Rotunno, M ; Rajaraman, P ; Andersson, U ; Freeman, LEB ; Berg, CD ; Buring, JE ; Butler, MA ; Carreon, T ; Feychting, M ; Ahlbom, A ; Gaziano, JM ; Giles, GG ; Hallmans, G ; Hankinson, SE ; Hartge, P ; Henriksson, R ; Inskip, PD ; Johansen, C ; Landgren, A ; McKean-Cowdin, R ; Michaud, DS ; Melin, BS ; Peters, U ; Ruder, AM ; Sesso, HD ; Severi, G ; Shu, X-O ; Visvanathan, K ; White, E ; Wolk, A ; Zeleniuch-Jacquotte, A ; Zheng, W ; Silverman, DT ; Kogevinas, M ; Gonzalez, JR ; Villa, O ; Li, D ; Duell, EJ ; Risch, HA ; Olson, SH ; Kooperberg, C ; Wolpin, BM ; Jiao, L ; Hassan, M ; Wheeler, W ; Arslan, AA ; Bueno-de-Mesquita, HB ; Fuchs, CS ; Gallinger, S ; Gross, MD ; Holly, EA ; Klein, AP ; LaCroix, A ; Mandelson, MT ; Petersen, G ; Boutron-Ruault, M-C ; Bracci, PM ; Canzian, F ; Chang, K ; Cotterchio, M ; Giovannucci, EL ; Goggins, M ; Bolton, JAH ; Jenab, M ; Khaw, K-T ; Krogh, V ; Kurtz, RC ; McWilliams, RR ; Mendelsohn, JB ; Rabe, KG ; Riboli, E ; Tjonneland, A ; Tobias, GS ; Trichopoulos, D ; Elena, JW ; Yu, H ; Amundadottir, L ; Stolzenberg-Solomon, RZ ; Kraft, P ; Schumacher, F ; Stram, D ; Savage, SA ; Mirabello, L ; Andrulis, IL ; Wunder, JS ; Patino Garcia, A ; Sierrasesumaga, L ; Barkauskas, DA ; Gorlick, RG ; Purdue, M ; Chow, W-H ; Moore, LE ; Schwartz, KL ; Davis, FG ; Hsing, AW ; Berndt, SI ; Black, A ; Wentzensen, N ; Brinton, LA ; Lissowska, J ; Peplonska, B ; McGlynn, KA ; Cook, MB ; Graubard, BI ; Kratz, CP ; Greene, MH ; Erickson, RL ; Hunter, DJ ; Thomas, G ; Hoover, RN ; Real, FX ; Fraumeni, JF ; Caporaso, NE ; Tucker, M ; Rothman, N ; Perez-Jurado, LA ; Chanock, SJ (NATURE PUBLISHING GROUP, 2012-06-01)
    In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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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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    Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
    Kirchhoff, T ; Gaudet, MM ; Antoniou, AC ; McGuffog, L ; Humphreys, MK ; Dunning, AM ; Bojesen, SE ; Nordestgaard, BG ; Flyger, H ; Kang, D ; Yoo, K-Y ; Noh, D-Y ; Ahn, S-H ; Dork, T ; Schuermann, P ; Karstens, JH ; Hillemanns, P ; Couch, FJ ; Olson, J ; Vachon, C ; Wang, X ; Cox, A ; Brock, I ; Elliott, G ; Reed, MWR ; Burwinkel, B ; Meindl, A ; Brauch, H ; Hamann, U ; Ko, Y-D ; Broeks, A ; Schmidt, MK ; Van 't Veer, LJ ; Braaf, LM ; Johnson, N ; Fletcher, O ; Gibson, L ; Peto, J ; Turnbull, C ; Seal, S ; Renwick, A ; Rahman, N ; Wu, P-E ; Yu, J-C ; Hsiung, C-N ; Shen, C-Y ; Southey, MC ; Hopper, JL ; Hammet, F ; Van Dorpe, T ; Dieudonne, A-S ; Hatse, S ; Lambrechts, D ; Andrulis, IL ; Bogdanova, N ; Antonenkova, N ; Rogov, JI ; Prokofieva, D ; Bermisheva, M ; Khusnutdinova, E ; van Asperen, CJ ; Tollenaar, RAEM ; Hooning, MJ ; Devilee, P ; Margolin, S ; Lindblom, A ; Milne, RL ; Ignacio Arias, J ; Pilar Zamora, M ; Benitez, J ; Severi, G ; Baglietto, L ; Giles, GG ; Spurdle, AB ; Beesley, J ; Chen, X ; Holland, H ; Healey, S ; Wang-Gohrke, S ; Chang-Claude, J ; Mannermaa, A ; Kosma, V-M ; Kauppinen, J ; Kataja, V ; Agnarsson, BA ; Caligo, MA ; Godwin, AK ; Nevanlinna, H ; Heikkinen, T ; Fredericksen, Z ; Lindor, N ; Nathanson, KL ; Domchek, SM ; Loman, N ; Karlsson, P ; Askmalm, MS ; Melin, B ; von Wachenfeldt, A ; Hogervorst, FBL ; Verheus, M ; Rookus, MA ; Seynaeve, C ; Oldenburg, RA ; Ligtenberg, MJ ; Ausems, MGEM ; Aalfs, CM ; Gille, HJP ; Wijnen, JT ; Garcia, EBG ; Peock, S ; Cook, M ; Oliver, CT ; Frost, D ; Luccarini, C ; Pichert, G ; Davidson, R ; Chu, C ; Eccles, D ; Ong, K-R ; Cook, J ; Douglas, F ; Hodgson, S ; Evans, DG ; Eeles, R ; Gold, B ; Pharoah, PDP ; Offit, K ; Chenevix-Trench, G ; Easton, DF ; Prokunina-Olsson, L (PUBLIC LIBRARY SCIENCE, 2012-06-29)
    Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
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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.
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    PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2
    Wishart, GC ; Bajdik, CD ; Dicks, E ; Provenzano, E ; Schmidt, MK ; Sherman, M ; Greenberg, DC ; Green, AR ; Gelmon, KA ; Kosma, V-M ; Olson, JE ; Beckmann, MW ; Winqvist, R ; Cross, SS ; Severi, G ; Huntsman, D ; Pylkas, K ; Ellis, I ; Nielsen, TO ; Giles, G ; Blomqvist, C ; Fasching, PA ; Couch, FJ ; Rakha, E ; Foulkes, WD ; Blows, FM ; Begin, LR ; van't Veer, LJ ; Southey, M ; Nevanlinna, H ; Mannermaa, A ; Cox, A ; Cheang, M ; Baglietto, L ; Caldas, C ; Garcia-Closas, M ; Pharoah, PDP (NATURE PUBLISHING GROUP, 2012-08-21)
    BACKGROUND: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. METHODS: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. RESULTS: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. CONCLUSION: Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.
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    Tumour morphology of early-onset breast cancers predicts breast cancer risk for first-degree relatives: the Australian Breast Cancer Family Registry
    Dite, GS ; Makalic, E ; Schmidt, DF ; Giles, GG ; Hopper, JL ; Southey, MC (BIOMED CENTRAL LTD, 2012-01-01)
    INTRODUCTION: We hypothesised that breast cancer risk for relatives of women with early-onset breast cancer could be predicted by tumour morphological features. METHODS: We studied female first-degree relatives of a population-based sample of 452 index cases with a first primary invasive breast cancer diagnosed before the age of 40 years. For the index cases, a standardised tumour morphology review had been conducted for all; estrogen (ER) and progesterone receptor (PR) status was available for 401 (89%), and 77 (17%) had a high-risk mutation in a breast cancer susceptibility gene or methylation of the BRCA1 promoter region in peripheral blood DNA. We calculated standardised incidence ratios (SIR) by comparing the number of mothers and sisters with breast cancer with the number expected based on Australian incidence rates specific for age and year of birth. RESULTS: Using Cox proportional hazards modelling, absence of extensive sclerosis, extensive intraductal carcinoma, absence of acinar and glandular growth patterns, and the presence of trabecular and lobular growth patterns were independent predictors with between a 1.8- and 3.1-fold increased risk for relatives (all P <0.02). Excluding index cases with known genetic predisposition or BRCA1 promoter methylation, absence of extensive sclerosis, circumscribed growth, extensive intraductal carcinoma and lobular growth pattern were independent predictors with between a 2.0- and 3.3-fold increased risk for relatives (all P <0.02). Relatives of the 128 (34%) index cases with none of these four features were at population risk (SIR = 1.03, 95% CI = 0.57 to 1.85) while relatives of the 37 (10%) index cases with two or more features were at high risk (SIR = 5.18, 95% CI = 3.22 to 8.33). CONCLUSIONS: This wide variation in risks for relatives based on tumour characteristics could be of clinical value, help discover new breast cancer susceptibility genes and be an advance on the current clinical practice of using ER and PR as pathology-based predictors of familial and possibly genetic risks.
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    A longitudinal study of the association between dietary factors, serum lipids, and bone marrow lesions of the knee
    Dore, D ; de Hoog, J ; Giles, G ; Ding, C ; Cicuttini, FM ; Jones, G (BIOMED CENTRAL LTD, 2012-01-01)
    INTRODUCTION: Bone marrow lesions (BMLs) play an important role in knee osteoarthritis, but their etiology is not well understood. The aim of this longitudinal study was to describe the association between dietary factors, serum lipids, and BMLs. METHODS: In total, 394 older men and women (mean age, 63 years; range, 52 to 79) were measured at baseline and approximately 2.7 years later. BMLs were determined by using T2-weighted fat-saturation magnetic resonance imaging (MRI) by measuring the maximal area of the lesion. Nutrient intake (total energy, fat, carbohydrate, protein, and sugar) and serum lipids were assessed at baseline. RESULTS: Cross-sectionally, dietary factors and lipids were not significantly associated with BMLs. Energy, carbohydrate, and sugar intake (but not fat) were positively associated with a change in BML size (β = 15.44 to 19.27 mm2 per 1 SD increase; all P < 0.05). High-density lipoprotein (HDL) cholesterol tended to be negatively associated with BML change (β = -11.66 mm2 per 1 SD increase; P = 0.088). CONCLUSIONS: Energy, carbohydrate, and sugar intake may be risk factors for BML development and progression. HDL cholesterol seems protective against BMLs. These results suggest that macronutrients and lipids may be important in BML etiology and that dietary modification may alter BML natural history.
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    Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)
    Hein, R ; Maranian, M ; Hopper, JL ; Kapuscinski, MK ; Southey, MC ; Park, DJ ; Schmidt, MK ; Broeks, A ; Hogervorst, FBL ; Bueno-de-Mesquit, HB ; Muir, KR ; Lophatananon, A ; Rattanamongkongul, S ; Puttawibul, P ; Fasching, PA ; Hein, A ; Ekici, AB ; Beckmann, MW ; Fletcher, O ; Johnson, N ; Silva, IDS ; Peto, J ; Sawyer, E ; Tomlinson, I ; Kerin, M ; Miller, N ; Marmee, F ; Schneeweiss, A ; Sohn, C ; Burwinkel, B ; Guenel, P ; Cordina-Duverger, E ; Menegaux, F ; Truong, T ; Bojesen, SE ; Nordestgaard, BG ; Flyger, H ; Milne, RL ; Arias Perez, JI ; Pilar Zamora, M ; Benitez, J ; Anton-Culver, H ; Ziogas, A ; Bernstein, L ; Clarke, CA ; Brenner, H ; Mueller, H ; Arndt, V ; Stegmaier, C ; Rahman, N ; Seal, S ; Turnbull, C ; Renwick, A ; Meindl, A ; Schott, S ; Bartram, CR ; Schmutzler, RK ; Brauch, H ; Hamann, U ; Ko, Y-D ; Wang-Gohrke, S ; Doerk, T ; Schuermann, P ; Karstens, JH ; Hillemanns, P ; Nevanlinna, H ; Heikkinen, T ; Aittomaki, K ; Blomqvist, C ; Bogdanova, NV ; Zalutsky, IV ; Antonenkova, NN ; Bermisheva, M ; Prokovieva, D ; Farahtdinova, A ; Khusnutdinova, E ; Lindblom, A ; Margolin, S ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, J ; Chen, X ; Beesley, J ; Lambrechts, D ; Zhao, H ; Neven, P ; Wildiers, H ; Nickels, S ; Flesch-Janys, D ; Radice, P ; Peterlongo, P ; Manoukian, S ; Barile, M ; Couch, FJ ; Olson, JE ; Wang, X ; Fredericksen, Z ; Giles, GG ; Baglietto, L ; McLean, CA ; Severi, G ; Offit, K ; Robson, M ; Gaudet, MM ; Vijai, J ; Alnaes, GG ; Kristensen, V ; Borresen-Dale, A-L ; John, EM ; Miron, A ; Winqvist, R ; Pylkas, K ; Jukkola-Vuorinen, A ; Grip, M ; Andrulis, IL ; Knight, JA ; Glendon, G ; Mulligan, AM ; Figueroa, JD ; Garcia-Closas, M ; Lissowska, J ; Sherman, ME ; Hooning, M ; Martens, JWM ; Seynaeve, C ; Collee, M ; Hall, P ; Humpreys, K ; Czene, K ; Liu, J ; Cox, A ; Brock, IW ; Cross, SS ; Reed, MWR ; Ahmed, S ; Ghoussaini, M ; Pharoah, PDP ; Kang, D ; Yoo, K-Y ; Noh, D-Y ; Jakubowska, A ; Jaworska, K ; Durda, K ; Zlowocka, E ; Sangrajrang, S ; Gaborieau, V ; Brennan, P ; McKay, J ; Shen, C-Y ; Yu, J-C ; Hsu, H-M ; Hou, M-F ; Orr, N ; Schoemaker, M ; Ashworth, A ; Swerdlow, A ; Trentham-Dietz, A ; Newcomb, PA ; Titus, L ; Egan, KM ; Chenevix-Trench, G ; Antoniou, AC ; Humphreys, MK ; Morrison, J ; Chang-Claude, J ; Easton, DF ; Dunning, AM ; Chan, KYK (PUBLIC LIBRARY SCIENCE, 2012-08-07)
    The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.