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    11q13 is a susceptibility locus for hormone receptor positive breast cancer
    Lambrechts, D ; Truong, T ; Justenhoven, C ; Humphreys, MK ; Wang, J ; Hopper, JL ; Dite, GS ; Apicella, C ; Southey, MC ; Schmidt, MK ; Broeks, A ; Cornelissen, S ; van Hien, R ; Sawyer, E ; Tomlinson, I ; Kerin, M ; Miller, N ; Milne, RL ; Pilar Zamora, M ; Arias Perez, JI ; Benitez, J ; Hamann, U ; Ko, Y-D ; Bruening, T ; Chang-Claude, J ; Eilber, U ; Hein, R ; Nickels, S ; Flesch-Janys, D ; Wang-Gohrke, S ; John, EM ; Miron, A ; Winqvist, R ; Pylkas, K ; Jukkola-Vuorinen, A ; Grip, M ; Chenevix-Trench, G ; Beesley, J ; Chen, X ; Menegaux, F ; Cordina-Duverger, E ; Shen, C-Y ; Yu, J-C ; Wu, P-E ; Hou, M-F ; Andrulis, IL ; Selander, T ; Glendon, G ; Mulligan, AM ; Anton-Culver, H ; Ziogas, A ; Muir, KR ; Lophatananon, A ; Rattanamongkongul, S ; Puttawibul, P ; Jones, M ; Orr, N ; Ashworth, A ; Swerdlow, A ; Severi, G ; Baglietto, L ; Giles, G ; Southey, M ; Marme, F ; Schneeweiss, A ; Sohn, C ; Burwinkel, B ; Yesilyurt, BT ; Neven, P ; Paridaens, R ; Wildiers, H ; Brenner, H ; Mueller, H ; Arndt, V ; Stegmaier, C ; Meindl, A ; Schott, S ; Bartram, CR ; Schmutzler, RK ; Cox, A ; Brock, IW ; Elliott, G ; Cross, SS ; Fasching, PA ; Schulz-Wendtland, R ; Ekici, AB ; Beckmann, MW ; Fletcher, O ; Johnson, N ; Silva, IDS ; Peto, J ; Nevanlinna, H ; Muranen, TA ; Aittomaki, K ; Blomqvist, C ; Doerk, T ; Schuermann, P ; Bremer, M ; Hillemanns, P ; Bogdanova, NV ; Antonenkova, NN ; Rogov, YI ; Karstens, JH ; Khusnutdinova, E ; Bermisheva, M ; Prokofieva, D ; Gancev, S ; Jakubowska, A ; Lubinski, J ; Jaworska, K ; Durda, K ; Nordestgaard, BG ; Bojesen, SE ; Lanng, C ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, JM ; Radice, P ; Peterlongo, P ; Manoukian, S ; Bernard, L ; Couch, FJ ; Olson, JE ; Wang, X ; Fredericksen, Z ; Alnaes, GG ; Kristensen, V ; Borresen-Dale, A-L ; Devilee, P ; Tollenaar, RAEM ; Seynaeve, CM ; Hooning, MJ ; Garcia-Closas, M ; Chanock, SJ ; Lissowska, J ; Sherman, ME ; Hall, P ; Liu, J ; Czene, K ; Kang, D ; Yoo, K-Y ; Noh, D-Y ; Lindblom, A ; Margolin, S ; Dunning, AM ; Pharoah, PDP ; Easton, DF ; Guenel, P ; Brauch, H (WILEY, 2012-07-01)
    A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.
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    Diagnostic Chest X-Rays and Breast Cancer Risk before Age 50 Years for BRCA1 and BRCA2 Mutation Carriers
    John, EM ; McGuire, V ; Thomas, D ; Haile, R ; Ozcelik, H ; Milne, RL ; Felberg, A ; West, DW ; Miron, A ; Knight, JA ; Terry, MB ; Daly, M ; Buys, SS ; Andrulis, IL ; Hopper, JL ; Southey, MC ; Giles, GG ; Apicella, C ; Thorne, H ; Whittemore, AS (AMER ASSOC CANCER RESEARCH, 2013-09-01)
    BACKGROUND: The effects of low-dose medical radiation on breast cancer risk are uncertain, and few studies have included genetically susceptible women, such as those who carry germline BRCA1 and BRCA2 mutations. METHODS: We studied 454 BRCA1 and 273 BRCA2 mutation carriers ages younger than 50 years from three breast cancer family registries in the United States, Canada, and Australia/New Zealand. We estimated breast cancer risk associated with diagnostic chest X-rays by comparing mutation carriers with breast cancer (cases) with those without breast cancer (controls). Exposure to chest X-rays was self-reported. Mammograms were not considered in the analysis. RESULTS: After adjusting for known risk factors for breast cancer, the ORs for a history of diagnostic chest X-rays, excluding those for tuberculosis or pneumonia, were 1.16 [95% confidence interval (CI), 0.64-2.11] for BRCA1 mutations carriers and 1.22 (95% CI, 0.62-2.42) for BRCA2 mutations carriers. The OR was statistically elevated for BRCA2 mutation carriers with three to five diagnostic chest X-rays (P = 0.01) but not for those with six or more chest X-rays. Few women reported chest fluoroscopy for tuberculosis or chest X-rays for pneumonia; the OR estimates were elevated, but not statistically significant, for BRCA1 mutation carriers. CONCLUSIONS: Our findings do not support a positive association between diagnostic chest X-rays and breast cancer risk before the ages of 50 years for BRCA1 or BRCA2 mutation carriers. IMPACT: Given the increasing use of diagnostic imaging involving higher ionizing radiation doses, further studies of genetically predisposed women are warranted.
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    9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium
    Warren, H ; Dudbridge, F ; Fletcher, O ; Orr, N ; Johnson, N ; Hopper, JL ; Apicella, C ; Southey, MC ; Mahmoodi, M ; Schmidt, MK ; Broeks, A ; Cornelissen, S ; Braaf, LM ; Muir, KR ; Lophatananon, A ; Chaiwerawattana, A ; Wiangnon, S ; Fasching, PA ; Beckmann, MW ; Ekici, AB ; Schulz-Wendtland, R ; Sawyer, EJ ; Tomlinson, I ; Kerin, M ; Burwinkel, B ; Marme, F ; Schneeweiss, A ; Sohn, C ; Guenel, P ; Therese, T ; Laurent-Puig, P ; Mulot, C ; Bojesen, SE ; Nielsen, SF ; Flyger, H ; Nordestgaard, BG ; Milne, RL ; Benitez, J ; Arias-Perez, J-I ; Pilar Zamora, M ; Anton-Culver, H ; Ziogas, A ; Bernstein, L ; Dur, CC ; Brenner, H ; Mueller, H ; Arndt, V ; Langheinz, A ; Meindl, A ; Golatta, M ; Bartram, CR ; Schmutzler, RK ; Brauch, H ; Justenhoven, C ; Bruening, T ; Chang-Claude, J ; Wang-Gohrke, S ; Eilber, U ; Doerk, T ; Schuermann, P ; Bremer, M ; Hillemanns, P ; Nevanlinna, H ; Muranen, TA ; Aittomaki, K ; Blomqvist, C ; Bogdanova, N ; Antonenkova, N ; Rogov, Y ; Bermisheva, M ; Prokofyeva, D ; Zinnatullina, G ; Khusnutdinova, E ; Lindblom, A ; Margolin, S ; Mannermaa, A ; Kosma, V-M ; Hartikainen, JM ; Kataja, V ; Chenevix-Trench, G ; Beesley, J ; Chen, X ; Lambrechts, D ; Smeets, A ; Paridaens, R ; Weltens, C ; Flesch-Janys, D ; Buck, K ; Behrens, S ; Peterlongo, P ; Bernard, L ; Manoukian, S ; Radice, P ; Couch, FJ ; Vachon, C ; Wang, X ; Olson, J ; Giles, G ; Baglietto, L ; McLean, CA ; Severi, G ; John, EM ; Miron, A ; Winqvist, R ; Pylkas, K ; Jukkola-Vuorinen, A ; Grip, M ; Andrulis, IL ; Knight, JA ; Mulligan, AM ; Weerasooriya, N ; Devilee, P ; Tollenaar, RAEM ; Martens, JWM ; Seynaeve, CM ; Hooning, MJ ; Hollestelle, A ; Jager, A ; Tilanus-Linthorst, MMA ; Hall, P ; Czene, K ; Liu, J ; Li, J ; Cox, A ; Cross, SS ; Brock, IW ; Reed, MWR ; Pharoah, P ; Blows, FM ; Dunning, AM ; Ghous-saini, M ; Ashworth, A ; Swerdlow, A ; Jones, M ; Schoemaker, M ; Easton, DF ; Humphreys, M ; Wang, Q ; Peto, J ; dos-Santos-Silva, I (AMER ASSOC CANCER RESEARCH, 2012-10-01)
    BACKGROUND: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). METHODS: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls). RESULTS: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors. CONCLUSIONS: This study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer. IMPACT: The findings further support the view that genetic susceptibility varies according to tumor subtype.
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    Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast
    Sawyer, E ; Roylance, R ; Petridis, C ; Brook, MN ; Nowinski, S ; Papouli, E ; Fletcher, O ; Pinder, S ; Hanby, A ; Kohut, K ; Gorman, P ; Caneppele, M ; Peto, J ; Silva, IDS ; Johnson, N ; Swann, R ; Dwek, M ; Perkins, K-A ; Gillett, C ; Houlston, R ; Ross, G ; De Ieso, P ; Southey, MC ; Hopper, JL ; Provenzano, E ; Apicella, C ; Wesseling, J ; Cornelissen, S ; Keeman, R ; Fasching, PA ; Jud, SM ; Ekici, AB ; Beckmann, MW ; Kerin, MJ ; Marme, F ; Schneeweiss, A ; Sohn, C ; Burwinkel, B ; Guenel, P ; Truong, T ; Laurent-Puig, P ; Kerbrat, P ; Bojesen, SE ; Nordestgaard, BG ; Nielsen, SF ; Flyger, H ; Milne, RL ; Perez, JIA ; Menendez, P ; Benitez, J ; Brenner, H ; Dieffenbach, AK ; Arndt, V ; Stegmaier, C ; Meindl, A ; Lichtner, P ; Schmutzler, RK ; Lochmann, M ; Brauch, H ; Fischer, H-P ; Ko, Y-D ; Nevanlinna, H ; Muranen, TA ; Aittomaki, K ; Blomqvist, C ; Bogdanova, NV ; Dork, T ; Lindblom, A ; Margolin, S ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, JM ; Chenevix-Trench, G ; Lambrechts, D ; Weltens, C ; Van Limbergen, E ; Hatse, S ; Chang-Claude, J ; Rudolph, A ; Seibold, P ; Flesch-Janys, D ; Radice, P ; Peterlongo, P ; Bonanni, B ; Volorio, S ; Giles, GG ; Severi, G ; Baglietto, L ; Mclean, CA ; Haiman, CA ; Henderson, BE ; Schumacher, F ; Le Marchand, L ; Simard, J ; Goldberg, MS ; Labreche, F ; Dumont, M ; Kristensen, V ; Winqvist, R ; Pylkas, K ; Jukkola-Vuorinen, A ; Kauppila, S ; Andrulis, IL ; Knight, JA ; Glendon, G ; Mulligan, AM ; Devillee, P ; Tollenaar, RAEM ; Seynaeve, CM ; Kriege, M ; Figueroa, J ; Chanock, SJ ; Sherman, ME ; Hooning, MJ ; Hollestelle, A ; van den Ouweland, AMW ; van Deurzen, CHM ; Li, J ; Czene, K ; Humphreys, K ; Cox, A ; Cross, SS ; Reed, MWR ; Shah, M ; Jakubowska, A ; Lubinski, J ; Jaworska-Bieniek, K ; Durda, K ; Swerdlow, A ; Ashworth, A ; Orr, N ; Schoemaker, M ; Couch, FJ ; Hallberg, E ; Gonzalez-Neira, A ; Pita, G ; Alonso, MR ; Tessier, DC ; Vincent, D ; Bacot, F ; Bolla, MK ; Wang, Q ; Dennis, J ; Michailidou, K ; Dunning, AM ; Hall, P ; Easton, D ; Pharoah, P ; Schmidt, MK ; Tomlinson, I ; Garcia-Closas, M ; Gibson, G (PUBLIC LIBRARY SCIENCE, 2014-04-01)
    Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.
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    Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors
    Nickels, S ; Truong, T ; Hein, R ; Stevens, K ; Buck, K ; Behrens, S ; Eilber, U ; Schmidt, M ; Haeberle, L ; Vrieling, A ; Gaudet, M ; Figueroa, J ; Schoof, N ; Spurdle, AB ; Rudolph, A ; Fasching, PA ; Hopper, JL ; Makalic, E ; Schmidt, DF ; Southey, MC ; Beckmann, MW ; Ekici, AB ; Fletcher, O ; Gibson, L ; Silva, IDS ; Peto, J ; Humphreys, MK ; Wang, J ; Cordina-Duverger, E ; Menegaux, F ; Nordestgaard, BG ; Bojesen, SE ; Lanng, C ; Anton-Culver, H ; Ziogas, A ; Bernstein, L ; Clarke, CA ; Brenner, H ; Mueller, H ; Arndt, V ; Stegmaier, C ; Brauch, H ; Bruening, T ; Harth, V ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, JM ; Lambrechts, D ; Smeets, D ; Neven, P ; Paridaens, R ; Flesch-Janys, D ; Obi, N ; Wang-Gohrke, S ; Couch, FJ ; Olson, JE ; Vachon, CM ; Giles, GG ; Severi, G ; Baglietto, L ; Offit, K ; John, EM ; Miron, A ; Andrulis, IL ; Knight, JA ; Glendon, G ; Mulligan, AM ; Chanock, SJ ; Lissowska, J ; Liu, J ; Cox, A ; Cramp, H ; Connley, D ; Balasubramanian, S ; Dunning, AM ; Shah, M ; Trentham-Dietz, A ; Newcomb, P ; Titus, L ; Egan, K ; Cahoon, EK ; Rajaraman, P ; Sigurdson, AJ ; Doody, MM ; Guenel, P ; Pharoah, PDP ; Schmidt, MK ; Hall, P ; Easton, DF ; Garcia-Closas, M ; Milne, RL ; Chang-Claude, J ; Horwitz, MS (PUBLIC LIBRARY SCIENCE, 2013-03-01)
    Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4 × 10(-6)) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1 × 10(-4)). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ≥ 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3 × 10(-5)), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.