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1. Common germline polymorphisms associated with breast cancer-specific survival

Author

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, 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, 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, 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, and Schmidt, MK

Abstract

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

Published
2015

2. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Author

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, 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, and Goldgar, DE

Abstract

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)

Published
2014

3. Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study

Author

Johnson, N, Dudbridge, F, Orr, N, Gibson, L, Jones, ME, Schoemaker, MJ, Folkerd, EJ, Haynes, BP, Hopper, JL, Southey, MC, Dite, GS, Apicella, C, Schmidt, MK, Broeks, A, Van't Veer, LJ, Atsma, F, Muir, K, Lophatananon, A, Fasching, PA, Beckmann, MW, Ekici, AB, Renner, SP, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Guenel, P, Truong, T, Cordina, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, R, Zamora, MP, Arias Perez, JI, Benitez, J, Bernstein, L, Anton-Culver, H, Ziogas, A, Dur, CC, Brenner, H, Mueller, H, Arndt, V, Dieffenbach, AK, Meindl, A, Heil, J, Bartram, CR, Schmutzler, RK, Brauch, H, Justenhoven, C, Ko, Y-D, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Matsuo, K, Doerk, T, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Chenevix-Trench, G, Beesley, J, Wu, AH, Van den Berg, D, Tseng, C-C, Lambrechts, D, Smeets, D, Neven, P, Wildiers, H, Chang-Claude, J, Rudolph, A, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Bonanni, B, Pensotti, V, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Pankratz, VS, Giles, GG, Severi, G, Baglietto, L, Haiman, C, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Soucy, P, Teo, S, Yip, CH, Phuah, SY, Cornes, BK, Kristensen, VN, Alnaes, GG, Borresen-Dale, A-L, Zheng, W, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Devillee, P, Figueroa, J, Chanock, SJ, Lissowska, J, Sherman, ME, Hall, P, Schoof, N, Hooning, M, Hollestelle, A, Oldenburg, RA, Tilanus-Linthorst, M, Liu, J, Cox, A, Brock, IW, Reed, MWR, Cross, SS, Blot, W, Signorello, LB, Pharoah, PDP, Dunning, AM, Shah, M, Kang, D, Noh, D-Y, Park, SK, Choi, J-Y, Hartman, M, Miao, H, Lim, WY, Tang, A, Hamann, U, Foersti, A, Ruediger, T, Ulmer, HU, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Slager, S, Toland, AE, Vachon, C, Yannoukakos, D, Shen, C-Y, Yu, J-C, Huang, C-S, Hou, M-F, Gonzalez-Neira, A, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Dennis, J, Michailidou, K, Bolla, MK, Wang, J, Easton, DF, Garcia-Closas, M, Dowsett, M, Ashworth, A, Swerdlow, AJ, Peto, J, Silva, IDS, Fletcher, O, Johnson, N, Dudbridge, F, Orr, N, Gibson, L, Jones, ME, Schoemaker, MJ, Folkerd, EJ, Haynes, BP, Hopper, JL, Southey, MC, Dite, GS, Apicella, C, Schmidt, MK, Broeks, A, Van't Veer, LJ, Atsma, F, Muir, K, Lophatananon, A, Fasching, PA, Beckmann, MW, Ekici, AB, Renner, SP, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Guenel, P, Truong, T, Cordina, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, R, Zamora, MP, Arias Perez, JI, Benitez, J, Bernstein, L, Anton-Culver, H, Ziogas, A, Dur, CC, Brenner, H, Mueller, H, Arndt, V, Dieffenbach, AK, Meindl, A, Heil, J, Bartram, CR, Schmutzler, RK, Brauch, H, Justenhoven, C, Ko, Y-D, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Matsuo, K, Doerk, T, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Chenevix-Trench, G, Beesley, J, Wu, AH, Van den Berg, D, Tseng, C-C, Lambrechts, D, Smeets, D, Neven, P, Wildiers, H, Chang-Claude, J, Rudolph, A, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Bonanni, B, Pensotti, V, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Pankratz, VS, Giles, GG, Severi, G, Baglietto, L, Haiman, C, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Soucy, P, Teo, S, Yip, CH, Phuah, SY, Cornes, BK, Kristensen, VN, Alnaes, GG, Borresen-Dale, A-L, Zheng, W, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Devillee, P, Figueroa, J, Chanock, SJ, Lissowska, J, Sherman, ME, Hall, P, Schoof, N, Hooning, M, Hollestelle, A, Oldenburg, RA, Tilanus-Linthorst, M, Liu, J, Cox, A, Brock, IW, Reed, MWR, Cross, SS, Blot, W, Signorello, LB, Pharoah, PDP, Dunning, AM, Shah, M, Kang, D, Noh, D-Y, Park, SK, Choi, J-Y, Hartman, M, Miao, H, Lim, WY, Tang, A, Hamann, U, Foersti, A, Ruediger, T, Ulmer, HU, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Slager, S, Toland, AE, Vachon, C, Yannoukakos, D, Shen, C-Y, Yu, J-C, Huang, C-S, Hou, M-F, Gonzalez-Neira, A, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Dennis, J, Michailidou, K, Bolla, MK, Wang, J, Easton, DF, Garcia-Closas, M, Dowsett, M, Ashworth, A, Swerdlow, AJ, Peto, J, Silva, IDS, and Fletcher, O

Abstract

INTRODUCTION: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. METHODS: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. RESULTS: We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P(trend) = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P(trend) = 0.005) but not cases (P(trend) = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P(het) = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (OR(het) = 0.84, 95% CI 0.75, 0.94; OR(hom) = 0.81, 95% CI 0.51, 1.30; P(trend) = 0.002) but not for those who had their menarche age ≤11 years (OR(het) = 1.06, 95% CI 0.95, 1.19, OR(hom) = 1.07, 95% CI 0.67, 1.72; P(trend) = 0.29). CONCLUSIONS: To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between la

Published
2014

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