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1. Rare variants in the ATM gene and risk of breast cancer

Author

Goldgar, DE, Healey, S, Dowty, JG, Da Silva, L, Chen, X, Spurdle, AB, Terry, MB, Daly, MJ, Buys, SM, Southey, MC, Andrulis, I, John, EM, Khanna, KK, Hopper, JL, Oefner, PJ, Lakhani, S, Chenevix-Trench, G, Goldgar, DE, Healey, S, Dowty, JG, Da Silva, L, Chen, X, Spurdle, AB, Terry, MB, Daly, MJ, Buys, SM, Southey, MC, Andrulis, I, John, EM, Khanna, KK, Hopper, JL, Oefner, PJ, Lakhani, S, and Chenevix-Trench, G

Abstract

INTRODUCTION: The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation of central players in the DNA damage-response pathway. Recent studies have confirmed that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude of risk and the subset of variants that are pathogenic for breast cancer remain unresolved. METHODS: To investigate the role of ATM in BC susceptibility, we studied 76 rare sequence variants in the ATM gene in a case-control family study of 2,570 cases of breast cancer and 1,448 controls. The variants were grouped into three categories based on their likely pathogenicity, as determined by in silico analysis and analyzed by conditional logistic regression. Likely pathogenic sequence variants were genotyped in 129 family members of 27 carrier probands (15 of which carried c.7271T > G), and modified segregation analysis was used to estimate the BC penetrance associated with these rare ATM variants. RESULTS: In the case-control analysis, we observed an odds ratio of 2.55 and 95% confidence interval (CI, 0.54 to 12.0) for the most likely deleterious variants. In the family-based analyses, the maximum-likelihood estimate of the increased risk associated with these variants was hazard ratio (HR) = 6.88 (95% CI, 2.33 to 20.3; P = 0.00008), corresponding to a 60% cumulative risk of BC by age 80 years. Analysis of loss of heterozygosity (LOH) in 18 breast tumors from women carrying likely pathogenic rare sequence variants revealed no consistent pattern of loss of the ATM variant. CONCLUSIONS: The risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline

Published
2011

2. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Mulligan, AM, Couch, FJ, Barrowdale, D, Domchek, SM, Eccles, D, Nevanlinna, H, Ramus, SJ, Robson, M, Sherman, M, Spurdle, AB, Wappenschmidt, B, Lee, A, McGuffog, L, Healey, S, Sinilnikova, OM, Janavicius, R, Hansen, TVO, Nielsen, FC, Ejlertsen, B, Osorio, A, Munoz-Repeto, I, Duran, M, Godino, J, Pertesi, M, Benitez, J, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Cattaneo, E, Bonanni, B, Viel, A, Pasini, B, Papi, L, Ottini, L, Savarese, A, Bernard, L, Radice, P, Hamann, U, Verheus, M, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Nelen, MR, Kets, CM, Seynaeve, C, Tilanus-Linthorst, MMA, van der Luijt, RB, van Os, T, Rookus, M, Frost, D, Jones, JL, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Adlard, J, Davidson, R, Cook, J, Donaldson, A, Dorkins, H, Gregory, H, Eason, J, Houghton, C, Barwell, J, Side, LE, McCann, E, Murray, A, Peock, S, Godwin, AK, Schmutzler, RK, Rhiem, K, Engel, C, Meindl, A, Ruehl, I, Arnold, N, Niederacher, D, Sutter, C, Deissler, H, Gadzicki, D, Kast, K, Preisler-Adams, S, Varon-Mateeva, R, Schoenbuchner, I, Fiebig, B, Heinritz, W, Schaefer, D, Gevensleben, H, Caux-Moncoutier, V, Fassy-Colcombet, M, Cornelis, F, Mazoyer, S, Leone, M, Boutry-Kryza, N, Hardouin, A, Berthet, P, Muller, D, Fricker, J-P, Mortemousque, I, Pujol, P, Coupier, I, Lebrun, M, Kientz, C, Longy, M, Sevenet, N, Stoppa-Lyonnet, D, Isaacs, C, Caldes, T, de la Hoya, M, Heikkinen, T, Aittomaki, K, Blanco, I, Lazaro, C, Barkardottir, RB, Soucy, P, Dumont, M, Simard, J, Montagna, M, Tognazzo, S, D'Andrea, E, Fox, S, Yan, M, Rebbeck, T, Olopade, OI, Weitzel, JN, Lynch, HT, Ganz, PA, Tomlinson, GE, Wang, X, Fredericksen, Z, Pankratz, VS, Lindor, NM, Szabo, C, Offit, K, Sakr, R, Gaudet, M, Bhatia, J, Kauff, N, Singer, CF, Tea, M-K, Gschwantler-Kaulich, D, Fink-Retter, A, Mai, PL, Greene, MH, Imyanitov, E, O'Malley, FP, Ozcelik, H, Glendon, G, Toland, AE, Gerdes, A-M, Thomassen, M, Kruse, TA, Jensen, UB, Skytte, A-B, Caligo, MA, Soller, M, Henriksson, K, Wachenfeldt, VA, Arver, B, Stenmark-Askmalm, M, Karlsson, P, Ding, YC, Neuhausen, SL, Beattie, M, Pharoah, PDP, Moysich, KB, Nathanson, KL, Karlan, BY, Gross, J, John, EM, Daly, MB, Buys, SM, Southey, MC, Hopper, JL, Terry, MB, Chung, W, Miron, AF, Goldgar, D, Chenevix-Trench, G, Easton, DF, Andrulis, IL, Antoniou, AC, Mulligan, AM, Couch, FJ, Barrowdale, D, Domchek, SM, Eccles, D, Nevanlinna, H, Ramus, SJ, Robson, M, Sherman, M, Spurdle, AB, Wappenschmidt, B, Lee, A, McGuffog, L, Healey, S, Sinilnikova, OM, Janavicius, R, Hansen, TVO, Nielsen, FC, Ejlertsen, B, Osorio, A, Munoz-Repeto, I, Duran, M, Godino, J, Pertesi, M, Benitez, J, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Cattaneo, E, Bonanni, B, Viel, A, Pasini, B, Papi, L, Ottini, L, Savarese, A, Bernard, L, Radice, P, Hamann, U, Verheus, M, Meijers-Heijboer, HEJ, Wijnen, J, Garcia, EBG, Nelen, MR, Kets, CM, Seynaeve, C, Tilanus-Linthorst, MMA, van der Luijt, RB, van Os, T, Rookus, M, Frost, D, Jones, JL, Evans, DG, Lalloo, F, Eeles, R, Izatt, L, Adlard, J, Davidson, R, Cook, J, Donaldson, A, Dorkins, H, Gregory, H, Eason, J, Houghton, C, Barwell, J, Side, LE, McCann, E, Murray, A, Peock, S, Godwin, AK, Schmutzler, RK, Rhiem, K, Engel, C, Meindl, A, Ruehl, I, Arnold, N, Niederacher, D, Sutter, C, Deissler, H, Gadzicki, D, Kast, K, Preisler-Adams, S, Varon-Mateeva, R, Schoenbuchner, I, Fiebig, B, Heinritz, W, Schaefer, D, Gevensleben, H, Caux-Moncoutier, V, Fassy-Colcombet, M, Cornelis, F, Mazoyer, S, Leone, M, Boutry-Kryza, N, Hardouin, A, Berthet, P, Muller, D, Fricker, J-P, Mortemousque, I, Pujol, P, Coupier, I, Lebrun, M, Kientz, C, Longy, M, Sevenet, N, Stoppa-Lyonnet, D, Isaacs, C, Caldes, T, de la Hoya, M, Heikkinen, T, Aittomaki, K, Blanco, I, Lazaro, C, Barkardottir, RB, Soucy, P, Dumont, M, Simard, J, Montagna, M, Tognazzo, S, D'Andrea, E, Fox, S, Yan, M, Rebbeck, T, Olopade, OI, Weitzel, JN, Lynch, HT, Ganz, PA, Tomlinson, GE, Wang, X, Fredericksen, Z, Pankratz, VS, Lindor, NM, Szabo, C, Offit, K, Sakr, R, Gaudet, M, Bhatia, J, Kauff, N, Singer, CF, Tea, M-K, Gschwantler-Kaulich, D, Fink-Retter, A, Mai, PL, Greene, MH, Imyanitov, E, O'Malley, FP, Ozcelik, H, Glendon, G, Toland, AE, Gerdes, A-M, Thomassen, M, Kruse, TA, Jensen, UB, Skytte, A-B, Caligo, MA, Soller, M, Henriksson, K, Wachenfeldt, VA, Arver, B, Stenmark-Askmalm, M, Karlsson, P, Ding, YC, Neuhausen, SL, Beattie, M, Pharoah, PDP, Moysich, KB, Nathanson, KL, Karlan, BY, Gross, J, John, EM, Daly, MB, Buys, SM, Southey, MC, Hopper, JL, Terry, MB, Chung, W, Miron, AF, Goldgar, D, Chenevix-Trench, G, Easton, DF, Andrulis, IL, and Antoniou, AC

Abstract

INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk mode

Published
2011

3. Rare variants in the ATM gene and risk of breast cancer.

Author

Goldgar DE, Healey S, Dowty JG, Da Silva L, Chen X, Spurdle AB, Terry MB, Daly MJ, Buys SM, Southey MC, Andrulis I, John EM, Khanna KK, Hopper JL, Oefner PJ, Lakhani S, and Chenevix-Trench G

Subjects
Ataxia Telangiectasia Mutated Proteins, Case-Control Studies, Female, Genetic Variation, Humans, Logistic Models, Loss of Heterozygosity, Middle Aged, Mutation, Missense, White People genetics, Breast Neoplasms genetics, Cell Cycle Proteins genetics, DNA-Binding Proteins genetics, Genetic Predisposition to Disease, Protein Serine-Threonine Kinases genetics, Tumor Suppressor Proteins genetics
Abstract

Introduction: The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation of central players in the DNA damage-response pathway. Recent studies have confirmed that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude of risk and the subset of variants that are pathogenic for breast cancer remain unresolved., Methods: To investigate the role of ATM in BC susceptibility, we studied 76 rare sequence variants in the ATM gene in a case-control family study of 2,570 cases of breast cancer and 1,448 controls. The variants were grouped into three categories based on their likely pathogenicity, as determined by in silico analysis and analyzed by conditional logistic regression. Likely pathogenic sequence variants were genotyped in 129 family members of 27 carrier probands (15 of which carried c.7271T > G), and modified segregation analysis was used to estimate the BC penetrance associated with these rare ATM variants., Results: In the case-control analysis, we observed an odds ratio of 2.55 and 95% confidence interval (CI, 0.54 to 12.0) for the most likely deleterious variants. In the family-based analyses, the maximum-likelihood estimate of the increased risk associated with these variants was hazard ratio (HR) = 6.88 (95% CI, 2.33 to 20.3; P = 0.00008), corresponding to a 60% cumulative risk of BC by age 80 years. Analysis of loss of heterozygosity (LOH) in 18 breast tumors from women carrying likely pathogenic rare sequence variants revealed no consistent pattern of loss of the ATM variant., Conclusions: The risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2.

Published
2011
Full Text
View/download PDF

4. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

Author

Mulligan AM, Couch FJ, Barrowdale D, Domchek SM, Eccles D, Nevanlinna H, Ramus SJ, Robson M, Sherman M, Spurdle AB, Wappenschmidt B, Lee A, McGuffog L, Healey S, Sinilnikova OM, Janavicius R, Hansen Tv, Nielsen FC, Ejlertsen B, Osorio A, Muñoz-Repeto I, Durán M, Godino J, Pertesi M, Benítez J, Peterlongo P, Manoukian S, Peissel B, Zaffaroni D, Cattaneo E, Bonanni B, Viel A, Pasini B, Papi L, Ottini L, Savarese A, Bernard L, Radice P, Hamann U, Verheus M, Meijers-Heijboer HE, Wijnen J, Gómez García EB, Nelen MR, Kets CM, Seynaeve C, Tilanus-Linthorst MM, van der Luijt RB, van Os T, Rookus M, Frost D, Jones JL, Evans DG, Lalloo F, Eeles R, Izatt L, Adlard J, Davidson R, Cook J, Donaldson A, Dorkins H, Gregory H, Eason J, Houghton C, Barwell J, Side LE, McCann E, Murray A, Peock S, Godwin AK, Schmutzler RK, Rhiem K, Engel C, Meindl A, Ruehl I, Arnold N, Niederacher D, Sutter C, Deissler H, Gadzicki D, Kast K, Preisler-Adams S, Varon-Mateeva R, Schoenbuchner I, Fiebig B, Heinritz W, Schäfer D, Gevensleben H, Caux-Moncoutier V, Fassy-Colcombet M, Cornelis F, Mazoyer S, Léoné M, Boutry-Kryza N, Hardouin A, Berthet P, Muller D, Fricker JP, Mortemousque I, Pujol P, Coupier I, Lebrun M, Kientz C, Longy M, Sevenet N, Stoppa-Lyonnet D, Isaacs C, Caldes T, de la Hoya M, Heikkinen T, Aittomäki K, Blanco I, Lazaro C, Barkardottir RB, Soucy P, Dumont M, Simard J, Montagna M, Tognazzo S, D'Andrea E, Fox S, Yan M, Rebbeck T, Olopade O, Weitzel JN, Lynch HT, Ganz PA, Tomlinson GE, Wang X, Fredericksen Z, Pankratz VS, Lindor NM, Szabo C, Offit K, Sakr R, Gaudet M, Bhatia J, Kauff N, Singer CF, Tea MK, Gschwantler-Kaulich D, Fink-Retter A, Mai PL, Greene MH, Imyanitov E, O'Malley FP, Ozcelik H, Glendon G, Toland AE, Gerdes AM, Thomassen M, Kruse TA, Jensen UB, Skytte AB, Caligo MA, Soller M, Henriksson K, Wachenfeldt vA, Arver B, Stenmark-Askmalm M, Karlsson P, Ding YC, Neuhausen SL, Beattie M, Pharoah PD, Moysich KB, Nathanson KL, Karlan BY, Gross J, John EM, Daly MB, Buys SM, Southey MC, Hopper JL, Terry MB, Chung W, Miron AF, Goldgar D, Chenevix-Trench G, Easton DF, Andrulis IL, and Antoniou AC

Subjects
Breast Neoplasms classification, Breast Neoplasms metabolism, Female, Humans, Polymorphism, Single Nucleotide, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Risk, Alleles, Breast Neoplasms genetics, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Heterozygote, Mutation
Abstract

Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour., Methods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach., Results: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status., Conclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

Published
2011
Full Text
View/download PDF

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