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9 results on '"Marchand, L. Le"'

1. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

Author

Purrington, K.S., Slettedahl, S., Bolla, M.K., Michailidou, K., Czene, K., Nevanlinna, H., Bojesen, S.E., Andrulis, I.L., Cox, A., Hall, P., Carpenter, J., Yannoukakos, D., Haiman, C.A., Fasching, P.A., Mannermaa, A., Winqvist, R., Brenner, H., Lindblom, A., Chenevix-Trench, G., Benitez, J., Swerdlow, A., Kristensen, V., Guenel, P., Meindl, A., Darabi, H., Eriksson, M., Fagerholm, R., Aittomaki, K., Blomqvist, C., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Wang, X.S., Olswold, C., Olson, J.E., Mulligan, A.M., Knight, J.A., Tchatchou, S., Reed, M.W.R., Cross, S.S., Liu, J.J., Li, J.M., Humphreys, K., Clarke, C., Scott, R., Fostira, F., Fountzilas, G., Konstantopoulou, I., Henderson, B.E., Schumacher, F., Marchand, L. le, Ekici, A.B., Hartmann, A., Beckmann, M.W., Hartikainen, J.M., Kosma, V.M., Kataja, V., Jukkola-Vuorinen, A., Pylkas, K., Kauppila, S., Dieffenbach, A.K., Stegmaier, C., Arndt, V., Margolin, S., Balleine, R., Perez, J.I.A., Zamora, M.P., Menendez, P., Ashworth, A., Jones, M., Orr, N., Arveux, P., Kerbrat, P., Truong, T., Bugert, P., Toland, A.E., Ambrosone, C.B., Labreche, F., Goldberg, M.S., Dumont, M., Ziogas, A., Lee, E., Dite, G.S., Apicella, C., Southey, M.C., Long, J.R., Shrubsole, M., Deming-Halverson, S., Ficarazzi, F., Barile, M., Peterlongo, P., Durda, K., Jaworska-Bieniek, K., Tollenaar, R.A.E.M., Seynaeve, C., Bruning, T., Ko, Y.D., Deurzen, C.H.M. van, Martens, J.W.M., Kriege, M., Figueroa, J.D., Chanock, S.J., Lissowska, J., Tomlinson, I., Kerin, M.J., Miller, N., Schneeweiss, A., Tapper, W.J., Gerty, S.M., Durcan, L., Mclean, C., Milne, R.L., Baglietto, L., Silva, I.D., Fletcher, O., Johnson, N., Van'T Veer, L.J., Cornelissen, S., Forsti, A., Torres, D., Rudiger, T., Rudolph, A., Flesch-Janys, D., Nickels, S., Weltens, C., Floris, G., Moisse, M., Dennis, J., Wang, Q., Dunning, A.M., Shah, M., Brown, J., Simard, J., Anton-Culver, H., Neuhausen, S.L., Hopper, J.L., Bogdanova, N., Dork, T., Zheng, W., Radice, P., Jakubowska, A., Lubinski, J., Devillee, P., Brauch, H., Hooning, M., Garcia-Closas, M., Sawyer, E., Burwinkel, B., Marmee, F., Eccles, D.M., Giles, G.G., Peto, J., Schmidt, M., Broeks, A., Hamann, U., Chang-Claude, J., Lambrechts, D., Pharoah, P.D.P., Easton, D., Pankratz, V.S., Slager, S., Vachon, C.M., Couch, F.J., ABCTB Investigators, Australian Ovarian Canc Study Grp, kConFab Investigators, GENICA Network, Medical Oncology, Pathology, and Clinical Genetics

Subjects
Oncology, Candidate gene, Fibroblast Growth Factor, amplification, cancer susceptibility loci, Bioinformatics, medicine.disease_cause, Medical and Health Sciences, prostate-cancer, Prostate cancer, Risk Factors, Medizinische Fakultät, Genetics (clinical), Genetics & Heredity, tacc2, Association Studies Articles, Single Nucleotide, General Medicine, Biological Sciences, ddc, risk loci, cell-division, kConFab Investigators, Female, GENICA Network, Type 2, Receptor, Australian Ovarian Cancer Study Group, Breast Neoplasms, Carrier Proteins, Case-Control Studies, Haplotypes, Humans, Neoplasm Staging, Polymorphism, Single Nucleotide, Receptor, Fibroblast Growth Factor, Type 2, Tumor Suppressor Proteins, Genetic Variation, Molecular Biology, Genetics, medicine.medical_specialty, Mitotic index, ABCTB Investigators, Single-nucleotide polymorphism, Biology, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, ddc:610, Polymorphism, Lung cancer, Odds ratio, medicine.disease, genome-wide association, lung-cancer, progression, Carcinogenesis
Abstract

Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.

Published
2014
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2. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Author

Ghoussaini, M., French, J.D., Michailidou, K., Nord, S., Beesley, J., Canisus, S., Hillman, K.M., Kaufmann, S., Sivakumaran, H., Marjaneh, M.M., Lee, J.S., Dennis, J., Bolla, M.K., Wang, Q., Dicks, E., Milne, R.L., Hopper, J.L., Southey, M.C., Schmidt, M.K., Broeks, A., Muir, K., Lophatananon, A., Fasching, P.A., Beckmann, M.W., Fletcher, O., Johnson, N., Sawyer, E.J., Tomlinson, I., Burwinkel, B., Marme, F., Guenel, P., Truong, T., Bojesen, S.E., Flyger, H., Benitez, J., Gonzalez-Neira, A., Alonso, R., Pita, G., Neuhausen, S.L., Anton-Culver, H., Brenner, H., Arndt, V., Meindl, A., Schmutzler, R.K., Brauch, H., Hamann, U., Tessier, D.C., Vincent, D., Nevanlinna, H., Khan, S., Matsuo, K., Ito, H., Dork, T., Bogdanova, N.V., Lindblom, A., Margolin, S., Mannermaa, A., Kosma, V.M., Wu, A.H., Berg, D. van den, Lambrechts, D., Floris, G., Chang-Claude, J., Rudolph, A., Radice, P., Barile, M., Couch, F.J., Hallberg, E., Giles, G.G., Haiman, C.A., Marchand, L. le, Goldberg, M.S., Teo, S.H., Yip, C.H., Borresen-Dale, A.L., Zheng, W., Cai, Q.Y., Winqvist, R., Pylkas, K., Andrulis, I.L., Devilee, P., Tollenaar, R.A.E.M., Garcia-Closas, M., Figueroa, J., Hall, P., Czene, K., Brand, J.S., Darabi, H., Eriksson, M., Hooning, M.J., Koppert, L.B., Li, J.M., Shu, X.O., Zheng, Y., Cox, A., Cross, S.S., Shah, M., Rhenius, V., Choi, J.Y., Kang, D., Hartman, M., Chia, K.S., Kabisch, M., Torres, D., Luccarini, C., Conroy, D.M., Jakubowska, A., Lubinski, J., Sangrajrang, S., Brennan, P., Olswold, C., Slager, S., Shen, C.Y., Hou, M.F., Swerdlow, A., Schoemaker, M.J., Simard, J., Pharoah, P.D.P., Kristensen, V., Chenevix-Trench, G., Easton, D.F., Dunning, A.M., Edwards, S.L., kConFab AOCS, NBCS Collaborators, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Dicks, Ed [0000-0002-0617-0401], Rhenius, Valerie [0000-0003-4215-3235], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository

Subjects
Quantitative Trait Loci, Breast Neoplasms, Polymorphism, Single Nucleotide, Enhancer Elements, Genetic, Haplotypes, Receptors, Estrogen, Case-Control Studies, Cell Line, Tumor, Chromosomes, Human, Pair 5, Humans, Genetic Predisposition to Disease, Receptor, Fibroblast Growth Factor, Type 2, Promoter Regions, Genetic, Fibroblast Growth Factor 10, Alleles
Abstract

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

Published
2016

3. Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk

Author

Lin, W.Y., Camp, N.J., Ghoussaini, M., Beesley, J., Michailidou, K., Hopper, J.L., Apicella, C., Southey, M.C., Stone, J., Schmidt, M.K., Broeks, A., Van't Veer, L.J., Rutgers, E.J.T., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Peto, J., Dos-Santos-Silva, I., Fletcher, O., Johnson, N., Bolla, M.K., Wang, Q., Dennis, J., Sawyer, E.J., Cheng, T., Tomlinson, I., Kerin, M.J., Miller, N., Marme, F., Surowy, H.M., Burwinkel, B., Guenel, P., Truong, T., Menegaux, F., Mulot, C., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Alvarez, N., Herrera, D., Anton-Culver, H., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Meindl, A., Lichtner, P., Schmutzler, R.K., Muller-Myhsok, B., Brauch, H., Bruning, T., Ko, Y.D., Tessier, D.C., Vincent, D., Bacot, F., Nevanlinna, H., Aittomaki, K., Blomqvist, C., Khan, S., Matsuo, K., Ito, H., Iwata, H., Horio, A., Bogdanova, N.V., Antonenkova, N.N., Dork, T., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Neven, P., Wauters, E., Wildiers, H., Lambrechts, D., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Radice, P., Peterlongo, P., Manoukian, S., Bonanni, B., Couch, F.J., Wang, X.S., Vachon, C., Purrington, K., Giles, G.G., Milne, R.L., Mclean, C., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Simard, J., Goldberg, M.S., Labreche, F., Dumont, M., Teo, S.H., Yip, C.H., Hassan, N., Vithana, E.N., Kristensen, V., Zheng, W., Deming-Halverson, S., Shrubsole, M.J., Long, J.R., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Kauppila, S., Andrulis, I.L., Knight, J.A., Glendon, G., Tchatchou, S., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Asperen, C.J. van, Garcia-Closas, M., Figueroa, J., Lissowska, J., Brinton, L., Czene, K., Darabi, H., Eriksson, M., Brand, J.S., Hooning, M.J., Hollestelle, A., Ouweland, A.M.W. van den, Jager, A., Li, J.M., Liu, J.J., Humphreys, K., Shu, X.O., Lu, W., Gao, Y.T., Cai, H., Cross, S.S., Reed, M.W.R., Blot, W., Signorello, L.B., Cai, Q.Y., Pharoah, P.D.P., Perkins, B., Shah, M., Blows, F.M., Kang, D., Yoo, K.Y., Noh, D.Y., Hartman, M., Miao, H., Chia, K.S., Putti, T.C., Hamann, U., Luccarini, C., Baynes, C., Ahmed, S., Maranian, M., Healey, C.S., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Sangrajrang, S., Gaborieau, V., Brennan, P., Mckay, J., Slager, S., Toland, A.E., Yannoukakos, D., Shen, C.Y., Hsiung, C.N., Wu, P.E., Ding, S.L., Ashworth, A., Jones, M., Orr, N., Swerdlow, A.J., Tsimiklis, H., Makalic, E., Schmidt, D.F., Bui, Q.M., Chanock, S.J., Hunter, D.J., Hein, R., Dahmen, N., Beckmann, L., Aaltonen, K., Muranen, T.A., Heikkinen, T., Irwanto, A., Rahman, N., Turnbull, C.A., Waisfisz, Q., Meijers-Heijboer, H.E.J., Adank, M.A., Luijt, R.B. van der, Hall, P., Chenevix-Trench, G., Dunning, A., Easton, D.F., Cox, A., GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, Breast Ovarian Canc Susceptibility, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Cardiothoracic Surgery, Cancer Center Amsterdam, Amsterdam Reproduction & Development (AR&D), Human Genetics, Human genetics, CCA - Oncogenesis, Ghoussaini, Maya [0000-0002-2415-2143], Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Genotyping Techniques, Research Support, U.S. Gov't, P.H.S, CASP8 and FADD-Like Apoptosis Regulating Protein, Genome-wide association study, P.H.S, Medical and Health Sciences, Breast and Ovarian Cancer Susceptibility (BOCS) Study, Medizinische Fakultät, Genetics(clinical), Non-U.S. Gov't, Genetics (clinical), Genetics, Genetics & Heredity, variants, Caspase 8, Research Support, Non-U.S. Gov't, Association Studies Articles, General Medicine, Biological Sciences, ddc, Chromosomes, Human, Pair 2, kConFab Investigators, Female, GENICA Network, Australian Ovarian Cancer Study Group, European Continental Ancestry Group, Non-P.H.S, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Research Support, Polymorphism, Single Nucleotide, White People, N.I.H, Breast cancer, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, medicine, Journal Article, Humans, Genetic Predisposition to Disease, ddc:610, gene, Genotyping, Molecular Biology, Genetic association, disease, Extramural, Proteins, Odds ratio, medicine.disease, susceptibility loci, Minor allele frequency, Case-Control Studies, genome-wide association, enhancers, U.S. Gov't, casp8, Research Support, U.S. Gov't, Non-P.H.S, Genome-Wide Association Study
Abstract

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regressionmodels adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10-5. Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P=3 × 10-6), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10-9. Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8might be the target gene, suggesting amechanism involving apoptosis.

Published
2016
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4. Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants

Author

Mavaddat, N., Pharoah, P.D.P., Michailidou, K., Tyrer, J., Brook, M.N., Bolla, M.K., Wang, Q., Dennis, J., Dunning, A.M., Shah, M., Luben, R., Brown, J., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Czene, K., Darabi, H., Eriksson, M., Peto, J., dos-Santos-Silva, I., Dudbridge, F., Johnson, N., Schmidt, M.K., Broeks, A., Verhoef, S., Rutgers, E.J., Swerdlow, A., Ashworth, A., Orr, N., Schoemaker, M.J., Figueroa, J., Chanock, S.J., Brinton, L., Lissowska, J., Couch, F.J., Olson, J.E., Vachon, C., Pankratz, V.S., Lambrechts, D., Wildiers, H., Ongeval, C. van, Limbergen, E. van, Kristensen, V., Alnaes, G.G., Nord, S., Borresen-Dale, A.L., Nevanlinna, H., Muranen, T.A., Aittomaki, K., Blomqvist, C., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Trentham-Dietz, A., Newcomb, P., Titus, L., Egan, K.M., Hunter, D.J., Lindstrom, S., Tamimi, R.M., Kraft, P., Rahman, N., Turnbull, C., Renwick, A., Seal, S., Li, J.M., Liu, J.J., Humphreys, K., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Bogdanova, N.V., Antonenkova, N.N., Dork, T., Anton-Culver, H., Neuhausen, S.L., Ziogas, A., Bernstein, L., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Asperen, C.J. van, Cox, A., Cross, S.S., Reed, M.W.R., Khusnutdinova, E., Bermisheva, M., Prokofyeva, D., Takhirova, Z., Meindl, A., Schmutzler, R.K., Sutter, C., Yang, R.X., Schurmann, P., Bremer, M., Christiansen, H., Park-Simon, T.W., Hillemanns, P., Guenel, P., Truong, T., Menegaux, F., Sanchez, M., Radice, P., Peterlongo, P., Manoukian, S., Pensotti, V., Hopper, J.L., Tsimiklis, H., Apicella, C., Southey, M.C., Brauch, H., Bruning, T., Ko, Y.D., Sigurdson, A.J., Doody, M.M., Hamann, U., Torres, D., Ulmer, H.U., Forsti, A., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Andrulis, I.L., Knight, J.A., Glendon, G., Mulligan, A.M., Chenevix-Trench, G., Balleine, R., Giles, G.G., Milne, R.L., McLean, C., Lindblom, A., Margolin, S., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Eilber, U., Wang-Gohrke, S., Hooning, M.J., Hollestelle, A., Ouweland, A.M.W. van den, Koppert, L.B., Carpenter, J., Clarke, C., Scott, R., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Brenner, H., Arndt, V., Stegmaier, C., Dieffenbach, A.K., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Offit, K., Vijai, J., Robson, M., Rau-Murthy, R., Dwek, M., Swann, R., Perkins, K.A., Goldberg, M.S., Labreche, F., Dumont, M., Eccles, D.M., Tapper, W.J., Rafiq, S., John, E.M., Whittemore, A.S., Slager, S., Yannoukakos, D., Toland, A.E., Yao, S., Zheng, W., Halverson, S.L., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Alvarez, N., Herrero, D., Tessier, D.C., Vincent, D., Bacot, F., Luccarini, C., Baynes, C., Ahmed, S., Maranian, M., Healey, C.S., Simard, J., Hall, P., Easton, D.F., Garcia-Closas, M., Clinical Genetics, Medical Oncology, Surgery, Department of Obstetrics and Gynecology, Clinicum, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Department of Oncology, HUS Gynecology and Obstetrics, Mavaddat, Nasim [0000-0003-0307-055X], Pharoah, Paul [0000-0001-8494-732X], Tyrer, Jonathan [0000-0003-3724-4757], Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Luben, Robert [0000-0002-5088-6343], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Adult, Genotype, 3122 Cancers, Breast Neoplasms, consortium, Polymorphism, Single Nucleotide, Risk Assessment, Article, prevention, SDG 3 - Good Health and Well-being, Predictive Value of Tests, Risk Factors, 3123 Gynaecology and paediatrics, Biomarkers, Tumor, Odds Ratio, Humans, Genetic Predisposition to Disease, family-history, Aged, prostate, Gene Expression Profiling, subtypes, Middle Aged, susceptibility loci, Europe, Gene Expression Regulation, Neoplastic, Receptors, Estrogen, Tumor Markers, Biological, Cancer and Oncology, genome-wide association, Female, women
Abstract

Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1 of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report. © 2015 © The Author 2015. Published by Oxford University Press.

Published
2015

5. Identification of novel genetic markers of breast cancer survival

Author

Guo, Q., Schmidt, M.K., Kraft, P., Canisius, S., Chen, C., Khan, S., Tyrer, J., Bolla, M.K., Wang, Q., Dennis, J., Michailidou, K., Lush, M., Kar, S., Beesley, J., Dunning, A.M., Shah, M., Czene, K., Darabi, H., Eriksson, M., Lambrechts, D., Weltens, C., Leunen, K., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Blomqvist, C., Aittomaki, K., Fagerholm, R., Muranen, T.A., Couch, F.J., Olson, J.E., Vachon, C., Andrulis, I.L., Knight, J.A., Glendon, G., Mulligan, A.M., Broeks, A., Hogervorst, F.B., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Hopper, J.L., Tsimiklis, H., Apicella, C., Southey, M.C., Cox, A., Cross, S.S., Reed, M.W.R., Giles, G.G., Milne, R.L., McLean, C., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Hooning, M.J., Hollestelle, A., Martens, J.W.M., Ouweland, A.M.W. van den, Marme, F., Schneeweiss, A., Yang, R.X., Burwinkel, B., Figueroa, J., Chanock, S.J., Lissowska, J., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Brenner, H., Dieffenbach, A.K., Arndt, V., Holleczek, B., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Li, J.M., Brand, J.S., Humphreys, K., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Radice, P., Peterlongo, P., Bonanni, B., Mariani, P., Fasching, P.A., Beckmann, M.W., Hein, A., Ekici, A.B., Chenevix-Trench, G., Balleine, R., Phillips, K.A., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Hamann, U., Kabisch, M., Ulmer, H.U., Rudiger, T., Margolin, S., Kristensen, V., Nord, S., Evans, D.G., Abraham, J.E., Earl, H.M., Hiller, L., Dunn, J.A., Bowden, S., Berg, C., Campa, D., Diver, W.R., Gapstur, S.M., Gaudet, M.M., Hankinson, S.E., Hoover, R.N., Husing, A., Kaaks, R., Machiela, M.J., Willett, W., Barrdahl, M., Canzian, F., Chin, S.F., Caldas, C., Hunter, D.J., Lindstrom, S., Garcia-Closas, M., Hall, P., Easton, D.F., Eccles, D.M., Rahman, N., Nevanlinna, H., Pharoah, P.D.P., kConFab Investigators, Tyrer, Jonathan [0000-0003-3724-4757], Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Abraham, Jean [0000-0003-0688-4807], Earl, Helena [0000-0003-1549-8094], Chin, Suet-Feung [0000-0001-5697-1082], Caldas, Carlos [0000-0003-3547-1489], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
Genetic Markers, Genotype, Receptors, Estrogen, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Prognosis, Polymorphism, Single Nucleotide, Survival Analysis, White People
Abstract

BACKGROUND: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. METHODS: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. RESULTS: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. CONCLUSIONS: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.

Published
2015

6. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

Author

Orr, N., Dudbridge, F., Dryden, N., Maguire, S., Novo, D., Perrakis, E., Johnson, N., Ghoussaini, M., Hopper, J.L., Southey, M.C., Apicella, C., Stone, J., Schmidt, M.K., Broeks, A., Van't Veer, L.J., Hogervorst, F.B., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Gibson, L., Aitken, Z., Warren, H., Sawyer, E., Tomlinson, I., Kerin, M.J., Miller, N., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Guenel, P., Truong, T., Cordina-Duverger, E., Sanchez, M., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Benitez, J., Zamora, M.P., Perez, J.I.A., Menendez, P., Anton-Culver, H., Neuhausen, S.L., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Hamann, U., Brauch, H., Justenhoven, C., Bruning, T., Ko, Y.D., Nevanlinna, H., Aittomaki, K., Blomqvist, C., Khan, S., Bogdanova, N., Dork, T., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Chenevix-Trench, G., Beesley, J., Lambrechts, D., Moisse, M., Floris, G., Beuselinck, B., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Radice, P., Peterlongo, P., Peissel, B., Pensotti, V., Couch, F.J., Olson, J.E., Slettedahl, S., Vachon, C., Giles, G.G., Milne, R.L., McLean, C., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Simard, J., Goldberg, M.S., Labreche, F., Dumont, M., Kristensen, V., Alnaes, G.G., Nord, S., Borresen-Dale, A.L., Zheng, W., Deming-Halverson, S., Shrubsole, M., Long, J.R., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I.L., Knight, J.A., Glendon, G., Tchatchou, S., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C.M., Asperen, C.J. van, Garcia-Closas, M., Figueroa, J., Chanock, S.J., Lissowska, J., Czene, K., Darabi, H., Eriksson, M., Klevebring, D., Hooning, M.J., Hollestelle, A., Deurzen, C.H.M. van, Kriege, M., Hall, P., Li, J.M., Liu, J.J., Humphreys, K., Cox, A., Cross, S.S., Reed, M.W.R., Pharoah, P.D.P., Dunning, A.M., Shah, M., Perkins, B.J., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Ashworth, A., Swerdlow, A., Jones, M., Schoemaker, M.J., Meindl, A., Schmutzler, R.K., Olswold, C., Slager, S., Toland, A.E., Yannoukakos, D., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Matsuo, K., Ito, H., Iwata, H., Ishiguro, J., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Teo, S.H., Yip, C.H., Kang, P., Ikram, M.K., Shu, X.O., Lu, W., Gao, Y.T., Cai, H., Kang, D., Choi, J.Y., Park, S.K., Noh, D.Y., Hartman, M., Miao, H., Lim, W.Y., Lee, S.C., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Wu, P.E., Hou, M.F., Yu, J.C., Shen, C.Y., Blot, W., Cai, Q.Y., Signorello, L.B., Luccarini, C., Bayes, C., Ahmed, S., Maranian, M., Healey, C.S., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Alvarez, N., Herrero, D., Tessier, D.C., Vincent, D., Bacot, F., Hunter, D.J., Lindstrom, S., Dennis, J., Michailidou, K., Bolla, M.K., Easton, D.F., Silva, I.D., Fletcher, O., Peto, J., GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, Obstetrics & Gynecology, Medical Oncology, Pathology, Ophthalmology, Cardiothoracic Surgery, and Clinical Genetics

Subjects
Asian Continental Ancestry Group, Adult, Hepatocyte Nuclear Factor 3-alpha, Risk, binding, European Continental Ancestry Group, Kruppel-Like Transcription Factors, estrogen-receptor-alpha, Breast Neoplasms, GATA3 Transcription Factor, Polymorphism, Single Nucleotide, White People, Kruppel-Like Factor 4, Asian People, SDG 3 - Good Health and Well-being, Medizinische Fakultät, common variants, expression, Humans, Genetic Predisposition to Disease, ddc:610, Genetic Association Studies, Aged, Association Studies Articles, Estrogen Receptor alpha, Chromosome Mapping, foxa1, Middle Aged, confer susceptibility, analyses reveal, Enhancer Elements, Genetic, risk locus, Genetic Loci, functional variants, genome-wide association, Female, Chromosomes, Human, Pair 9
Abstract

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis. ispartof: Human Molecular Genetics vol:24 issue:10 pages:2966-84 ispartof: location:England status: published

Published
2015

7. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

Author

Milne, R.L., Burwinkel, B., Michailidou, K., Arias-Perez, J.I., Zamora, M.P., Menendez-Rodriguez, P., Hardisson, D., Mendiola, M., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Dennis, J., Wang, Q., Bolla, M.K., Swerdlow, A., Ashworth, A., Orr, N., Schoemaker, M., Ko, Y.D., Brauch, H., Hamann, U., Andrulis, I.L., Knight, J.A., Glendon, G., Tchatchou, S., Matsuo, K., Ito, H., Iwata, H., Tajima, K., Li, J.M., Brand, J.S., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Lambrechts, D., Peuteman, G., Christiaens, M.R., Smeets, A., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Hartman, M., Hui, M., Lim, W.Y., Chan, C.W., Marme, F., Yang, R.X., Bugert, P., Lindblom, A., Margolin, S., Garcia-Closas, M., Chanock, S.J., Lissowska, J., Figueroa, J.D., Bojesen, S.E., Nordestgaard, B.G., Flyger, H., Hooning, M.J., Kriege, M., Ouweland, A.M.W. van den, Koppert, L.B., Fletcher, O., Johnson, N., Dos-Santos-Silva, I., Peto, J., Zheng, W., Deming-Halverson, S., Shrubsole, M.J., Long, J.R., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Cox, A., Cross, S.S., Reed, M.W.R., Schmidt, M.K., Broeks, A., Cornelissen, S., Braaf, L., Kang, D., Choi, J.Y., Park, S.K., Noh, D.Y., Simard, J., Dumont, M., Goldberg, M.S., Labreche, F., Fasching, P.A., Hein, A., Ekici, A.B., Beckmann, M.W., Radice, P., Peterlongo, P., Azzollini, J., Barile, M., Sawyer, E., Tomlinson, I., Kerin, M., Miller, N., Hopper, J.L., Schmidt, D.F., Makalic, E., Southey, M.C., Teo, S.H., Yip, C.H., Sivanandan, K., Tay, W.T., Shen, C.Y., Hsiung, C.N., Yu, J.C., Hou, M.F., Guenel, P., Truong, T., Sanchez, M., Mulot, C., Blot, W., Cai, Q.Y., Nevanlinna, H., Muranen, T.A., Aittomaki, K., Blomqvist, C., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Bogdanova, N., Dork, T., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Shu, X.O., Lu, W., Gao, Y.T., Zhang, B., Couch, F.J., Toland, A.E., Yannoukakos, D., Sangrajrang, S., McKay, J., Wang, X.S., Olson, J.E., Vachon, C., Purrington, K., Severi, G., Baglietto, L., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Czene, K., Eriksson, M., Humphreys, K., Darabi, H., Ahmed, S., Shah, M., Pharoah, P.D.P., Hall, P., Giles, G.G., Benitez, J., Dunning, A.M., Chenevix-Trench, G., Easton, D.F., GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, TNBCC, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Adult, Ataxin-7, A Kinase Anchor Proteins, Breast Neoplasms, Nerve Tissue Proteins, Middle Aged, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Cytoskeletal Proteins, Case-Control Studies, Humans, NIMA-Related Kinases, Female, Genetic Predisposition to Disease, health care economics and organizations, Alleles, Genome-Wide Association Study
Abstract

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility\ud variants, although most studies have been underpowered to detect associations of a realistic magnitude.\ud We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which\ud evidence of association with breast cancer risk had been previously reported. Case-control data were combined\ud from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional\ud logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21\ud [rs1053338, per allele OR 5 1.07, 95% confidence interval (CI) 5 1.04–1.10, P 5 2.9 3 1026\ud ], AKAP9-M463I at\ud 7q21 (rs6964587, OR 5 1.05, 95% CI 5 1.03–1.07, P 5 1.7 3 1026\ud ) and NEK10-L513S at 3p24 (rs10510592,\ud OR 5 1.10, 95% CI 5 1.07 –1.12, P 5 5.1 3 10217). The first two associations reached genome-wide statistical\ud significance in a combined analysis of available data, including independent data from nine genome-wide association\ud studies (GWASs): for ATXN7-K264R, OR 5 1.07 (95% CI 5 1.05–1.10, P 5 1.0 3 1028\ud ); for AKAP9-M463I,\ud OR 5 1.05 (95% CI 5 1.04–1.07, P 5 2.0 3 10210). Further analysis of other common variants in these two\ud regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified\ud a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is\ud associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility\ud region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of\ud the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast\ud cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying\ud variants and the genes through which they act.

Published
2014

8. MicroRNA related polymorphisms and breast cancer risk

Author

Khan, S., Greco, D., Michailidou, K., Milne, R.L., Muranen, T.A., Heikkinen, T., Aaltonen, K., Dennis, J., Bolla, M.K., Liu, J., Hall, P., Irwanto, A., Humphreys, K., Li, J., Czene, K., Chang-Claude, J., Hein, R., Rudolph, A., Seibold, P., Flesch-Janys, D., Fletcher, O., Peto, J., Silva, I.D., Johnson, N., Gibson, L., Aitken, Z., Hopper, J.L., Tsimiklis, H., Bui, M., Makalic, E., Schmidt, D.F., Southey, M.C., Apicella, C., Stone, J., Waisfisz, Q., Meijers-Heijboer, H., Adank, M.A., Luijt, R.B. van der, Meindl, A., Schmutzler, R.K., Muller-Myhsok, B., Lichtner, P., Turnbull, C., Rahman, N., Chanock, S.J., Hunter, D.J., Cox, A., Cross, S.S., Reed, M.W.R., Schmidt, M.K., Broeks, A., Van't Veer, L.J., Hogervorst, F.B., Fasching, P.A., Schrauder, M.G., Ekici, A.B., Beckmann, M.W., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Benitez, J., Zamora, P.M., Perez, J.I.A., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Pharoah, P.D.P., Dunning, A.M., Shah, M., Luben, R., Brown, J., Couch, F.J., Wang, X., Vachon, C., Olson, J.E., Lambrechts, D., Moisse, M., Paridaens, R., Christiaens, M.R., Guenel, P., Truong, T., Laurent-Puig, P., Mulot, C., Marme, F., Burwinkel, B., Schneeweiss, A., Sohn, C., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Andrulis, I.L., Knight, J.A., Tchatchou, S., Mulligan, A.M., Dork, T., Bogdanova, N.V., Antonenkova, N.N., Anton-Culver, H., Darabi, H., Eriksson, M., Garcia-Closas, M., Figueroa, J., Lissowska, J., Brinton, L., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Asperen, C.J. van, Kristensen, V.N., Slager, S., Toland, A.E., Ambrosone, C.B., Yannoukakos, D., Lindblom, A., Margolin, S., Radice, P., Peterlongo, P., Barile, M., Mariani, P., Hooning, M.J., Martens, J.W.M., Collee, J.M., Jager, A., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Giles, G.G., McLean, C., Brauch, H., Bruning, T., Ko, Y.D., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Swerdlow, A., Ashworth, A., Orr, N., Jones, M., Simard, J., Goldberg, M.S., Labreche, F., Dumont, M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Kataja, V., Kosma, V.M., Hartikainen, J.M., Mannermaa, A., Hamann, U., Chenevix-Trench, G., Blomqvist, C., Aittomaki, K., Easton, D.F., Nevanlinna, H., KConFab Investigators, Australian Ovarian Canc Study Grp, GENICA Network, Department of Obstetrics and Gynecology, Clinicum, Department of Oncology, Haartman Institute (-2014), Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, Human genetics, CCA - Oncogenesis, Obstetrics & Gynecology, Medical Oncology, Erasmus MC other, and Clinical Genetics

Subjects
Heredity, IDENTIFIES 3, lcsh:Medicine, Estrogen receptor, Genome-wide association study, Bioinformatics, 3123 Gynaecology and paediatrics, HUMAN GENES, lcsh:Science, 3' Untranslated Regions, Multidisciplinary, Research Support, Non-U.S. Gov't, Chromosome Mapping, SINGLE-NUCLEOTIDE POLYMORPHISMS, 3. Good health, Receptors, Estrogen, Female, CASP8 GENE, Research Article, EXPRESSION, Genotype, SUSCEPTIBILITY LOCI, education, 3122 Cancers, MiRNA binding, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Genetic Predisposition, Polymorphism, Single Nucleotide, BINDING-SITES, Breast cancer, REDUCED RISK, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, microRNA, Genetic predisposition, medicine, Journal Article, Genetics, Cancer Genetics, Humans, GENOME-WIDE ASSOCIATION, Drosha, Genetic Association Studies, Binding Sites, Complex Traits, lcsh:R, Biology and Life Sciences, Computational Biology, Human Genetics, medicine.disease, Research Support, N.I.H., Intramural, COMMON VARIANT, MicroRNAs, Case-Control Studies, Genetics of Disease, lcsh:Q, Research Support, U.S. Gov't, Non-P.H.S, Genome-Wide Association Study
Abstract

Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95 confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95 CI: 0.95-0.99), rs10719 (OR 0.97; 95 Cl: 0.94-0.99), rs4687554 (OR 0.97; 95 CI: 0.95-0.99, and rs3134615 (OR 1.03; 95 CI: 1.01 -1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects. This is an open-access article free of all copyright.

Published
2014
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9. Large-scale genotyping identifies 41 new loci associated with breast cancer risk

Author

Michailidou, K., Hall, P., Gonzalez-Neira, A., Ghoussaini, M., Dennis, J., Milne, R.L., Schmidt, M.K., Chang-Claude, J., Bojesen, S.E., Bolla, M.K., Wang, Q., Dicks, E., Lee, A., Turnbull, C., Rahman, N., Fletcher, O., Peto, J., Gibson, L., Silva, I.D., Nevanlinna, H., Muranen, T.A., Aittomaki, K., Blomqvist, C., Czene, K., Irwanto, A., Liu, J.J., Waisfisz, Q., Meijers-Heijboer, H., Adank, M., Luijt, R.B. van der, Hein, R., Dahmen, N., Beckman, L., Meindl, A., Schmutzler, R.K., Muller-Myhsok, B., Lichtner, P., Hopper, J.L., Southey, M.C., Makalic, E., Schmidt, D.F., Uitterlinden, A.G., Hofman, A., Hunter, D.J., Chanock, S.J., Vincent, D., Bacot, F., Tessier, D.C., Canisius, S., Wessels, L.F.A., Haiman, C.A., Shah, M., Luben, R., Brown, J., Luccarini, C., Schoof, N., Humphreys, K., Li, J.M., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Couch, F.J., Wang, X.S., Vachon, C., Stevens, K.N., Lambrechts, D., Moisse, M., Paridaens, R., Christiaens, M.R., Rudolph, A., Nickels, S., Flesch-Janys, D., Johnson, N., Aitken, Z., Aaltonen, K., Heikkinen, T., Broeks, A., Van't Veer, L.J., Schoot, C.E. van der, Guenel, P., Truong, T., Laurent-Puig, P., Menegaux, F., Marme, F., Schneeweiss, A., Sohn, C., Burwinke, B., Zamora, M.P., Perez, J.I.A., Pita, G., Alonso, M.R., Cox, A., Brock, I.W., Cross, S.S., Reed, M.W.R., Sawyer, E.J., Tomlinson, I., Kerin, M.J., Miller, N., Henderson, B.E., Schumacher, F., Marchand, L. le, Andrulis, I.L., Knight, J.A., Glendon, G., Mulligan, A.M., Lindblom, A., Margolin, S., Hooning, M.J., Hollestelle, A., Ouweland, A.M.W. van den, Jager, A., Bui, Q.M., Stone, J., Dite, G.S., Apicella, C., Tsimiklis, H., Giles, G.G., Severi, G., Baglietto, L., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Brenner, H., Muller, H., Arndt, V., Stegmaier, C., Swerdlown, A., Ashworth, A., Orr, N., Jones, M., Figueroa, J., Lissowska, J., Brinton, L., Goldberg, M.S., Labreche, F., Dumont, M., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Brauch, H., Hamann, U., Bruning, T., Radice, P., Peterlongo, P., Manouldan, S., Bonanni, B., Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Asperen, C.J. van, Jakubowska, A., Lubinski, J., Jaworska, K., Durda, K., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Bogdanova, N.V., Antonenkova, N.N., Dork, T., Kristensen, V.N., Anton-Culver, H., Slager, S., Toland, A.E., Edge, S., Fostira, F., Kang, D., Yoo, K.Y., Noh, D.Y., Matsuo, K., Ito, H., Iwata, H., Sueta, A., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Shu, X.O., Lu, W., Gao, Y.T., Cai, H., Teo, S.H., Yip, C.H., Phuah, S.Y., Cornes, B.K., Hartman, M., Miao, H., Lim, W.Y., Sng, J.H., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Shen, C.Y., Hsiung, C.N., Wu, P.E., Ding, S.L., Sangrajrang, S., Gaborieau, V., Brennan, P., Mckay, J., Blot, W.J., Signorello, L.B., Cai, Q.Y., Zheng, W., Deming-Halverson, S., Shrubsole, M., Long, J.R., Simard, J., Garcia-Closas, M., Pharoah, P.D.P., Chenevix-Trench, G., Dunning, A.M., Benitez, J., Easton, D.F., Breast Ovarian Canc Susceptibility, Hereditary Breast Ovarian Canc Res, kConFab Investigators, Australian Ovarian Can Study Grp, GENICA Gene Environm Interaction B, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, Landsteiner Laboratory, Clinical Haematology, Clinical Genetics, Internal Medicine, Epidemiology, Medical Oncology, Cardiothoracic Surgery, Human genetics, CCA - Oncogenesis, and ~

Subjects
signaling pathway, Genotyping, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Breast Neoplasms, consortium, Biology, Case-Control Studies, Cooperative Behavior, Female, Gene-Environment Interaction, Genetic Loci, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Risk Factors, Genetic Predisposition to Disease, Genetics, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, common variants, expression, medicine, Polymorphism, gene, hormone-related protein, 030304 developmental biology, Genetic association, 0303 health sciences, Breast cancer susceptibility, Cancer, Single Nucleotide, medicine.disease, confer susceptibility, susceptibility loci, 3. Good health, 14q24.1 rad51l1, TOX3, 030220 oncology & carcinogenesis, genome-wide association
Abstract

Journal article Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ~9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10!¿8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility. European Community Seventh Framework Programme - grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) peer-reviewed

Published
2013
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