Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk. Gaudet, M. M., Kuchenbaecker, K. B., Vijai, J., Klein, R. J., Kirchhoff, T., McGuffog, L., Barrowdale, D., Dunning, A. M., Lee, A., Dennis, J., Healey, S., Dicks, E., Soucy, P., Sinilnikova, O. M., Pankratz, V. S., Wang, X., Eldridge, R. C., Tessier, D. C., Vincent, D., Bacot, F., Hogervorst, F. B. L., Peock, S., Stoppa-Lyonnet, D., KConFab Investigators, Peterlongo, P., Schmutzler, R. K., Nathanson, K. L., Piedmonte, M., Singer, C. F., Thomassen, M., Ontario Cancer Genetics Network, Hansen, T. v O., Neuhausen, S. L., Blanco, I., Greene, M. H., Garber, J., Weitzel, J. N., Andrulis, I. L., Goldgar, D. E., D'Andrea, E., Caldes, T., Nevanlinna, H., Osorio, A., van Rensburg, E. J., Arason, A., Rennert, G., van den Ouweland, A. M. W., van der Hout, A. H., Kets, C. M., Aalfs, C. M., Wijnen, J. T., Ausems, M. G. E. M., HEBON, EMBRACE, Frost, D., Ellis, S., Fineberg, E., Platte, R., Evans, D. G., Jacobs, C., Adlard, J., Tischkowitz, M., Porteous, M. E., Damiola, F., GEMO Study Collaborators, Golmard, L., Barjhoux, L., Longy, M., Belotti, M., Ferrer, S. F., Mazoyer, S., Spurdle, A. B., Manoukian, S., Barile, M., Genuardi, M., Arnold, N., Meindl, A., Sutter, C., Wappenschmidt, B., Domchek, S. M., Pfeiler, G., Friedman, E., Jensen, U. B., Robson, M., Shah, S., Lazaro, C., Mai, P. L., Benitez, J., Southey, M. C., Schmidt, M. K., Fasching, P. A., Peto, J., Humphreys, M. K., Wang, Q., Michailidou, K., Sawyer, E. J., Burwinkel, B., Guénel, P., Bojesen, S. E., Milne, R. L., Brenner, H., Lochmann, M., GENICA Network, Aittomäki, K., Dörk, T., Margolin, S., Mannermaa, A., Lambrechts, D., Chang-Claude, J., Radice, P., Giles, G. G., Haiman, C. A., Winqvist, R., Devillee, P., García-Closas, M., Schoof, N., Hooning, M. J., Cox, A., Pharoah, P. D. P., Jakubowska, A., Orr, N., González-Neira, A., Pita, G., Alonso, M. R., Hall, P., Couch, F. J., Simard, J., Altshuler, D., Easton, D. F., Chenevix-Trench, G., Antoniou, A. C., & Offit, K. PLoS genetics, 9(3):e1003173, 2013.
doi  abstract   bibtex   
Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
@article{gaudet_identification_2013,
	title = {Identification of a {BRCA2}-specific modifier locus at 6p24 related to breast cancer risk},
	volume = {9},
	issn = {1553-7404},
	doi = {10.1371/journal.pgen.1003173},
	abstract = {Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95\% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.},
	language = {eng},
	number = {3},
	journal = {PLoS genetics},
	author = {Gaudet, Mia M. and Kuchenbaecker, Karoline B. and Vijai, Joseph and Klein, Robert J. and Kirchhoff, Tomas and McGuffog, Lesley and Barrowdale, Daniel and Dunning, Alison M. and Lee, Andrew and Dennis, Joe and Healey, Sue and Dicks, Ed and Soucy, Penny and Sinilnikova, Olga M. and Pankratz, Vernon S. and Wang, Xianshu and Eldridge, Ronald C. and Tessier, Daniel C. and Vincent, Daniel and Bacot, Francois and Hogervorst, Frans B. L. and Peock, Susan and Stoppa-Lyonnet, Dominique and {KConFab Investigators} and Peterlongo, Paolo and Schmutzler, Rita K. and Nathanson, Katherine L. and Piedmonte, Marion and Singer, Christian F. and Thomassen, Mads and {Ontario Cancer Genetics Network} and Hansen, Thomas v O. and Neuhausen, Susan L. and Blanco, Ignacio and Greene, Mark H. and Garber, Judith and Weitzel, Jeffrey N. and Andrulis, Irene L. and Goldgar, David E. and D'Andrea, Emma and Caldes, Trinidad and Nevanlinna, Heli and Osorio, Ana and van Rensburg, Elizabeth J. and Arason, Adalgeir and Rennert, Gad and van den Ouweland, Ans M. W. and van der Hout, Annemarie H. and Kets, Carolien M. and Aalfs, Cora M. and Wijnen, Juul T. and Ausems, Margreet G. E. M. and {HEBON} and {EMBRACE} and Frost, Debra and Ellis, Steve and Fineberg, Elena and Platte, Radka and Evans, D. Gareth and Jacobs, Chris and Adlard, Julian and Tischkowitz, Marc and Porteous, Mary E. and Damiola, Francesca and {GEMO Study Collaborators} and Golmard, Lisa and Barjhoux, Laure and Longy, Michel and Belotti, Muriel and Ferrer, Sandra Fert and Mazoyer, Sylvie and Spurdle, Amanda B. and Manoukian, Siranoush and Barile, Monica and Genuardi, Maurizio and Arnold, Norbert and Meindl, Alfons and Sutter, Christian and Wappenschmidt, Barbara and Domchek, Susan M. and Pfeiler, Georg and Friedman, Eitan and Jensen, Uffe Birk and Robson, Mark and Shah, Sohela and Lazaro, Conxi and Mai, Phuong L. and Benitez, Javier and Southey, Melissa C. and Schmidt, Marjanka K. and Fasching, Peter A. and Peto, Julian and Humphreys, Manjeet K. and Wang, Qin and Michailidou, Kyriaki and Sawyer, Elinor J. and Burwinkel, Barbara and Guénel, Pascal and Bojesen, Stig E. and Milne, Roger L. and Brenner, Hermann and Lochmann, Magdalena and {GENICA Network} and Aittomäki, Kristiina and Dörk, Thilo and Margolin, Sara and Mannermaa, Arto and Lambrechts, Diether and Chang-Claude, Jenny and Radice, Paolo and Giles, Graham G. and Haiman, Christopher A. and Winqvist, Robert and Devillee, Peter and García-Closas, Montserrat and Schoof, Nils and Hooning, Maartje J. and Cox, Angela and Pharoah, Paul D. P. and Jakubowska, Anna and Orr, Nick and González-Neira, Anna and Pita, Guillermo and Alonso, M. Rosario and Hall, Per and Couch, Fergus J. and Simard, Jacques and Altshuler, David and Easton, Douglas F. and Chenevix-Trench, Georgia and Antoniou, Antonis C. and Offit, Kenneth},
	year = {2013},
	pmid = {23544012},
	pmcid = {PMC3609647},
	keywords = {Adult, Aged, Alleles, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Chromosomes, Human, Pair 6, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heterozygote, Humans, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Risk Factors},
	pages = {e1003173},
}
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