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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Article scientifique 2016 Anglais

Résumé

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.

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Zeng, C., Guo, X., Long, J., Kuchenbaecker, K., Droit, A., Michailidou, K., Ghoussaini, M., Kar, S., Freeman, A., Hopper, J., Milne, R., Bolla, M., Dennis, J., Agata, S., Ahmed, S., Aittomäki, K., Andrulis, I., Anton‐Culver, H., Antonenkova, N., Arason, A., Arndt, V., Arun, B., Arver, B., Bacot, F., Barrowdale, D., Baynes, C., Beeghly‐Fadiel, A., Benı́tez, J., Bermisheva, M., Blomqvist, C., Blot, W., Bogdanova, N., Bojesen, S., Bonanni, B., Børresen‐Dale, A., Brand, J., Brauch, H., Brennan, P., Brenner, H., Broeks, A., Brüning, T., Burwinkel, B., Buys, S., Cai, Q., Caldés, T., Campbell, I., Carpenter, J., Chang‐Claude, J., Choi, J., Claes, K., Clarke, C., Cox, A., Cross, S., Czene, K., Daly, M., Hoya, M., Leeneer, K., Devilee, P., Dı́ez, O., Domchek, S., Doody, M., Dorfling, C., Dörk, T., dos‐Santos‐Silva, I., Dumont, M., Dwek, M., Dworniczak, B., Egan, K., Eilber, U., Einbeigi, Z., Ejlertsen, B., Frost, D., Lalloo, F., Fasching, P., Figueroa, J., Flyger, H., Friedländer, M., Friedman, E., Gambino, G., Gao, Y., Garber, J., García‐Closas, M., Gehrig, A., Damiola, F., Lesueur, F., Mazoyer, S., Stoppa‐Lyonnet, D., Giles, G., Godwin, A., Goldgar, D., González‐Neira, A., Greene, M., Guénel, P. (2016). Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus. https://doi.org/10.1186/s13058-016-0718-0

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Auteur(s)

Chenjie Zeng Xingyi Guo Jirong Long Karoline Kuchenbaecker Arnaud Droit Kyriaki Michailidou Maya Ghoussaini Siddhartha Kar Adam N. Freeman John L. Hopper Roger L. Milne Manjeet K. Bolla Joe Dennis Simona Agata Shahana Ahmed Kristiina Aittomäki Irene L. Andrulis Hoda Anton‐Culver Natalia Antonenkova Aðalgeir Arason Volker Arndt Banu Arun Brita Arver François Bacot Daniel Barrowdale Caroline Baynes Alicia Beeghly‐Fadiel Javier Benı́tez Marina Bermisheva Carl Blomqvist William J. Blot Natalia Bogdanova Stig E. Bojesen Bernardo Bonanni Anne‐Lise Børresen‐Dale Judith S. Brand Hiltrud Brauch Paul Brennan Hermann Brenner Annegien Broeks Thomas Brüning Barbara Burwinkel Saundra S. Buys Qiuyin Cai Trinidad Caldés Ian Campbell Jane Carpenter Jenny Chang‐Claude Ji‐Yeob Choi Kathleen Claes Christine L. Clarke Angela Cox Simon S. Cross Kamila Czene Mary B. Daly Miguel de la Hoya Kim De Leeneer Peter Devilee Orland Dı́ez Susan M. Domchek Michele M. Doody Cecilia M. Dorfling Thilo Dörk Isabel dos‐Santos‐Silva Martine Dumont Miriam Dwek Bernd Dworniczak Kathleen M. Egan Ursula Eilber Zakaria Einbeigi Bent Ejlertsen Debra Frost Fiona Lalloo Peter A. Fasching Jonine D. Figueroa Henrik Flyger Michael Friedländer Eitan Friedman Gaetana Gambino Yu‐Tang Gao Judy E. Garber Montserrat García‐Closas Andrea Gehrig Francesca Damiola Fabienne Lesueur Sylvie Mazoyer Dominique Stoppa‐Lyonnet Graham G. Giles Andrew K. Godwin David E. Goldgar Anna González‐Neira Mark H. Greene Pascal Guénel

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