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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus

Article scientifique 2016 Anglais

Résumé

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.

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Lawrenson, K., Kar, S., McCue, K., Kuchenbaeker, K., Michailidou, K., Tyrer, J., Beesley, J., Ramus, S., Li, Q., Delgado, M., Lee, J., Aittomäki, K., Andrulis, I., Anton‐Culver, H., Arndt, V., Arun, B., Arver, B., Bandera, E., Barile, M., Barkardóttir, R., Barrowdale, D., Beckmann, M., Benı́tez, J., Berchuck, A., Bisogna, M., Bjørge, L., Blomqvist, C., Blot, W., Bogdanova, N., Bojesen, A., Bojesen, S., Bolla, M., Bonanni, B., Børresen‐Dale, A., Brauch, H., Brennan, P., Brenner, H., Bruinsma, F., Brunet, J., Buhari, S., Burwinkel, B., Bützow, R., Buys, S., Cai, Q., Caldés, T., Campbell, I., Cannioto, R., Chang‐Claude, J., Chiquette, J., Choi, J., Claes, K., Collaborators, G., Collonge-Rame, M., Damette, A., Barouk-Simonet, E., Bonnet, F., Bubien, V., Sévenet, N., Longy, M., Berthet, P., Vaur, D., Castéra, L., Ferrer, S., Bignon, Y., Uhrhammer, N., Coron, F., Faivre, L., Baurand, A., Jacquot, C., Bertolone, G., Lizard, S., Leroux, D., Dreyfus, H., Rebischung, C., Peysselon, M., Peyrat, J., Fournier, J., Révillion, F., Adenis, C., Venat‐Bouvet, L., Léone, M., Boutry‐Kryza, N., Calender, A., Giraud, S., Verny-Pierre, C., Lasset, C., Bonadona, V., Barjhoux, L., Sobol, H., Bourdon, V., Noguchi, T., Remenieras, A., Coupier, I., Pujol, P., Sokolowska, J., Bronner, M., Delnatte, C., Bezieau, S., Mari, V., Gauthier‐Villars, M. (2016). Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus. https://doi.org/10.1038/ncomms12675

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Auteur(s)

Kate Lawrenson Siddhartha Kar Karen McCue Karoline Kuchenbaeker Kyriaki Michailidou Jonathan P. Tyrer Jonathan Beesley Susan J. Ramus Qiyuan Li Melissa K. Delgado Janet M. Lee Kristiina Aittomäki Irene L. Andrulis Hoda Anton‐Culver Volker Arndt Banu Arun Brita Arver Elisa V. Bandera Monica Barile Rósa B. Barkardóttir Daniel Barrowdale Matthias W. Beckmann Javier Benı́tez Andrew Berchuck Maria Bisogna Line Bjørge Carl Blomqvist William J. Blot Natalia Bogdanova Anders Bojesen Stig E. Bojesen Manjeet K. Bolla Bernardo Bonanni Anne‐Lise Børresen‐Dale Hiltrud Brauch Paul Brennan Hermann Brenner Fiona Bruinsma Joan Brunet Shaik Ahmad Buhari Barbara Burwinkel Ralf Bützow Saundra S. Buys Qiuyin Cai Trinidad Caldés Ian Campbell Rikki Cannioto Jenny Chang‐Claude Jocelyne Chiquette Ji‐Yeob Choi Kathleen Claes GEMO Study Collaborators Marie- Agnès Collonge-Rame Alexandre Damette Emmanuelle Barouk-Simonet Françoise Bonnet Virginie Bubien Nicolas Sévenet Michel Longy Pascaline Berthet Dominique Vaur Laurent Castéra Sandra Fert Ferrer Yves‐Jean Bignon Nancy Uhrhammer Fanny Coron Laurence Faivre Amandine Baurand Caroline Jacquot Geoffrey Bertolone Sarab Lizard Dominique Leroux Hélène Dreyfus Christine Rebischung Magalie Peysselon Jean‐Philippe Peyrat Joëlle Fournier Françoise Révillion Claude Adenis Laurence Venat‐Bouvet Mélanie Léone Nadia Boutry‐Kryza Alain Calender Sophie Giraud Carole Verny-Pierre Christine Lasset Valérie Bonadona Laure Barjhoux Hagay Sobol Violaine Bourdon Tetsuro Noguchi Audrey Remenieras Isabelle Coupier Pascal Pujol Johanna Sokolowska Myriam Bronner Capucine Delnatte Stéphane Bezieau Véronique Mari Marion Gauthier‐Villars

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