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

Lawrenson, Kate; Kar, Siddhartha; McCue, Karen; Kuchenbaeker, Karoline; Michailidou, Kyriaki; Tyrer, Jonathan; Beesley, Jonathan; Ramus, Susan J.; Li, Qiyuan and Delgado, Melissa K., et al. (2016) In Nature Communications 7.
Abstract

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... (More)

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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Nature Communications
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7
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Nature Publishing Group
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  • scopus:84987880304
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2041-1723
DOI
10.1038/ncomms12675
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@article{beb9d88a-99d9-48ff-915a-49012509606d,
  abstract     = {<p>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<sup>-20</sup>), ER-negative BC (P=1.1 × 10<sup>-13</sup>), BRCA1-associated BC (P=7.7 × 10<sup>-16</sup>) and triple negative BC (P-diff=2 × 10<sup>-5</sup>). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10<sup>-3</sup>) and ABHD8 (P&lt;2 × 10<sup>-3</sup>). 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.</p>},
  articleno    = {12675},
  author       = {Lawrenson, Kate and Kar, Siddhartha and McCue, Karen and Kuchenbaeker, Karoline and Michailidou, Kyriaki and Tyrer, Jonathan and Beesley, Jonathan and Ramus, Susan J. and Li, Qiyuan and Delgado, Melissa K. and Lee, Janet M. and Aittomäki, Kristiina and Andrulis, Irene L. and Anton-Culver, Hoda and Arndt, Volker and Arun, Banu K. and Arver, Brita and Bandera, Elisa V. and Barile, Monica and Barkardottir, Rosa B. and Barrowdale, Daniel and Beckmann, Matthias W. and Benitez, Javier and Berchuck, Andrew and Bisogna, Maria and Bjorge, Line and Blomqvist, Carl and Blot, William and Bogdanova, Natalia and Bojesen, Anders and Bojesen, Stig E. and Bolla, Manjeet K. and Bonanni, Bernardo and Børresen-Dale, Anne Lise and Brauch, Hiltrud and Brennan, Paul and Brenner, Hermann and Bruinsma, Fiona and Brunet, Joan and Buhari, Shaik Ahmad and Burwinkel, Barbara and Butzow, Ralf and Buys, Saundra S. and Cai, Qiuyin and Caldes, Trinidad and Campbell, Ian and Canniotto, Rikki and Chang-Claude, Jenny and Chiquette, Jocelyne and Choi, Ji Yeob and Claes, Kathleen B M and Cook, Linda S. and Cox, Angela and Cramer, Daniel W. and Cross, Simon S. and Cybulski, Cezary and Czene, Kamila and Daly, Mary B. and Damiola, Francesca and Dansonka-Mieszkowska, Agnieszka and Darabi, Hatef and Dennis, Joe and Devilee, Peter and Diez, Orland and Doherty, Jennifer A. and Domchek, Susan M. and Dorfling, Cecilia M. and Dörk, Thilo and Dumont, Martine and Ehrencrona, Hans and Ejlertsen, Bent and Ellis, Steve and Engel, Christoph and Lee, Eunjung and Evans, D. 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  issn         = {2041-1723},
  language     = {eng},
  month        = {09},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus},
  url          = {http://dx.doi.org/10.1038/ncomms12675},
  volume       = {7},
  year         = {2016},
}