1. Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element
- Author
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NBCS Collaborators, kConFab Investigators, ABCTB Investigators, Joseph S. Baxter, Nichola Johnson, Katarzyna Tomczyk, Andrea Gillespie, Sarah Maguire, Rachel Brough, Laura Fachal, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Annelie Augustinsson, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Natalia V. Bogdanova, Stig E. Bojesen, Hermann Brenner, Sara Y. Brucker, Qiuyin Cai, Daniele Campa, Federico Canzian, Jose E. Castelao, Tsun L. Chan, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Ji Yeob Choi, Christine L. Clarke, Sarah Colonna, Don M. Conroy, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, CW (Christoph) Engel, A. (Antoinette) Hollestelle, A. (Agnes) Jager, PJA (Peter) van Kraft, A.M.W. (Ans) van den Ouweland, SA (Syed) Haider, NBCS Collaborators, kConFab Investigators, ABCTB Investigators, Joseph S. Baxter, Nichola Johnson, Katarzyna Tomczyk, Andrea Gillespie, Sarah Maguire, Rachel Brough, Laura Fachal, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Annelie Augustinsson, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Natalia V. Bogdanova, Stig E. Bojesen, Hermann Brenner, Sara Y. Brucker, Qiuyin Cai, Daniele Campa, Federico Canzian, Jose E. Castelao, Tsun L. Chan, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Ji Yeob Choi, Christine L. Clarke, Sarah Colonna, Don M. Conroy, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, CW (Christoph) Engel, A. (Antoinette) Hollestelle, A. (Agnes) Jager, PJA (Peter) van Kraft, A.M.W. (Ans) van den Ouweland, and SA (Syed) Haider
- Abstract
A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in whic
- Published
- 2021
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