{"entity": "publication", "iuid": "3f10baed3ec24eb98617d0cf282676fc", "timestamp": "2026-09-23T21:35:47.197Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/3f10baed3ec24eb98617d0cf282676fc.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/3f10baed3ec24eb98617d0cf282676fc"}}, "title": "Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.", "authors": [{"family": "Baxter", "given": "Joseph S", "initials": "JS"}, {"family": "Johnson", "given": "Nichola", "initials": "N"}, {"family": "Tomczyk", "given": "Katarzyna", "initials": "K"}, {"family": "Gillespie", "given": "Andrea", "initials": "A"}, {"family": "Maguire", "given": "Sarah", "initials": "S"}, {"family": "Brough", "given": "Rachel", "initials": "R"}, {"family": "Fachal", "given": "Laura", "initials": "L"}, {"family": "Michailidou", "given": "Kyriaki", 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"given": "William J", "initials": "WJ"}, {"family": "Taylor", "given": "Jack A", "initials": "JA"}, {"family": "Teo", "given": "Soo Hwang", "initials": "SH"}, {"family": "Teras", "given": "Lauren R", "initials": "LR"}, {"family": "Terry", "given": "Mary Beth", "initials": "MB"}, {"family": "Toland", "given": "Amanda E", "initials": "AE"}, {"family": "Tomlinson", "given": "Ian", "initials": "I"}, {"family": "Truong", "given": "Th\u00e9r\u00e8se", "initials": "T"}, {"family": "Tseng", "given": "Chiu-Chen", "initials": "CC"}, {"family": "Untch", "given": "Michael", "initials": "M"}, {"family": "Vachon", "given": "Celine M", "initials": "CM"}, {"family": "van den Ouweland", "given": "Ans M W", "initials": "AMW"}, {"family": "Wang", "given": "Sophia S", "initials": "SS"}, {"family": "Weinberg", "given": "Clarice R", "initials": "CR"}, {"family": "Wendt", "given": "Camilla", "initials": "C"}, {"family": "Winham", "given": "Stacey J", "initials": "SJ"}, {"family": "Winqvist", "given": "Robert", "initials": "R"}, {"family": "Wolk", "given": "Alicja", "initials": "A"}, {"family": "Wu", "given": "Anna H", "initials": "AH"}, {"family": "Yamaji", "given": "Taiki", "initials": "T"}, {"family": "Zheng", "given": "Wei", "initials": "W"}, {"family": "Ziogas", "given": "Argyrios", "initials": "A"}, {"family": "Pharoah", "given": "Paul D P", "initials": "PDP"}, {"family": "Dunning", "given": "Alison M", "initials": "AM"}, {"family": "Easton", "given": "Douglas F", "initials": "DF"}, {"family": "Pettitt", "given": "Stephen J", "initials": "SJ"}, {"family": "Lord", "given": "Christopher J", "initials": "CJ"}, {"family": "Haider", "given": "Syed", "initials": "S"}, {"family": "Orr", "given": "Nick", "initials": "N"}, {"family": "Fletcher", "given": "Olivia", "initials": "O"}], "type": "journal article", "published": "2021-07-01", "journal": {"title": "Am. J. Hum. Genet.", "issn": "1537-6605", "volume": "108", "issue": "7", "pages": "1190-1203", "issn-l": "0002-9297"}, "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 which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 \u00d7 10-31).", "doi": "10.1016/j.ajhg.2021.05.013", "pmid": "34146516", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC8322933"}, {"db": "pii", "key": "S0002-9297(21)00218-4"}], "notes": [], "created": "2026-09-23T12:07:08.040Z", "modified": "2026-09-23T12:07:08.057Z"}