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An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.

ABSTRACT: Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ER?-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ER? binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR?=?0.68 95%CI 0.55-0.83, P?=?0.0002; replication OR?=?0.77 95% CI 0.73-0.82, P?=?2.1 × 10-19) and identify 13 additional linked variants (r2?>?0.8) in the 20Kb linkage block containing the enCNV (P?=?3.2?×?10-15 - 5.6?×?10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.

SUBMITTER: Wyszynski A

PROVIDER: S-EPMC5216618 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.

Wyszynski Asaf A Hong Chi-Chen CC Lam Kristin K Michailidou Kyriaki K Lytle Christian C Yao Song S Zhang Yali Y Bolla Manjeet K MK Wang Qin Q Dennis Joe J Hopper John L JL Southey Melissa C MC Schmidt Marjanka K MK Broeks Annegien A Muir Kenneth K Lophatananon Artitaya A Fasching Peter A PA Beckmann Matthias W MW Peto Julian J Dos-Santos-Silva Isabel I Sawyer Elinor J EJ Tomlinson Ian I Burwinkel Barbara B Marme Frederik F Guénel Pascal P Truong Thérèse T Bojesen Stig E SE Nordestgaard Børge G BG González-Neira Anna A Benitez Javier J Neuhausen Susan L SL Brenner Hermann H Dieffenbach Aida Karina AK Meindl Alfons A Schmutzler Rita K RK Brauch Hiltrud H Nevanlinna Heli H Khan Sofia S Matsuo Keitaro K Ito Hidemi H Dörk Thilo T Bogdanova Natalia V NV Lindblom Annika A Margolin Sara S Mannermaa Arto A Kosma Veli-Matti VM Wu Anna H AH Van Den Berg David D Lambrechts Diether D Wildiers Hans H Chang-Claude Jenny J Rudolph Anja A Radice Paolo P Peterlongo Paolo P Couch Fergus J FJ Olson Janet E JE Giles Graham G GG Milne Roger L RL Haiman Christopher A CA Henderson Brian E BE Dumont Martine M Teo Soo Hwang SH Wong Tien Y TY Kristensen Vessela V Zheng Wei W Long Jirong J Winqvist Robert R Pylkäs Katri K Andrulis Irene L IL Knight Julia A JA Devilee Peter P Seynaeve Caroline C García-Closas Montserrat M Figueroa Jonine J Klevebring Daniel D Czene Kamila K Hooning Maartje J MJ van den Ouweland Ans M W AM Darabi Hatef H Shu Xiao-Ou XO Gao Yu-Tang YT Cox Angela A Blot William W Signorello Lisa B LB Shah Mitul M Kang Daehee D Choi Ji-Yeob JY Hartman Mikael M Miao Hui H Hamann Ute U Jakubowska Anna A Lubinski Jan J Sangrajrang Suleeporn S McKay James J Toland Amanda E AE Yannoukakos Drakoulis D Shen Chen-Yang CY Wu Pei-Ei PE Swerdlow Anthony A Orr Nick N Simard Jacques J Pharoah Paul D P PD Dunning Alison M AM Chenevix-Trench Georgia G Hall Per P Bandera Elisa E Amos Chris C Ambrosone Christine C Easton Douglas F DF Cole Michael D MD

Human molecular genetics 20160711 17

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enC ...[more]

PMID: 27402876

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Project description:BackgroundAngiogenesis is critical for forming new blood vessels from antedating vascular vessels. The endothelium is essential for angiogenesis, vascular remodelling and minimisation of functional deficits following ischaemia. The insulin-like growth factor (IGF) family is crucial for angiogenesis. Insulin-like growth factor-binding protein 5 (IGFBP5), a binding protein of the IGF family, may have places in angiogenesis, but the mechanisms are not yet completely understood. We sought to probe whether IGFBP5 is involved in pathological angiogenesis and uncover the molecular mechanisms behind it.Methods and resultsIGFBP5 expression was elevated in the vascular endothelium of gastrocnemius muscle from critical limb ischaemia patients and hindlimb ischaemic (HLI) mice and hypoxic human umbilical vein endothelial cells (HUVECs). In vivo, loss of endothelial IGFBP5 (IGFBP5EKO) facilitated the recovery of blood vessel function and limb necrosis in HLI mice. Moreover, skin damage healing and aortic ring sprouting were faster in IGFBP5EKO mice than in control mice. In vitro, the genetic inhibition of IGFBP5 in HUVECs significantly promoted tube formation, cell proliferation and migration by mediating the phosphorylation of IGF1R, Erk1/2 and Akt. Intriguingly, pharmacological treatment of HUVECs with recombinant human IGFBP5 ensued a contrasting effect on angiogenesis by inhibiting the IGF1 or IGF2 function. Genetic inhibition of IGFBP5 promoted cellular oxygen consumption and extracellular acidification rates via IGF1R-mediated glycolytic adenosine triphosphate (ATP) metabolism. Mechanistically, IGFBP5 exerted its role via E3 ubiquitin ligase Von Hippel-Lindau (VHL)-regulated HIF1α stability. Furthermore, the knockdown of the endothelial IGF1R partially abolished the reformative effect of IGFBP5EKO mice post-HLI.ConclusionOur findings demonstrate that IGFBP5 ablation enhances angiogenesis by promoting ATP metabolism and stabilising HIF1α, implying IGFBP5 is a novel therapeutic target for treating abnormal angiogenesis-related conditions.

Project description:Key messageA novel structural variant was discovered in the FLOWERING LOCUS T orthologue BnaFT.A02 by long-read sequencing. Nested association mapping in an elite winter oilseed rape population revealed that this 288 bp deletion associates with early flowering, putatively by modification of binding-sites for important flowering regulation genes. Perfect timing of flowering is crucial for optimal pollination and high seed yield. Extensive previous studies of flowering behavior in Brassica napus (canola, rapeseed) identified mutations in key flowering regulators which differentiate winter, semi-winter and spring ecotypes. However, because these are generally fixed in locally adapted genotypes, they have only limited relevance for fine adjustment of flowering time in elite cultivar gene pools. In crosses between ecotypes, the ecotype-specific major-effect mutations mask minor-effect loci of interest for breeding. Here, we investigated flowering time in a multiparental mapping population derived from seven elite winter oilseed rape cultivars which are fixed for major-effect mutations separating winter-type rapeseed from other ecotypes. Association mapping revealed eight genomic regions on chromosomes A02, C02 and C03 associating with fine modulation of flowering time. Long-read genomic resequencing of the seven parental lines identified seven structural variants coinciding with candidate genes for flowering time within chromosome regions associated with flowering time. Segregation patterns for these variants in the elite multiparental population and a diversity set of winter types using locus-specific assays revealed significant associations with flowering time for three deletions on chromosome A02. One of these was a previously undescribed 288 bp deletion within the second intron of FLOWERING LOCUS T on chromosome A02, emphasizing the advantage of long-read sequencing for detection of structural variants in this size range. Detailed analysis revealed the impact of this specific deletion on flowering-time modulation under extreme environments and varying day lengths in elite, winter-type oilseed rape.

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An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.

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An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.

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