Publisher: BioMed Central
Journal: Breast Cancer Research : BCR
Subjects: PTHLH, LOCALIZATION, BRAC1 mutation carriers; Breast cancer; CCDC91; Fine-scale mapping; Genetic risk factor; PTHLH, BRAC1 mutation carriers, Cancer och onkologi, Research Article, GENETIC MODIFIERS, Oncology, Cancer Research, UOWSAT, 3111 Biomedicine, METASTASIS, PTHLH-CCDC91, OVARIAN-CANCER, HORMONE-RELATED PROTEIN, 3122 Cancers, Biology and Life Sciences, EXPRESSION, ENHANCERS, SUSCEPTIBILITY LOCI, CCDC91, Breast cancer, -, Genetic risk factor, Cancer and Oncology, Fine-scale mapping, Medizin, Medical Genetics, Medicinsk genetik, /dk/atira/pure/subjectarea/asjc/2700/2730, BRCA2 MUTATION CARRIERS, /dk/atira/pure/subjectarea/asjc/1300/1306, Journal Article, GENOME-WIDE ASSOCIATION, Medicine and Health Sciences
Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk. Electronic supplementary material The online version of this article (doi:10.1186/s13058-016-0718-0) contains supplementary material, which is available to authorized users.
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- 1. Ghoussaini M, Fletcher O, Michailidou K, Turnbull C, Schmidt MK, Dicks E, et al. Genome-wide association analysis identifies three new breast cancer susceptibility loci. Nat Genet. 2012;44(3):312-8.
- 2. Antoniou AC, Kuchenbaecker KB, Soucy P, Beesley J, Chen X, McGuffog L, et al. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. Breast Cancer Res. 2012;14(1):R33.
- 3. Kuchenbaecker KB, Neuhausen SL, Robson M, Barrowdale D, McGuffog L, Mulligan AM, et al. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res. 2014;16(6):3416.
- 4. Zheng W, Zhang B, Cai Q, Sung H, Michailidou K, Shi J, et al. Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls. Hum Mol Genet. 2013;22(12):2539-50.
- 5. Li J, Karaplis AC, Huang DC, Siegel PM, Camirand A, Yang XF, et al. PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target. J Clin Invest. 2011;121(12):4655-69.
- 6. Fleming NI, Trivett MK, George J, Slavin JL, Murray WK, Moseley JM, et al. Parathyroid hormone-related protein protects against mammary tumor emergence and is associated with monocyte infiltration in ductal carcinoma in situ. Cancer Res. 2009;69(18):7473-9.
- 7. Henderson MA, Danks JA, Slavin JL, Byrnes GB, Choong PF, Spillane JB, et al. Parathyroid hormone-related protein localization in breast cancers predict improved prognosis. Cancer Res. 2006;66(4):2250-6.
- 8. Corradin O, Saiakhova A, Akhtar-Zaidi B, Myeroff L, Willis J, Cowper-Sal lari R, et al. Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits. Genome Res. 2014;24(1):1-13.
- 9. Edwards SL, Beesley J, French JD, Dunning AM. Beyond GWASs: illuminating the dark road from association to function. Am J Hum Genet. 2013;93(5): 779-97.
- 10. Bojesen SE, Pooley KA, Johnatty SE, Beesley J, Michailidou K, Tyrer JP, et al. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat Genet. 2013; 45(4):371-84. 384e371-372.
- 11. French JD, Ghoussaini M, Edwards SL, Meyer KB, Michailidou K, Ahmed S, et al. Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers. Am J Hum Genet. 2013;92(4):489-503.
- 12. Meyer KB, O'Reilly M, Michailidou K, Carlebur S, Edwards SL, French JD, et al. Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1. Am J Hum Genet. 2013;93(6):1046-60.
- 13. Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL, et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet. 2013;45(4):353-61. 361e351-352.
- 14. Chenevix-Trench G, Milne RL, Antoniou AC, Couch FJ, Easton DF, Goldgar DE. Cimba: An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res. 2007;9(2):104.
- 15. Genomes Project C, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061-73.
- 16. International HapMap C. The International HapMap Project. Nature. 2003;426(6968):789-96.
- 17. Howie B, Marchini J, Stephens M. Genotype imputation with thousands of genomes. G3. 2011;1(6):457-70.
- 18. Long JC, Williams RC, Urbanek M. An E-M algorithm and testing strategy for multiple-locus haplotypes. Am J Hum Genet. 1995;56(3):799-810.
- 19. Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007;447(7148):1087-93.
- 20. Zheng W, Long J, Gao YT, Li C, Zheng Y, Xiang YB, et al. Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet. 2009;41(3):324-8.
- 21. Barnes DR, Antoniou AC. Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers. J Intern Med. 2012;271(4):331-43.
- 22. Antoniou AC, Wang X, Fredericksen ZS, McGuffog L, Tarrell R, Sinilnikova OM, et al. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat Genet. 2010;42(10):885-92.
- 23. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26(17):2190-1.
- 24. Consortium EP. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57-74.
- 25. He B, Chen C, Teng L, Tan K. Global view of enhancer-promoter interactome in human cells. Proc Natl Acad Sci USA. 2014;111(21):E2191-9.
- 26. Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-Andre V, Sigova AA, et al. Super-enhancers in the control of cell identity and disease. Cell. 2013;155(4):934-47.
- 27. Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22(9):1790-7.
- 28. Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40(Database issue):D930-4.
- 29. Cline MS, Craft B, Swatloski T, Goldman M, Ma S, Haussler D, et al. Exploring TCGA pan-cancer data at the UCSC Cancer Genomics Browser. Sci Rep. 2013;3:2652.
- 30. Cai Q, Zhang B, Sung H, Low SK, Kweon SS, Lu W, et al. Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nat Genet. 2014;46(8):886-90.
- 31. Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346-52.
- 32. Shabalin AA. Matrix eQTL: ultra fast eQTL analysis via large matrix operations. Bioinformatics. 2012;28(10):1353-8.
- 33. Pique-Regi R, Degner JF, Pai AA, Gaffney DJ, Gilad Y, Pritchard JK. Accurate inference of transcription factor binding from DNA sequence and chromatin accessibility data. Genome Res. 2011;21(3):447-55.
- 34. Robson EJ, He SJ, Eccles MR. A PANorama of PAX genes in cancer and development. Nat Rev Cancer. 2006;6(1):52-62.
- 35. Ballestar E, Paz MF, Valle L, Wei S, Fraga MF, Espada J, et al. Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J. 2003;22(23):6335-45.
- 36. Miao D, Su H, He B, Gao J, Xia Q, Zhu M, et al. Severe growth retardation and early lethality in mice lacking the nuclear localization sequence and C-terminus of PTH-related protein. Proc Natl Acad Sci USA. 2008;105(51): 20309-14.
- 37. Suva LJ, Winslow GA, Wettenhall RE, Hammonds RG, Moseley JM, Diefenbach-Jagger H, et al. A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science. 1987;237(4817):893-6.
- 38. Southby J, Kissin MW, Danks JA, Hayman JA, Moseley JM, Henderson MA, et al. Immunohistochemical localization of parathyroid hormone-related protein in human breast cancer. Cancer Res. 1990;50(23):7710-6.
- 39. Dittmer A, Vetter M, Schunke D, Span PN, Sweep F, Thomssen C, et al. Parathyroid hormone-related protein regulates tumor-relevant genes in breast cancer cells. J Biol Chem. 2006;281(21):14563-72.
- 40. Akhtari M, Mansuri J, Newman KA, Guise TM, Seth P. Biology of breast cancer bone metastasis. Cancer Biol Ther. 2008;7(1):3-9.
- 41. Okoumassoun LE, Russo C, Denizeau F, Averill-Bates D, Henderson JE. Parathyroid hormone-related protein (PTHrP) inhibits mitochondrialdependent apoptosis through CK2. J Cell Physiol. 2007;212(3):591-9.
- 42. Mardones GA, Burgos PV, Brooks DA, Parkinson-Lawrence E, Mattera R, Bonifacino JS. The trans-Golgi network accessory protein p56 promotes long-range movement of GGA/clathrin-containing transport carriers and lysosomal enzyme sorting. Mol Biol Cell. 2007;18(9):3486-501.
- 43. Kolker E, Higdon R, Haynes W, Welch D, Broomall W, Lancet D, et al. MOPED: Model Organism Protein Expression Database. Nucleic Acids Res. 2012;40(Database issue):D1093-9.
- 44. Feng Y, Stram DO, Rhie SK, Millikan RC, Ambrosone CB, John EM, et al. A comprehensive examination of breast cancer risk loci in African American women. Hum Mol Genet. 2014;23(20):5518-26.
- 45. Ernst J, Kellis M. ChromHMM: automating chromatin-state discovery and characterization. Nat Methods. 2012;9(3):215-6.
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