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01-06-2015 | Epidemiology

Body mass index associated with genome-wide methylation in breast tissue

Authors: Brionna Y. Hair, Zongli Xu, Erin L. Kirk, Sophia Harlid, Rupninder Sandhu, Whitney R. Robinson, Michael C. Wu, Andrew F. Olshan, Kathleen Conway, Jack A. Taylor, Melissa A. Troester

Published in: Breast Cancer Research and Treatment | Issue 2/2015

Abstract

Gene expression studies indicate that body mass index (BMI) is associated with molecular pathways involved in inflammation, insulin-like growth factor activation, and other carcinogenic processes in breast tissue. The goal of this study was to determine whether BMI is associated with gene methylation in breast tissue and to identify pathways that are commonly methylated in association with high BMI. Epigenome-wide methylation profiles were determined using the Illumina HumanMethylation450 BeadChip array in the non-diseased breast tissue of 81 women undergoing breast surgery between 2009 and 2013 at the University of North Carolina Hospitals. Multivariable, robust linear regression was performed to identify methylation sites associated with BMI at a false discovery rate q value <0.05. Gene expression microarray data was used to identify which of the BMI-associated methylation sites also showed correlation with gene expression. Gene set enrichment analysis was conducted to assess which pathways were enriched among the BMI-associated methylation sites. Of the 431,568 methylation sites analyzed, 2573 were associated with BMI (q value <0.05), 57 % of which showed an inverse correlation with BMI. Pathways enriched among the 2573 probe sites included those involved in inflammation, insulin receptor signaling, and leptin signaling. We were able to map 1251 of the BMI-associated methylation sites to gene expression data, and, of these, 226 (18 %) showed substantial correlations with gene expression. Our results suggest that BMI is associated with genome-wide methylation in non-diseased breast tissue and may influence epigenetic pathways involved in inflammatory and other carcinogenic processes.

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Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. doi:10.1038/35021093 CrossRefPubMed

Sommer S, Fuqua SA (2001) Estrogen receptor and breast cancer. Semin Cancer Biol 11(5):339–352. doi:10.1006/scbi.2001.0389 CrossRefPubMed

Millikan RC, Newman B, Tse CK et al (2008) Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 109(1):123–139. doi:10.1007/s10549-007-9632-6 CrossRefPubMedCentralPubMed

Carey LA, Perou CM, Livasy CA et al (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502. doi:10.1001/jama.295.21.2492 CrossRefPubMed

Carmichael AR (2006) Obesity as a risk factor for development and poor prognosis of breast cancer. BJOG 113(10):1160–1166. doi:10.1111/j.1471-0528.2006.01021.x CrossRefPubMed

Carmichael AR, Bates T (2004) Obesity and breast cancer: a review of the literature. Breast 13(2):85–92. doi:10.1016/j.breast.2003.03.001 CrossRefPubMed

Gaudet MM, Press MF, Haile RW et al (2011) Risk factors by molecular subtypes of breast cancer across a population-based study of women 56 years or younger. Breast Cancer Res Treat 130(2):587–597. doi:10.1007/s10549-011-1616-x CrossRefPubMedCentralPubMed

Phipps AI, Buist DS, Malone KE et al (2012) Breast density, body mass index, and risk of tumor marker-defined subtypes of breast cancer. Ann Epidemiol. doi:10.1016/j.annepidem.2012.02.002 PubMedCentralPubMed

Ritte R, Lukanova A, Berrino F et al (2012) Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study. Breast Cancer Res 14(3):R76. doi:10.1186/bcr3186 CrossRefPubMedCentralPubMed

10.

Yang XR, Chang-Claude J, Goode EL et al (2011) Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies. J Natl Cancer Inst 103(3):250–263. doi:10.1093/jnci/djq526 CrossRefPubMedCentralPubMed

11.

Enger SM, Ross RK, Paganini-Hill A et al (2000) Body size, physical activity, and breast cancer hormone receptor status: results from two case-control studies. Cancer Epidemiol Biomark Prev 9(7):681–687

12.

Suga K, Imai K, Eguchi H et al (2001) Molecular significance of excess body weight in postmenopausal breast cancer patients, in relation to expression of insulin-like growth factor I receptor and insulin-like growth factor II genes. Jpn J Cancer Res 92(2):127–134CrossRefPubMed

13.

Sun X, Casbas-Hernandez P, Bigelow C et al (2012) Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression. Breast Cancer Res Treat 131(3):1003–1012. doi:10.1007/s10549-011-1789-3 CrossRefPubMedCentralPubMed

14.

Lorincz AM, Sukumar S (2006) Molecular links between obesity and breast cancer. Endocr Relat Cancer 13(2):279–292. doi:10.1677/erc.1.00729 CrossRefPubMed

15.

Parrizas M, Saltiel AR, LeRoith D (1997) Insulin-like growth factor 1 inhibits apoptosis using the phosphatidylinositol 3′-kinase and mitogen-activated protein kinase pathways. J Biol Chem 272(1):154–161CrossRefPubMed

16.

Mantovani A, Allavena P, Sica A et al (2008) Cancer-related inflammation. Nature 454(7203):436–444. doi:10.1038/nature07205 CrossRefPubMed

17.

Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867. doi:10.1038/nature01322 CrossRefPubMedCentralPubMed

18.

Jones PA, Takai D (2001) The role of DNA methylation in mammalian epigenetics. Science 293(5532):1068–1070. doi:10.1126/science.1063852 CrossRefPubMed

19.

Sandoval J, Heyn H, Moran S et al (2011) Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics 6(6):692–702CrossRefPubMed

20.

Irizarry RA, Hobbs B, Collin F et al (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4(2):249–264. doi:10.1093/biostatistics/4.2.249 CrossRefPubMed

21.

Handle Illumina methylation data. R package

22.

1000 Genomes Project Consortium, Abecasis GR, Auton A et al (2012) An integrated map of genetic variation from 1092 human genomes. Nature 491(7422):56–65. doi:10.1038/nature11632 CrossRef

23.

Price ME, Cotton AM, Lam LL et al. (2013) Additional annotation enhances potential for biologically-relevant analysis of the Illumina Infinium HumanMethylation450 BeadChip array. Epigenetics Chromatin. 6(1):4,8935-6-4. doi: 10.1186/1756-8935-6-4

24.

Xu Z, Taylor JA (2014) Genome-wide age-related DNA methylation changes in blood and other tissues relate to histone modification, expression and cancer. Carcinogenesis 35(2):356–364. doi:10.1093/carcin/bgt391 CrossRefPubMedCentralPubMed

25.

Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci USA 100(16):9440–9445. doi:10.1073/pnas.1530509100 CrossRefPubMedCentralPubMed

26.

NCBI News, September (2009) Bethesda (MD), National Center for Biotechnology Information (US), 2009

27.

Wu MC, Lin X (2009) Prior biological knowledge-based approaches for the analysis of genome-wide expression profiles using gene sets and pathways. Stat Methods Med Res 18(6):577–593. doi:10.1177/0962280209351925 CrossRefPubMedCentralPubMed

28.

Creighton CJ, Sada YH, Zhang Y et al (2011) A gene transcription signature of obesity in breast cancer. Breast Cancer Res Treat. doi:10.1007/s10549-011-1595-y PubMedCentral

29.

Saxonov S, Berg P, Brutlag DL (2006) A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc Natl Acad Sci USA 103(5):1412–1417CrossRefPubMedCentralPubMed

30.

Price ME, Cotton AM, Lam LL, et al (2013) Additional annotation enhances potential for biologically-relevant analysis of the Illumina Infinium HumanMethylation450 BeadChip array. Epigenet Chromatin 6(1):4,8935-6-4. doi: 10.1186/1756-8935-6-4

31.

Irizarry RA, Ladd-Acosta C, Wen B et al (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41(2):178–186. doi:10.1038/ng.298 CrossRefPubMedCentralPubMed

32.

Robertson KD (2001) DNA methylation, methyltransferases, and cancer. Oncogene 20(24):3139–3155. doi:10.1038/sj.onc.1204341 CrossRefPubMed

33.

Fantuzzi G (2005) Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 115(5):911–920. doi:10.1016/j.jaci.2005.02.023 CrossRefPubMed

34.

Antuna-Puente B, Feve B, Fellahi S et al (2008) Adipokines: the missing link between insulin resistance and obesity. Diabetes Metab 34(1):2–11. doi:10.1016/j.diabet.2007.09.004 CrossRefPubMed

35.

Knupfer H, Preiss R (2007) Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res Treat 102(2):129–135. doi:10.1007/s10549-006-9328-3 CrossRefPubMed

36.

Mantovani A, Marchesi F, Porta C et al (2007) Inflammation and cancer: breast cancer as a prototype. Breast 16(Suppl 2):S27–S33. doi:10.1016/j.breast.2007.07.013 CrossRefPubMed

37.

Sundaram S, Freemerman AJ, Johnson AR et al (2013) Role of HGF in obesity-associated tumorigenesis: C3(1)-TAg mice as a model for human basal-like breast cancer. Breast Cancer Res Treat 142(3):489–503. doi:10.1007/s10549-013-2741-5 CrossRefPubMedCentralPubMed

38.

Singh A, Purohit A, Ghilchik MW et al (1999) The regulation of aromatase activity in breast fibroblasts: the role of interleukin-6 and prostaglandin E2. Endocr Relat Cancer 6(2):139–147CrossRefPubMed

39.

Zhao Y, Nichols JE, Valdez R et al (1996) Tumor necrosis factor-alpha stimulates aromatase gene expression in human adipose stromal cells through use of an activating protein-1 binding site upstream of promoter 1.4. Mol Endocrinol 10(11):1350–1357PubMed

40.

Kitawaki J, Kusuki I, Koshiba H et al (1999) Leptin directly stimulates aromatase activity in human luteinized granulosa cells. Mol Hum Reprod 5(8):708–713CrossRefPubMed

41.

Magoffin DA, Weitsman SR, Aagarwal SK et al (1999) Leptin regulation of aromatase activity in adipose stromal cells from regularly cycling women. Ginekol Pol 70(1):1–7PubMed

42.

Renehan AG, Frystyk J, Flyvbjerg A (2006) Obesity and cancer risk: the role of the insulin-IGF axis. Trends Endocrinol Metab 17(8):328–336. doi:10.1016/j.tem.2006.08.006 CrossRefPubMed

43.

Casbas-Hernandez P, D’Arcy M, Roman-Perez E et al (2013) Role of HGF in epithelial-stromal cell interactions during progression from benign breast disease to ductal carcinoma in situ. Breast Cancer Res 15(5):R82CrossRefPubMedCentralPubMed

44.

Di LJ, Byun JS, Wong MM et al (2013) Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer. Nat Commun 4:1449. doi:10.1038/ncomms2438 CrossRefPubMedCentralPubMed

45.

Byun JS, Gardner K (2013) C-terminal binding protein: a molecular link between metabolic imbalance and epigenetic regulation in breast cancer. Int J Cell Biol 2013:647975. doi:10.1155/2013/647975 CrossRefPubMedCentralPubMed

46.

Tao MH, Marian C, Nie J et al (2011) Body mass and DNA promoter methylation in breast tumors in the Western New York Exposures and Breast Cancer Study. Am J Clin Nutr 94(3):831–838. doi:10.3945/ajcn.110.009365 CrossRefPubMedCentralPubMed

47.

Dumitrescu RG, Marian C, Krishnan SS et al (2010) Familial and racial determinants of tumour suppressor genes promoter hypermethylation in breast tissues from healthy women. J Cell Mol Med 14(6B):1468–1475. doi:10.1111/j.1582-4934.2009.00924.x CrossRefPubMedCentralPubMed

48.

Choi JD, Lee JS (2013) Interplay between epigenetics and genetics in cancer. Genomics Inform 11(4):164–173. doi:10.5808/GI.2013.11.4.164 CrossRefPubMedCentralPubMed

49.

Trujillo KA, Heaphy CM, Mai M et al (2011) Markers of fibrosis and epithelial to mesenchymal transition demonstrate field cancerization in histologically normal tissue adjacent to breast tumors. Int J Cancer 129(6):1310–1321. doi:10.1002/ijc.25788 CrossRefPubMedCentralPubMed

50.

Heaphy CM, Bisoffi M, Fordyce CA et al (2006) Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumors. Int J Cancer 119(1):108–116. doi:10.1002/ijc.21815 CrossRefPubMed

51.

Heaphy CM, Griffith JK, Bisoffi M (2009) Mammary field cancerization: molecular evidence and clinical importance. Breast Cancer Res Treat 118(2):229–239. doi:10.1007/s10549-009-0504-0 CrossRefPubMed

Title: Body mass index associated with genome-wide methylation in breast tissue
Authors: Brionna Y. Hair
Zongli Xu
Erin L. Kirk
Sophia Harlid
Rupninder Sandhu
Whitney R. Robinson
Michael C. Wu
Andrew F. Olshan
Kathleen Conway
Jack A. Taylor
Melissa A. Troester
Publication date: 01-06-2015
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2015
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-015-3401-8

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