Normal breast tissue DNA methylation differences at regulatory elements are associated with the cancer risk factor age

被引:47
作者
Johnson, Kevin C. [1 ,2 ,3 ]
Houseman, E. Andres [4 ]
King, Jessica E. [1 ,2 ]
Christensen, Brock C. [1 ,2 ,5 ]
机构
[1] Geisel Sch Med Dartmouth, Dept Epidemiol, Lebanon, NH 03756 USA
[2] Geisel Sch Med Dartmouth, Dept Mol & Syst Biol, Lebanon, NH 03756 USA
[3] Jackson Lab Genom Med, Farmington, CT 06032 USA
[4] Oregon State Univ, Coll Publ Hlth & Human Sci, Dept Biostat, Corvallis, OR 97331 USA
[5] Geisel Sch Med Dartmouth, Dept Community & Family Med, Lebanon, NH 03756 USA
基金
美国国家卫生研究院;
关键词
Normal breast; DNA methylation; Aging; 5mC; Risk factors; Reference-free; Breast cancer; Epigenetics; Epigenetic drift; IN-SITU; DECONVOLUTION; PROPORTION; EPITHELIUM; CARCINOMA; OBESITY;
D O I
10.1186/s13058-017-0873-y
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: The underlying biological mechanisms through which epidemiologically defined breast cancer risk factors contribute to disease risk remain poorly understood. Identification of the molecular changes associated with cancer risk factors in normal tissues may aid in determining the earliest events of carcinogenesis and informing cancer prevention strategies. Methods: Here we investigated the impact cancer risk factors have on the normal breast epigenome by analyzing DNA methylation genome-wide (Infinium 450 K array) in cancer-free women from the Susan G. Komen Tissue Bank (n = 100). We tested the relation of established breast cancer risk factors, age, body mass index, parity, and family history of disease, with DNA methylation adjusting for potential variation in cell-type proportions. Results: We identified 787 cytosine-guanine dinucleotide (CpG) sites that demonstrated significant associations (Q value <0.01) with subject age. Notably, DNA methylation was not strongly associated with the other evaluated breast cancer risk factors. Age-related DNA methylation changes are primarily increases in methylation enriched at breast epithelial cell enhancer regions (P = 7.1E-20), and binding sites of chromatin remodelers (MYC and CTCF). We validated the age-related associations in two independent populations, using normal breast tissue samples (n = 18) and samples of normal tissue adjacent to tumor tissue (n = 97). The genomic regions classified as age-related were more likely to be regions altered in both pre-invasive (n = 40, P = 3.0E-03) and invasive breast tumors (n = 731, P = 1.1E-13). Conclusions: DNA methylation changes with age occur at regulatory regions, and are further exacerbated in cancer, suggesting that age influences breast cancer risk in part through its contribution to epigenetic dysregulation in normal breast tissue.
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页数:11
相关论文
共 42 条
[1]   Adiposity is associated with DNA methylation profile in adipose tissue [J].
Agha, Golareh ;
Houseman, E. Andres ;
Kelsey, Karl T. ;
Eaton, Charles B. ;
Buka, Stephen L. ;
Loucks, Eric B. .
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, 2015, 44 (04) :1277-1287
[2]  
Assenov Y, 2014, NAT METHODS, V11, P1138, DOI [10.1038/NMETH.3115, 10.1038/nmeth.3115]
[3]   Alcohol, tobacco and breast cancer -: collaborative reanalysis of individual data from 53 epidemiological studies, including 58515 women with breast cancer and 95067 women without the disease [J].
Beral, V ;
Hamajima, N ;
Hirose, K ;
Rohan, T ;
Calle, EE ;
Heath, CW ;
Coates, RJ ;
Liff, JM ;
Talamini, R ;
Chantarakul, N ;
Koetsawang, S ;
Rachawat, D ;
Morabia, A ;
Schuman, L ;
Stewart, W ;
Szklo, M ;
Bain, C ;
Schofield, F ;
Siskind, V ;
Band, P ;
Coldman, AJ ;
Gallagher, RP ;
Hislop, TG ;
Yang, P ;
Kolonel, LM ;
Nomura, AMY ;
Hu, J ;
Johnson, KC ;
Mao, Y ;
De Sanjose, S ;
Lee, N ;
Marchbanks, P ;
Ory, HW ;
Peterson, HB ;
Wilson, HG ;
Wingo, PA ;
Ebeling, K ;
Kunde, D ;
Nishan, P ;
Hopper, JL ;
Colditz, G ;
Gajalakshmi, V ;
Martin, N ;
Pardthaisong, T ;
Solpisornkosol, S ;
Theetranont, C ;
Boosiri, B ;
Chutivongse, S ;
Jimakorn, P ;
Virutamasen, P .
BRITISH JOURNAL OF CANCER, 2002, 87 (11) :1234-1245
[4]   eFORGE: A Tool for Identifying Cell Type-Specific Signal in Epigenomic Data [J].
Breeze, Charles E. ;
Paul, Dirk S. ;
van Dongen, Jenny ;
Butcher, Lee M. ;
Ambrose, John C. ;
Barrett, James E. ;
Lowe, Robert ;
Rakyan, Vardhman K. ;
Iotchkova, Valentina ;
Frontini, Mattia ;
Downes, Kate ;
Ouwehand, Willem H. ;
Laperle, Jonathan ;
Jacques, Pierre-ETienne ;
Bourque, Guillaume ;
Bergmann, Anke K. ;
Siebert, Reiner ;
Vellenga, Edo ;
Saeed, Sadia ;
Matarese, Filomena ;
Martens, Joost H. A. ;
Stunnenberg, Hendrik G. ;
Teschendorff, Andrew E. ;
Herrero, Javier ;
Birney, Ewan ;
Dunham, Ian ;
Beck, Stephan .
CELL REPORTS, 2016, 17 (08) :2137-2150
[5]   Obesity and breast cancer: a review of the literature [J].
Carmichael, AR ;
Bates, T .
BREAST, 2004, 13 (02) :85-92
[6]   Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray [J].
Chen, Yi-an ;
Lemire, Mathieu ;
Choufani, Sanaa ;
Butcher, Darci T. ;
Grafodatskaya, Daria ;
Zanke, Brent W. ;
Gallinger, Steven ;
Hudson, Thomas J. ;
Weksberg, Rosanna .
EPIGENETICS, 2013, 8 (02) :203-209
[7]   Breast Cancer DNA Methylation Profiles Are Associated with Tumor Size and Alcohol and Folate Intake [J].
Christensen, Brock C. ;
Kelsey, Karl T. ;
Zheng, Shichun ;
Houseman, E. Andres ;
Marsit, Carmen J. ;
Wrensch, Margaret R. ;
Wiemels, Joseph L. ;
Nelson, Heather H. ;
Karagas, Margaret R. ;
Kushi, Lawrence H. ;
Kwan, Marilyn L. ;
Wiencke, John K. .
PLOS GENETICS, 2010, 6 (07) :1-10
[8]   Aging and Environmental Exposures Alter Tissue-Specific DNA Methylation Dependent upon CpG Island Context [J].
Christensen, Brock C. ;
Houseman, E. Andres ;
Marsit, Carmen J. ;
Zheng, Shichun ;
Wrensch, Margaret R. ;
Wiemels, Joseph L. ;
Nelson, Heather H. ;
Karagas, Margaret R. ;
Padbury, James F. ;
Bueno, Raphael ;
Sugarbaker, David J. ;
Yeh, Ru-Fang ;
Wiencke, John K. ;
Kelsey, Karl T. .
PLOS GENETICS, 2009, 5 (08)
[9]   STAT3 as a target for cancer drug discovery [J].
Costantino, Luca ;
Barlocco, Daniela .
CURRENT MEDICINAL CHEMISTRY, 2008, 15 (09) :834-843
[10]   DNA methylation in benign breast epithelium in relation to age and breast cancer risk [J].
Euhus, David M. ;
Bu, Dawei ;
Milchgrub, Sara ;
Xie, Xian-Jin ;
Bian, Aihua ;
Leitch, A. Marilyn ;
Lewis, Cheryl M. .
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 2008, 17 (05) :1051-1059