Top

Published in:

Open Access 01-12-2018 | Research article

DNA methylation signatures of breast cancer in peripheral T-cells

Authors: Surabhi Parashar, David Cheishvili, Niaz Mahmood, Ani Arakelian, Imrana Tanvir, Haseeb Ahmed Khan, Richard Kremer, Catalin Mihalcioiu, Moshe Szyf, Shafaat A. Rabbani

Published in: BMC Cancer | Issue 1/2018

Abstract

Background

Immune surveillance acts as a defense mechanism in cancer, and its disruption is involved in cancer progression. DNA methylation reflects the phenotypic identity of cells and recent data suggested that DNA methylation profiles of T cells and peripheral blood mononuclear cells (PBMC) are altered in cancer progression.

Methods

We enrolled 19 females with stage 1 and 2, nine with stage 3 and 4 and 9 age matched healthy women. T cells were isolated from peripheral blood and extracted DNA was subjected to Illumina 450 K DNA methylation array analysis. Raw data was analyzed by BMIQ, ChAMP and ComBat followed by validation of identified genes by pyrosequencing.

Results

Analysis of data revealed ~ 10,000 sites that correlated with breast cancer progression and established a list of 89 CG sites that were highly correlated (p < 0.01, r > 0.7, r < − 0.7) with breast cancer progression. The vast majority of these sites were hypomethylated and enriched in genes with functions in the immune system.

Conclusions

The study points to the possibility of using DNA methylation signatures as a noninvasive method for early detection of breast cancer and its progression which need to be tested in clinical studies.

Available only for authorised users

Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359-E86.CrossRef

Jones HB. On a new substance occurring in the urine of a petient with mollities ossium. Phil Trans R Soc Lond. 1848;138:55-62.

Ehrlich P. Über den jetzigen Stand der Karzinomforschung. Onderzoek; 1909.

Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450–61.CrossRefPubMedPubMedCentral

Burnet M. Cancer - a biological approach .1. The processes of control. Br Med J. 1957;1:779–86.CrossRefPubMedPubMedCentral

Gubin MM, et al. Tumor neoantigens: building a framework for personalized cancer immunotherapy. J Clin Invest. 2015;125(9):3413–21.CrossRefPubMedPubMedCentral

Jr PK, Otahal P, Klener P. Immunotherapy Approaches in Cancer Treatment. Curr Pharm Biotechnol. 2015;16(9):771-81.

Flanagan JM, et al. Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients. Hum Mol Genet. 2009;18(7):1332–42.CrossRefPubMedPubMedCentral

Chik F, Szyf M, Rabbani SA. Role of epigenetics in cancer initiation and progression. Adv Exp Med Biol. 2011;720:91–104.CrossRefPubMed

10.

Breiling A, Lyko F. Epigenetic regulatory functions of DNA modifications: 5-methylcytosine and beyond. Epigenetics Chromatin. 2015;8:24.CrossRefPubMedPubMedCentral

11.

Paska AV, Hudler P. Aberrant methylation patterns in cancer: a clinical view. Biochem Med (Zagreb). 2015;25(2):161–76.CrossRef

12.

Zauri M, et al. CDA directs metabolism of epigenetic nucleosides revealing a therapeutic window in cancer. Nature. 2015;524:114-118.

13.

Koestler DC, et al. Peripheral blood immune cell methylation profiles are associated with nonhematopoietic cancers. Cancer Epidemiol Biomark Prev. 2012;21(8):1293–302.CrossRef

14.

Fridley BL, et al. Methylation of leukocyte DNA and ovarian cancer: relationships with disease status and outcome. BMC Med Genet. 2014;7:21.

15.

Huang WY, et al. Prospective study of genomic hypomethylation of leukocyte DNA and colorectal cancer risk. Cancer Epidemiol Biomark Prev. 2012;21(11):2014–21.CrossRef

16.

Kao WY, et al. Genome-wide identification of blood DNA methylation patterns associated with early-onset hepatocellular carcinoma development in hepatitis B carriers. Mol Carcinog. 2016;56(2):425-435.

17.

Teschendorff AE, et al. A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics. 2013;29(2):189–96.CrossRefPubMed

18.

Morris TJ, et al. ChAMP: 450k chip analysis methylation pipeline. Bioinformatics. 2014;30(3):428–30.CrossRefPubMed

19.

Johnson WE, Li C, Rabinovic A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2007;8(1):118–27.CrossRefPubMed

20.

Nordlund J, et al. Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia. Genome Biol. 2013;14(9):r105.CrossRefPubMedPubMedCentral

21.

Györffy B, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123(3):725–31.CrossRefPubMed

22.

Bibikova M, et al. High density DNA methylation array with single CpG site resolution. Genomics. 2011;98(4):288–95.CrossRefPubMed

23.

Fernandez-Jimenez N, Sklias A, Ecsedi S, Cahais V, Degli-Esposti D, Jay A, Ancey PB, Woo HD, Hernandez-Vargas H, Herceg Z. Lowly methylated region analysis identifies EBF1 as a potential epigenetic modifier in breast cancer. Epigenetics. 2017:1–9. https://doi.org/10.1080/15592294.2017.1373919. [Epub ahead of print]

24.

Smyth GK. Limma: linear models for microarray data. In: Gentleman VCR, Dudoit S, Irizarry R, Huber W, editors. Bioinformatics and computational biology solutions using R and Bioconductor. New York: Springer; 2005. p. 397–420.CrossRef

25.

Vainio H, Bianchini F. IARC handbooks of cancer prevention. Iarc.Lyon, France. vol. 7: Iarc; 2002.

26.

Sawyers CL. The cancer biomarker problem. Nature. 2008;452(7187):548.CrossRefPubMed

27.

Bonini C, Mondino A. Adoptive T-cell therapy for cancer: the era of engineered T cells. Eur J Immunol. 2015;45(9):2457-2469.

28.

Sagiv-Barfi I, et al. Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Nat Acad Sci USA. 2015;112(9):E966–72.CrossRefPubMedPubMedCentral

29.

Dedeurwaerder S, et al. DNA methylation profiling reveals a predominant immune component in breast cancers. EMBO Mol Med. 2011;3(12):726–41.CrossRefPubMedPubMedCentral

30.

Nestor CE, Barrenäs F, Wang H, Lentini A, Zhang H, Bruhn S, Jörnsten R, Langston MA, Rogers G, Gustafsson M, Benson M. DNA methylation changes separate allergic patients from healthy controls and may reflect altered CD4+ T-cell population structure. PLoS Genet. 2014 Jan;10(1):e1004059.CrossRefPubMedPubMedCentral

31.

Chavez-Valencia RA, Chiaroni-Clarke RC, Martino DJ, Munro JE, Allen RC, Akikusa JD, Ponsonby AL, Craig JM, Saffery R, Ellis JA. The DNA methylation landscape of CD4+ T cells in oligoarticular juvenile idiopathic arthritis. J Autoimmun. 2017; https://doi.org/10.1016/j.jaut.2017.09.010. [Epub ahead of print].

32.

Shukeir N, et al. Pharmacological methyl group donors block skeletal metastasis in vitro and in vivo. Br J Pharmacol. 2015;172(11):2769–81.CrossRefPubMedPubMedCentral

33.

Parashar S, et al. S-adenosylmethionine blocks osteosarcoma cells proliferation and invasion in vitro and tumor metastasis in vivo: therapeutic and diagnostic clinical applications. Cancer Med. 2015;4(5):732–44.CrossRefPubMedPubMedCentral

34.

Stefanska B, et al. Genome-wide study of hypomethylated and induced genes in patients with liver cancer unravels novel anticancer targets. Clin Cancer Res. 2014;20(12):3118–32.CrossRefPubMed

35.

Shukeir N, et al. Alteration of the methylation status of tumor-promoting genes decreases prostate cancer cell invasiveness and tumorigenesis in vitro and in vivo. Cancer Res. 2006;66(18):9202–10.CrossRefPubMed

36.

Anjum S, et al. A BRCA1-mutation associated DNA methylation signature in blood cells predicts sporadic breast cancer incidence and survival. Genome Med. 2014;6(6):47.CrossRefPubMedPubMedCentral

37.

Xu Z, et al. Epigenome-wide association study of breast cancer using prospectively collected sister study samples. J Natl Cancer Inst. 2013;105(10):694–700.CrossRefPubMedPubMedCentral

38.

Severi G, et al. Epigenome-wide methylation in DNA from peripheral blood as a marker of risk for breast cancer. Breast Cancer Res Treat. 2014;148(3):665–73.CrossRefPubMed

39.

Shenker NS, et al. Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking. Hum Mol Genet. 2013;22(5):843–51.CrossRefPubMed

40.

van Veldhoven K, et al. Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis. Clin Epigenetics. 2015;7:67.CrossRefPubMedPubMedCentral

41.

Ambatipudi S, et al. DNA methylome analysis identifies accelerated epigenetic ageing associated with postmenopausal breast cancer susceptibility. Eur J Cancer. 2017;75:299–307.CrossRefPubMedPubMedCentral

42.

Conway K, Edmiston SN, Parrish E, Bryant C, Tse CK, Swift-Scanlan T, McCullough LE, Kuan PF. Breast tumor DNA methylation patterns associated with smoking in the Carolina Breast Cancer Study. Breast Cancer Res Treat. 2017;163(2):349–61.CrossRefPubMedPubMedCentral

Title: DNA methylation signatures of breast cancer in peripheral T-cells
Authors: Surabhi Parashar
David Cheishvili
Niaz Mahmood
Ani Arakelian
Imrana Tanvir
Haseeb Ahmed Khan
Richard Kremer
Catalin Mihalcioiu
Moshe Szyf
Shafaat A. Rabbani
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-018-4482-7

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2018

Study on safety of laparoscopic total gastrectomy for clinical stage I gastric cancer: the protocol of the CLASS02–01 multicenter randomized controlled clinical trial

Evaluation of Endoglin (CD105) expression in pediatric rhabdomyosarcoma

Limb saving surgery for Ewing’s sarcoma of the distal tibia: a case report

Compressed collagen and decellularized tissue – novel components in a pipeline approach for the study of cancer metastasis

Second primary colorectal cancer after the initial primary colorectal cancer

Risk factors for paclitaxel-induced peripheral neuropathy in patients with breast cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer