The signature of liver cancer in immune cells DNA methylation

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Abstract

Background

The idea that changes to the host immune system are critical for cancer progression was proposed a century ago and recently regained experimental support.

Results

Herein, the hypothesis that hepatocellular carcinoma (HCC) leaves a molecular signature in the host peripheral immune system was tested by profiling DNA methylation in peripheral blood mononuclear cells (PBMC) and T cells from a discovery cohort ( n = 69) of healthy controls, chronic hepatitis, and HCC using Illumina 450K platform and was validated in two validation sets ( n = 80 and n = 48) using pyrosequencing.

Conclusions

The study reveals a broad signature of hepatocellular carcinoma in PBMC and T cells DNA methylation which discriminates early HCC stage from chronic hepatitis B and C and healthy controls, intensifies with progression of HCC, and is highly enriched in immune function-related genes such as PD-1, a current cancer immunotherapy target. These data also support the feasibility of using these profiles for early detection of HCC.

Electronic supplementary material

The online version of this article (10.1186/s13148-017-0436-1) contains supplementary material, which is available to authorized users.

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Most cited references 33

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Effector memory T cells, early metastasis, and survival in colorectal cancer.

Franck Pagès, Anne Berger, Matthieu Camus … (2005)

The role of tumor-infiltrating immune cells in the early metastatic invasion of colorectal cancer is unknown. We studied pathological signs of early metastatic invasion (venous emboli and lymphatic and perineural invasion) in 959 specimens of resected colorectal cancer. The local immune response within the tumor was studied by flow cytometry (39 tumors), low-density-array real-time polymerase-chain-reaction assay (75 tumors), and tissue microarrays (415 tumors). Univariate analysis showed significant differences in disease-free and overall survival according to the presence or absence of histologic signs of early metastatic invasion (P<0.001). Multivariate Cox analysis showed that an early conventional pathological tumor-node-metastasis stage (P<0.001) and the absence of early metastatic invasion (P=0.04) were independently associated with increased survival. As compared with tumors with signs of early metastatic invasion, tumors without such signs had increased infiltrates of immune cells and increased levels of messenger RNA (mRNA) for products of type 1 helper effector T cells (CD8, T-BET [T-box transcription factor 21], interferon regulatory factor 1, interferon-gamma, granulysin, and granzyme B) but not increased levels of inflammatory mediators or immunosuppressive molecules. The two types of tumors had significant differences in the levels of expression of 65 combinations of T-cell markers, and hierarchical clustering showed that markers of T-cell migration, activation, and differentiation were increased in tumors without signs of early metastatic invasion. The latter type of tumors also had increased numbers of CD8+ T cells, ranging from early memory (CD45RO+CCR7-CD28+CD27+) to effector memory (CD45RO+CCR7-CD28-CD27-) T cells. The presence of high levels of infiltrating memory CD45RO+ cells, evaluated immunohistochemically, correlated with the absence of signs of early metastatic invasion, a less advanced pathological stage, and increased survival. Signs of an immune response within colorectal cancers are associated with the absence of pathological evidence of early metastatic invasion and with prolonged survival. Copyright 2005 Massachusetts Medical Society.

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Stromal gene expression predicts clinical outcome in breast cancer.

Greg Finak, Nicholas Bertos, François Pépin … (2008)

Although it is increasingly evident that cancer is influenced by signals emanating from tumor stroma, little is known regarding how changes in stromal gene expression affect epithelial tumor progression. We used laser capture microdissection to compare gene expression profiles of tumor stroma from 53 primary breast tumors and derived signatures strongly associated with clinical outcome. We present a new stroma-derived prognostic predictor (SDPP) that stratifies disease outcome independently of standard clinical prognostic factors and published expression-based predictors. The SDPP predicts outcome in several published whole tumor-derived expression data sets, identifies poor-outcome individuals from multiple clinical subtypes, including lymph node-negative tumors, and shows increased accuracy with respect to previously published predictors, especially for HER2-positive tumors. Prognostic power increases substantially when the predictor is combined with existing outcome predictors. Genes represented in the SDPP reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumor progression.

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Models, mechanisms and clinical evidence for cancer dormancy.

Julio Aguirre-Ghiso (2007)

Patients with cancer can develop recurrent metastatic disease with latency periods that range from years even to decades. This pause can be explained by cancer dormancy, a stage in cancer progression in which residual disease is present but remains asymptomatic. Cancer dormancy is poorly understood, resulting in major shortcomings in our understanding of the full complexity of the disease. Here, I review experimental and clinical evidence that supports the existence of various mechanisms of cancer dormancy including angiogenic dormancy, cellular dormancy (G0-G1 arrest) and immunosurveillance. The advances in this field provide an emerging picture of how cancer dormancy can ensue and how it could be therapeutically targeted.

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Author and article information

Contributors

Yonghong Zhang: 13810108505@163.com

Sophie Petropoulos: sophie.petropoulos@gmail.com

Jinhua Liu: ljhgy@163.com

David Cheishvili: david.cheishvili@epiterapia.com

Rudy Zhou: zhourudy2@gmail.com

Sergiy Dymov: sergiy.dymov@mcgill.ca

Kang Li: bjyahlk@163.com

Ning Li: liningbjyah@vip.sina.com

Moshe Szyf:

ORCID: http://orcid.org/0000-0003-3881-8214

(514) 398-7107 , moshe.szyf@mcgill.ca

Journal

Journal ID (nlm-ta): Clin Epigenetics

Journal ID (iso-abbrev): Clin Epigenetics

Title: Clinical Epigenetics

Publisher: BioMed Central (London )

ISSN (Print): 1868-7075

ISSN (Electronic): 1868-7083

Publication date (Electronic): 18 January 2018

Publication date PMC-release: 18 January 2018

Publication date Collection: 2018

Volume: 10

Electronic Location Identifier: 8

Affiliations

[1 ]GRID grid.414379.c, Beijing Youan Hospital, Capital Medical School, ; Beijing, China

[2 ]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Department of Pharmacology and Therapeutics, , McGill University, ; 3655 Sir William Osler Promenade, Montreal, Quebec H3G 1Y6 Canada

[3 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Deparment of Clinical Science, , Karolinska Institutet, ; Alfred Nobels Allé 8, 141 52 Huddinge, Sweden

[4 ]Montreal EpiTerapia Inc., 4567 Cecile, H9K1N2, Montreal, QC Canada

Author information

Moshe Szyf http://orcid.org/0000-0003-3881-8214

Article

Publisher ID: 436

DOI: 10.1186/s13148-017-0436-1

PMC ID: 5774119

PubMed ID: 29312470

SO-VID: 013e6af0-b3d6-456c-96a2-ddc6c4ffe8d9

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 12 May 2017

Date accepted : 15 December 2017

Funding

Funded by: the ministère de l’Enseignement supérieur, de la Recherche, de la Science et de la Technologie (MESRST) of the government of Quebec

Award ID: (2012DFA30850)

Award Recipient : Moshe Szyf

Funded by: Beijing Municipal Science & Technology Commission

Award ID: (D131100005313004, D131100005313005)

Award Recipient : Ning Li

Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;

Award ID: MOP-42411

Award Recipient : Moshe Szyf

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: dna methylation,hepatocellular carcinoma,peripheral white blood cells,immune functions

Data availability:

ScienceOpen disciplines: Genetics

Keywords: dna methylation, hepatocellular carcinoma, peripheral white blood cells, immune functions

The signature of liver cancer in immune cells DNA methylation

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Karger: Oncology

Most cited references 33

Effector memory T cells, early metastasis, and survival in colorectal cancer.

Stromal gene expression predicts clinical outcome in breast cancer.

Models, mechanisms and clinical evidence for cancer dormancy.

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