Initiation of aberrant DNA methylation patterns and heterogeneity in precancerous lesions of human hepatocellular cancer

Ryan A. Hlady, Dan Zhou, William Puszyk, Lewis Rowland Roberts, Chen Liu, Keith D Robertson

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

While intratumor heterogeneity contributes to disease progression, metastasis, and resistance to chemotherapy, it also provides a route to understanding the evolution and drivers of disease. Defects in epigenetic landscapes are intimately linked to pathogenesis of a variety of human diseases, with epigenetic deregulation promoting tumorigenesis. Understanding epigenetic heterogeneity is crucial in hepatocellular carcinoma (HCC), where epigenetic alterations are frequent, early, and pathogenic events. We determined genome-wide DNA methylation and copy number variation leveraging the Infinium 450K in a series of regenerative nodules from within single patient livers. Bioinformatics strategies were used to ascertain within-patient heterogeneity, link epigenetic changes to clinical features, and determine their relevance to disease pathogenesis. Our data demonstrate that DNA methylation and copy number alterations evolve during the pre-neoplastic phase of HCC and independently segregate regenerative nodules into distinct clusters. Regenerative nodules with a high frequency of epigenetic changes have significantly lower copy number variation, suggesting that individual nodules have differential enrichment of epigenetic and genetic components, with both contributing to disease progression. Regenerative nodules were scored based on ‘epigenetic progression’ with higher scores associated with increased proliferation measured by Ki67 staining. Early events observed in epigenetically ‘aggressive’ nodules are enriched for genes involved in liver cancer. Our study demonstrates that marked epigenetic and genetic heterogeneity exists in early pre-neoplastic liver tissue within individual patients, emphasizing the potential contributions of each mechanism to driving liver disease progression, and it unveils strategies for identifying epigenetic drivers of hepatocellular carcinoma.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalEpigenetics
DOIs
StateAccepted/In press - Jan 27 2017

Fingerprint

DNA Methylation
Liver Neoplasms
Epigenomics
Disease Progression
Hepatocellular Carcinoma
DNA Copy Number Variations
Disease Resistance
Genetic Heterogeneity
Liver
Computational Biology
Liver Diseases
Carcinogenesis
Genome
Staining and Labeling
Neoplasm Metastasis
Drug Therapy

Keywords

  • copy number variation
  • DNA methylation
  • early changes
  • hepatocellular cancer
  • heterogeneity

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Initiation of aberrant DNA methylation patterns and heterogeneity in precancerous lesions of human hepatocellular cancer. / Hlady, Ryan A.; Zhou, Dan; Puszyk, William; Roberts, Lewis Rowland; Liu, Chen; Robertson, Keith D.

In: Epigenetics, 27.01.2017, p. 1-11.

Research output: Contribution to journalArticle

@article{edb73d75ed724451aa14a56670d59e42,
title = "Initiation of aberrant DNA methylation patterns and heterogeneity in precancerous lesions of human hepatocellular cancer",
abstract = "While intratumor heterogeneity contributes to disease progression, metastasis, and resistance to chemotherapy, it also provides a route to understanding the evolution and drivers of disease. Defects in epigenetic landscapes are intimately linked to pathogenesis of a variety of human diseases, with epigenetic deregulation promoting tumorigenesis. Understanding epigenetic heterogeneity is crucial in hepatocellular carcinoma (HCC), where epigenetic alterations are frequent, early, and pathogenic events. We determined genome-wide DNA methylation and copy number variation leveraging the Infinium 450K in a series of regenerative nodules from within single patient livers. Bioinformatics strategies were used to ascertain within-patient heterogeneity, link epigenetic changes to clinical features, and determine their relevance to disease pathogenesis. Our data demonstrate that DNA methylation and copy number alterations evolve during the pre-neoplastic phase of HCC and independently segregate regenerative nodules into distinct clusters. Regenerative nodules with a high frequency of epigenetic changes have significantly lower copy number variation, suggesting that individual nodules have differential enrichment of epigenetic and genetic components, with both contributing to disease progression. Regenerative nodules were scored based on ‘epigenetic progression’ with higher scores associated with increased proliferation measured by Ki67 staining. Early events observed in epigenetically ‘aggressive’ nodules are enriched for genes involved in liver cancer. Our study demonstrates that marked epigenetic and genetic heterogeneity exists in early pre-neoplastic liver tissue within individual patients, emphasizing the potential contributions of each mechanism to driving liver disease progression, and it unveils strategies for identifying epigenetic drivers of hepatocellular carcinoma.",
keywords = "copy number variation, DNA methylation, early changes, hepatocellular cancer, heterogeneity",
author = "Hlady, {Ryan A.} and Dan Zhou and William Puszyk and Roberts, {Lewis Rowland} and Chen Liu and Robertson, {Keith D}",
year = "2017",
month = "1",
day = "27",
doi = "10.1080/15592294.2016.1277297",
language = "English (US)",
pages = "1--11",
journal = "Epigenetics",
issn = "1559-2294",
publisher = "Landes Bioscience",

}

TY - JOUR

T1 - Initiation of aberrant DNA methylation patterns and heterogeneity in precancerous lesions of human hepatocellular cancer

AU - Hlady, Ryan A.

AU - Zhou, Dan

AU - Puszyk, William

AU - Roberts, Lewis Rowland

AU - Liu, Chen

AU - Robertson, Keith D

PY - 2017/1/27

Y1 - 2017/1/27

N2 - While intratumor heterogeneity contributes to disease progression, metastasis, and resistance to chemotherapy, it also provides a route to understanding the evolution and drivers of disease. Defects in epigenetic landscapes are intimately linked to pathogenesis of a variety of human diseases, with epigenetic deregulation promoting tumorigenesis. Understanding epigenetic heterogeneity is crucial in hepatocellular carcinoma (HCC), where epigenetic alterations are frequent, early, and pathogenic events. We determined genome-wide DNA methylation and copy number variation leveraging the Infinium 450K in a series of regenerative nodules from within single patient livers. Bioinformatics strategies were used to ascertain within-patient heterogeneity, link epigenetic changes to clinical features, and determine their relevance to disease pathogenesis. Our data demonstrate that DNA methylation and copy number alterations evolve during the pre-neoplastic phase of HCC and independently segregate regenerative nodules into distinct clusters. Regenerative nodules with a high frequency of epigenetic changes have significantly lower copy number variation, suggesting that individual nodules have differential enrichment of epigenetic and genetic components, with both contributing to disease progression. Regenerative nodules were scored based on ‘epigenetic progression’ with higher scores associated with increased proliferation measured by Ki67 staining. Early events observed in epigenetically ‘aggressive’ nodules are enriched for genes involved in liver cancer. Our study demonstrates that marked epigenetic and genetic heterogeneity exists in early pre-neoplastic liver tissue within individual patients, emphasizing the potential contributions of each mechanism to driving liver disease progression, and it unveils strategies for identifying epigenetic drivers of hepatocellular carcinoma.

AB - While intratumor heterogeneity contributes to disease progression, metastasis, and resistance to chemotherapy, it also provides a route to understanding the evolution and drivers of disease. Defects in epigenetic landscapes are intimately linked to pathogenesis of a variety of human diseases, with epigenetic deregulation promoting tumorigenesis. Understanding epigenetic heterogeneity is crucial in hepatocellular carcinoma (HCC), where epigenetic alterations are frequent, early, and pathogenic events. We determined genome-wide DNA methylation and copy number variation leveraging the Infinium 450K in a series of regenerative nodules from within single patient livers. Bioinformatics strategies were used to ascertain within-patient heterogeneity, link epigenetic changes to clinical features, and determine their relevance to disease pathogenesis. Our data demonstrate that DNA methylation and copy number alterations evolve during the pre-neoplastic phase of HCC and independently segregate regenerative nodules into distinct clusters. Regenerative nodules with a high frequency of epigenetic changes have significantly lower copy number variation, suggesting that individual nodules have differential enrichment of epigenetic and genetic components, with both contributing to disease progression. Regenerative nodules were scored based on ‘epigenetic progression’ with higher scores associated with increased proliferation measured by Ki67 staining. Early events observed in epigenetically ‘aggressive’ nodules are enriched for genes involved in liver cancer. Our study demonstrates that marked epigenetic and genetic heterogeneity exists in early pre-neoplastic liver tissue within individual patients, emphasizing the potential contributions of each mechanism to driving liver disease progression, and it unveils strategies for identifying epigenetic drivers of hepatocellular carcinoma.

KW - copy number variation

KW - DNA methylation

KW - early changes

KW - hepatocellular cancer

KW - heterogeneity

UR - http://www.scopus.com/inward/record.url?scp=85011838474&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85011838474&partnerID=8YFLogxK

U2 - 10.1080/15592294.2016.1277297

DO - 10.1080/15592294.2016.1277297

M3 - Article

C2 - 28059585

AN - SCOPUS:85011838474

SP - 1

EP - 11

JO - Epigenetics

JF - Epigenetics

SN - 1559-2294

ER -