title: Methylation profiles reveal distinct subgroup of hepatocellular carcinoma patients with poor prognosis.
abstract: Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-associated mortality worldwide. However, the role of epigenetic changes such as aberrant DNA methylation in hepatocarcinogenesis remains largely unclear. In this study, we examined the methylation profiles of 59 HCC patients. Using consensus hierarchical clustering with feature selection, we identified three tumor subgroups based on their methylation profiles and correlated these subgroups with clinicopathological parameters. Interestingly, one tumor subgroup is different from the other 2 subgroups and the methylation profile of this subgroup is the most distinctly different from the non-tumorous liver tissues. Significantly, this subgroup of patients was found to be associated with poor overall as well as disease-free survival. To further understand the pathways modulated by the deregulation of methylation in HCC patients, we integrated data from both the methylation as well as the gene expression profiles of these 59 HCC patients. In these patients, while 4416 CpG sites were differentially methylated between the tumors compared to the adjacent non-tumorous tissues, only 536 of these CpG sites were associated with differences in the expression of their associated genes. Pathway analysis revealed that forty-four percent of the most significant upstream regulators of these 536 genes were involved in inflammation-related NFκB pathway. These data suggest that inflammation via the NFκB pathway play an important role in modulating gene expression of HCC patients through methylation. Overall, our analysis provides an understanding on aberrant methylation profile in HCC patients.
authors.affiliation: Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore.
authors.forename: Way-Champ
authors.initials: WC
authors.lastname: Mah
authors.affiliation: NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore; Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thurnherr
authors.affiliation: Duke-NUS Graduate Medical School, Singapore, Singapore; Department of Surgery, Singapore General Hospital, Singapore, Singapore.
authors.forename: Pierce K H
authors.initials: PK
authors.lastname: Chow
authors.affiliation: Department of Surgery, Singapore General Hospital, Singapore, Singapore.
authors.forename: Alexander Y F
authors.initials: AY
authors.lastname: Chung
authors.affiliation: Department of Surgery, Singapore General Hospital, Singapore, Singapore; Department of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: London L P J
authors.initials: LL
authors.lastname: Ooi
authors.affiliation: Department of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Han Chong
authors.initials: HC
authors.lastname: Toh
authors.affiliation: Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore; Duke-NUS Graduate Medical School, Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore; Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Caroline G L
authors.initials: CG
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000145:classification* / Q000235:genetics*; D016000:Cluster Analysis; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D006801:Humans; D008113:Liver Neoplasms / Q000145:classification* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016328:NF-kappa B
references.citation: Sci Transl Med. 2012 Oct 17;4(156):156ra140
references.pmid: 23076357
references.citation: Nat Genet. 2012 May 06;44(6):694-8
references.pmid: 22561517
references.citation: BMC Cancer. 2010 Oct 22;10:577
references.pmid: 20969767
references.citation: Nature. 1991 Apr 4;350(6317):429-31
references.pmid: 1672732
references.citation: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references.pmid: 21296855
references.citation: Gastroenterology. 2013 Sep;145(3):554-65
references.pmid: 23684942
references.citation: J Hepatol. 2002 Aug;37(2):231-9
references.pmid: 12127428
references.citation: Hepatology. 2012 Jun;55(6):1799-808
references.pmid: 22234943
references.citation: Tumour Biol. 2012 Oct;33(5):1307-17
references.pmid: 22457049
references.citation: Epigenetics. 2013 Jan;8(1):34-43
references.pmid: 23208076
references.citation: Cancer Lett. 2005 Apr 28;221(2):135-43
references.pmid: 15808399
references.citation: Stat Appl Genet Mol Biol. 2004;3:Article3
references.pmid: 16646809
references.citation: Gastroenterology. 2014 Feb;146(2):562-72
references.pmid: 24184133
references.citation: Int J Cancer. 2009 Apr 15;124(8):1811-9
references.pmid: 19107935
references.citation: Carcinogenesis. 2008 Oct;29(10):1901-10
references.pmid: 18632756
references.citation: Nat Genet. 2000 Mar;24(3):245-50
references.pmid: 10700176
references.citation: PLoS One. 2013;8(2):e55761
references.pmid: 23437062
references.citation: J Hepatol. 2011 May;54(5):939-47
references.pmid: 21145824
references.citation: Int J Oncol. 2004 May;24(5):1077-83
references.pmid: 15067328
references.citation: Am J Pathol. 2003 Oct;163(4):1371-8
references.pmid: 14507645
references.citation: Cold Spring Harb Perspect Biol. 2009 Nov;1(5):a000141
references.pmid: 20066113
references.citation: Biostatistics. 2007 Jan;8(1):118-27
references.pmid: 16632515
references.citation: Hepatology. 2009 May;49(5 Suppl):S56-60
references.pmid: 19399807
references.citation: Cancer Cell. 2010 May 18;17(5):510-22
references.pmid: 20399149
references.citation: Bioinformatics. 2010 Jun 15;26(12):1572-3
references.pmid: 20427518
references.citation: Cell Res. 2003 Oct;13(5):319-33
references.pmid: 14672555
references.citation: Nat Genet. 2005 Aug;37(8):853-62
references.pmid: 16007088
references.citation: Int J Cancer. 2003 Sep 1;106(3):334-41
references.pmid: 12845670
references.citation: Curr Genomics. 2011 Apr;12(2):130-7
references.pmid: 21966251
references.citation: Gastroenterology. 2006 Nov;131(5):1418-30
references.pmid: 17101318
references.citation: Int J Mol Med. 2004 Mar;13(3):413-7
references.pmid: 14767572
references.citation: PLoS One. 2010 Mar 17;5(3):e9749
references.pmid: 20305825
references.citation: Sci Transl Med. 2011 Mar 23;3(75):75ra25
references.pmid: 21430268
references.citation: Genome Res. 2012 Jul;22(7):1197-211
references.pmid: 22613842
references.citation: Int J Cancer. 2012 Mar 15;130(6):1319-28
references.pmid: 21500188
references.citation: Cancer Lett. 2003 Feb 20;190(2):213-9
references.pmid: 12565176
references.citation: Am J Pathol. 2003 Sep;163(3):1101-7
references.pmid: 12937151
references.citation: J Biol Chem. 2009 Aug 14;284(33):21941-21954
references.pmid: 19439406
references.citation: Mol Genet Genomics. 2010 Apr;283(4):341-9
references.pmid: 20165882
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Biomark Res. 2014 Mar 17;2(1):5
references.pmid: 24635883
references.citation: Cancer Res. 2003 Dec 15;63(24):8674-9
references.pmid: 14695180
references.citation: Methods Mol Biol. 2009;512:55-69
references.pmid: 19347273
references.citation: PLoS One. 2011;6(5):e19862
references.pmid: 21625442
references.citation: J Gastroenterol Hepatol. 2009 Mar;24(3):346-53
references.pmid: 19220670
references.citation: Am J Gastroenterol. 2011 Jun;106(6):1110-8
references.pmid: 21326223
references.citation: Ann N Y Acad Sci. 2009 Feb;1155:206-21
references.pmid: 19250206
references.citation: Cancer Res. 2011 Sep 1;71(17):5891-903
references.pmid: 21747116
references.citation: Oncogene. 2002 Jul 18;21(31):4863-71
references.pmid: 12101426
references.citation: Cancer. 2014 Jan 15;120(2):172-80
references.pmid: 24243398