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DNA methylation aberrancies delineate clinically distinct subsets of colorectal cancer and provide novel targets for epigenetic therapies

Oncogene volume 37, pages 566–577 (2018)Cite this article

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Abstract

Colorectal cancer (CRC) is a worldwide health concern with respect to both incidence and mortality, and as a result, CRC tumorigenesis, progression and metastasis have been heavily studied, especially with respect to identifying genetic, epigenetic, transcriptomic and proteomic profiles of disease. DNA methylation alterations are hallmarks of CRC, and epigenetic driver genes have been identified that are thought to be involved in early stages of tumorigenesis. Moreover, distinct CRC patient subgroups are organized based on DNA methylation profiles. CRC tumors displaying CpG island methylator phenotypes (CIMPs), defined as DNA hypermethylation at specific CpG islands in subsets of tumors, show high concordance with specific genetic alterations, disease risk factors and patient outcome. This review details the DNA methylation alterations in CRC, the significance of CIMP status, the development of treatments based on specific molecular profiles and the application of epigenetic therapies for CRC patient treatment.

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Abbreviations

2-HG:

2-hydroxyglutarate

5-Aza-CR:

5-aza-cytidine

5-Aza-CdR:

5-aza-2’-deoxycytidine

5-FU:

5-fluorouracil

5caC:

5-carboxylcytosine

5fC:

5-formylcytosine

5hmC:

5-hydroxymethylcytosine

5mC:

5-methylcytosine

α-KG:

alpha-ketoglutarate

ADAM2:

ADAM metallopeptidase domain 2

ADAM23:

ADAM metallopeptidase domain 23

APC:

adenomatous polyposis coli

ARMCX1:

armadillo repeat containing, X-linked 1

ATM:

ataxia telangiectasia mutated

BACH1:

BTB domain and CNC homolog 1

BCHE:

butyrylcholinesterase

BRAF:

B-Raf proto-oncogene, serine/threonine kinase

BRAF-mut:

mutant BRAF

BTG4:

BTG anti-proliferation factor 4

C9ORF50:

chromosome 9 open reading frame 50

CALGB:

aancer and leukemia group B

CAPOX:

capecitabine and oxaliplatin

CDKN2A:

cyclin-dependent kinase inhibitor 2A

CDH1:

E-cadherin

CDO1:

cysteine dioxygenase type 1

CEA:

carcino-embryonic antigen

cfDNA:

cell-free DNA

CHD8:

chromodomain-helicase-DNA-binding protein 8

CIN:

chromosomal instability

CRC:

colorectal cancer

CIMP:

CpG island methylator phenotype

CIMP-H:

CIMP-high

CIMP-L:

CIMP-low

CMS:

Consensus molecular subgroup

CRCSC:

CRC subtyping condortium

ctDNA:

circulating tumor DNA

DCC:

deleted in colorectal cancer

DKO:

DNMT1/DNMT3B double knockout

DNMT:

DNA Methyltransferase

DNMT1:

DNA methyltransferase 1

DNMT3A:

DNA methyltransferase 3A

DNMT3B:

DNA methyltransferase 3B

DPYD:

dihydropyrimidine dehydrogenase

EGFR:

epidermal growth factor receptor

ES:

embryonic stem

ESX1:

ESX homeobox 1

EPCAM:

epithelial cell adhesion molecule

FOLFIRI:

5-FU, folinic acid and irinotecan

FOLFOX:

folinic acid, 5-FU and oxaliplatin

FOXD2:

forkhead box D2

GGH:

gamma-glutamyl hydrolase

H3K36me3:

histone H3 lysine 36 trimethylation

HER2:

ERBB2 (erb-b2 receptor tyrosine kinase 2)

HINT1:

histidine triad nucleotide-binding protein 1

HNPCC:

hereditary non-polyposis colorectal cancer

HPP:

hyperplastic polyp

IDH1:

isocitrate dehydrogenase 1

IME:

intermediate methylation epigenotype

IRAK3:

interleukin receptor associated kinase 3

KAP1:

KRAB-associated protein 1

KRAS:

V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog

KRAS-mut:

mutant KRAS

MAFG:

MAF BZIP transcription factor G

MEK1:

mitogen-activated protein kinase 1

MEK2:

mitogen-activated protein kinase 2

MGMT:

O-6-methylguanine-DNA methyltransferase

miRNA:

microRNA

MMP9:

matrix metallopeptidase 9

MSH2:

MutS homolog 2

MSI:

microsatellite instability

MSI-H:

MSI-high

MSI-L:

MSI-low

MLH1:

Mut-L homolog 1

MSH6:

MutS homolog 6

MSS:

microsatellite stable

MYC:

MYC proto-oncogene, bHLH transcription factor

OS:

overall survival

P2RY14:

purigenic receptor P2Y14

PFS:

progression-free survival

PIK3CA:

phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

PMS1:

post-meiotic separation increased 1

RASSF1:

RAS association domain family member 1

RB:

retinoblastoma

RECK:

reversion inducing cysteine-rich protein with kazal motifs

RFS:

relapse-free survival

RUNX3:

Runt-related transcription factor 3

SAHA:

suberoylanilide hydroxamic acid

SAM:

S-adenosylmethionine

SCNA:

somatic copy number alteration

SEPT9:

septin 9

SETDB1:

SET domain bifurcated 1

SFRP:

secreted frizzled-related protein 1

SGI-110:

Guadecitabine

SMAD2:

SMAD family member 2

SMAD4:

SMAD family member 4

SSA:

sessile serrated sdenoma

SWOG:

southwest oncology group

SYCP3:

synaptonemal complex protein 3

TAC1:

techykinin precursor 1

TCGA:

The cancer genome atlas

TET:

Ten eleven translocase

TGF-β:

transforming growth factor beta

THBS1:

thrombospondin 1

TMEFF2:

transmembrane protein with EGF-like and two follistatin-like domains 2

TP53:

Tumor protein 53

TPEF:

transmembrane protein with EGF-like and two follistatin-like domains 2

TSA:

traditional serrated adenoma

VEGFR:

vascular endothelial growth factor receptors

VIM:

vimentin

WNT:

wingless-related integration site

ZNF304:

zinc finger protein 304.

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Acknowledgements

This work was supported by the Vicky Joseph Cancer Research Lab (to GL), NIH 5R21 CA201865 (to GL and DJW) and NIH/NCI P30 CA014089 (to DJW).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Medicine, University of Southern California, USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    D J Weisenberger

  2. Department of Urology, University of Southern California, USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    G Liang

  3. Department of Medicine, University of Southern California, USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    H-J Lenz

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  1. D J Weisenberger
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  2. G Liang
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  3. H-J Lenz
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Correspondence to D J Weisenberger, G Liang or H-J Lenz.

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DJW is a consultant for Zymo Research Corporation. Zymo did not contribute to this report, nor has an interest in this research.

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Weisenberger, D., Liang, G. & Lenz, HJ. DNA methylation aberrancies delineate clinically distinct subsets of colorectal cancer and provide novel targets for epigenetic therapies. Oncogene 37, 566–577 (2018). https://doi.org/10.1038/onc.2017.374

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