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Table 2 Pan-cancer patterns of DNA methylation

From: Pan-cancer patterns of DNA methylation

Tumor type (number of methylation groups)

Methylation subgroup

Genomic aberrations

Methylation pattern*

Comments

References

AML

High

IDH1/2 or TET2 mutations

A

Associated with patients presenting with an intermediate-risk karyotype

[43],[51],[107]

    

Co-occurrence of IDH1/2 and NPM1 mutations is associated with good clinical outcome

 

Bladder urothelial

(3)

High

RB1 mutations

 

Smoking-pack years as predictor of CIMP phenotype

Frequent mutations in chromatin regulators such as MLL2, ARID1A, KDM6A, and EP300†

Mutations in chromatin regulators were more frequent than in any other TCGA tumor

[35]

Low

↑ TP53 mutations

B

Breast

(5)

B-CIMP

↓ mutation rate

 

Luminal ER/PR-positive tumors

[31],[32]

Low metastatic risk and better clinical outcome

Enriched for genes targeted by the PRC2 (e.g. SUZ12 and EZH2)

B-CIMP-negative

↑ TP53 mutations

B

Basal-like tumors (ER/PR-negative)

High metastatic risk and poor clinical outcome

Cholangiocarcinoma

High

IDH1 and/or IDH2 mutations

A

Longer survival

[47]

Chondrosarcoma

High

IDH1 and/or IDH2 mutations

A

 

[46],[64]

Colorectal

(4)

CIMP-H

MLH1 hypermethylation

C

MSI

[29],[108]

Right/ascending colonic region

↑ mutation rate

↑ BRAFV600E mutation

Good prognosis

↑ BRAFV600E mutation

CIMP-L

KRAS mutations

 

CIN (non-MSI)

Poor prognosis

Two non-CIMP

↑ TP53 mutations

B

Anatomic origins distinct from CIMP groups

↑ SCNAs

Endometrial

(4)

High

MLH1 hypermethylation

C

MSI

[33]

ARID5B mutations

↑ mutation rate

Low

↑ TP53 mutations

B

Serous-like tumors

↑ SCNAs

 

Poor prognosis

Two non-methylated

↑ POLE mutations

 

Endometrioid tumors

 

↑ SCNAs

ARID1A and PTEN mutations were present in all groups without high TP53 mutations

Gastric

(4)

EBV-CIMP

↑ PIK3CA, ARID1A and BCOR mutations

 

EBV-positive tumors

Highest frequency of hypermethylation events among TCGA tumors

[30]

CDKN2A hypermethylation

Amplifications of JAK2, CD274 and PDCD1LG2

Gastric CIMP

MLH1 silencing

C

MSI

↑ mutation rate

Cluster 3-low

RHOA and CDH1 mutations

 

Enriched for the diffuse histological variant

Genomically stable

Also fusions involving RHO-family GTPase-activating proteins

Cluster 4-low

↑ TP53 mutation

B

CIN

Focal amplifications of receptor tyrosine kinases

Glioblastoma

(6)

G-CIMP

IDH1 mutations

A

Secondary tumors with proneural expression

[41],[42],[48]

ATRX mutations

MYC mutations and amplifications

Younger age at diagnosis

Better survival rates

G-CIMP negative proneural

No IDH1 mutations

 

Relative hypomethylation

PDGFRA amplifications

Proneural subtype cases without IDH1 mutations

Pediatric glioblastoma

(6)

Global loss of methylation at non-promoter regions

H3F3A mutations

 

H3F3A mutations are mutually exclusive with IDH1 mutations and are associated with TP53 mutations and alternative lengthening of telomeres (ALT)

[49],[109]

Renal cell carcinoma

Global loss of methylation

SETD2 mutations

 

VHL hypermethylation in about 7 % of the tumors†

[36]

Loss of methylation at non-promoter regions

One of the tumor types with the lowest frequency of DNA methylation events

Lung ADCA

(3)

CIMP-high

CDKN2A hypermethylation

 

Associated either with ↑ ploidy, ↑ mutation and the PI subtype or with ↓ ploidy, ↓ mutation rate and the TRU subtype

[39]

MYC overexpression

Mutations in chromatin modifiers such as SETD2, ARID1A, SMARCA4†

Lung SQCC

(4)

High

CDKN2A inactivation

 

Classical expression subtype

[38]

NFE2L2, KEAP1, PTEN mutations

Chromosomal instability

↑ SCNAs

Low

  

Primitive expression subtype

Serous ovarian

(4)

High

Germline and somatic BRCA1 mutations

 

More differentiated tumors

[34]

Better survival

Low

↑ TP53 mutation

B

TP53 mutations occur in 90 % of the tumors and are not exclusive for the low methylation group

↑ SCNAs

BRAC1 hypermethylation

Poor clinical outcome

  1. *Methylation patterns A, B and C indicate common genetic and epigenetic aberrations across different tumors. †These molecular aberrations were not necessarily associated with a specific methylation subgroup. ADCA, adenocarcinoma; AML, acute myeloid leukemia; CIMP, CpG island methylator phenotype; CIN, chromosomal instability; EBV, Epstein-Barr virus; ER, estrogen receptor; MSI, microsatellite instability; PI, proximal inflammatory; PR, progesterone receptor; PRC, polycomb repressor complex; SCNAs, somatic copy-number alterations; SQCC, squamous cell carcinoma; TCGA, The Cancer Genome Atlas; TRU, terminal respiratory unit.