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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
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
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
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.