Table 2.
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 | |||||
| ↑ BRAF V600E mutation | |||||
| Good prognosis | |||||
| ↑ BRAF V600E 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 |
*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.