Table 1.
A summary of aberrant DNA methylation associated with outcome in breast cancer
| Gene symbol | Tissue type | Hyper/Hypo | Cohort size | Detection method | Association with prognosis | P value | Hazard ratioa | Reference |
|---|---|---|---|---|---|---|---|---|
| ACADL | NR | Hyper | 59 ductal carcinomas, 24 matched normal | IA/CoBRA | Reduced relapse-free survival | 0.0001 | [50] | |
| BMP4 | FF | Hyper | 241 patients with breast cancer | MethyLight | Reduced time to distant metastasis | 0.0002 | [51] | |
| BRCA1 | FFPE | Hyper | 536 tumors (Chinese patients) | MSP | Reduced disease-free survival | 0.045 | 1.45 | [52] |
| Reduced disease-specific survival | 0.038 | 1.56 | ||||||
| FF | Hyper | 241 patients with breast cancer | MethyLight | Reduced time to distant metastasis | 0.018 | [51] | ||
| Serum | Hyper | 105 tumors, 20 unmatched normal | MSP | Poor prognosis | 0.002 | 6.4 | [53] | |
| FF | Hyper | 82 primary breast cancer tissues (Tunisian cohort) | MSP | Five-year survival | 0.016 | [54] | ||
| BRCA1 or P16 or both | Serum | Hyper | 105 tumors, 20 unmatched normal | MSP | Poor prognosis | 0.002 | 10.7 | [53] |
| C20ORF55 | FF | Hyper | 241 patients with breast cancer | MethyLight | Reduced time to distant metastasis | 0.001 | [51] | |
| CDO1 | FF | Hyper | 163 tumors, 64 with distant metastasis | Q-BSSeq | Reduced time to distant metastasis | <0.0128 | >3.5 | [55] |
| Reduced metastasis-free survival | <0.0034 | |||||||
| CIDEB | FF | Hyper | 110 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.002 | 4.02 | [56] |
| CST6 | FFPE | Hyper | 93 carcinomas, 10 carcinomas with adjacent normal, 10 fibroadenomas, and 11 normal | MSP | Reduced disease-free interval Reduced overall survival | 0.004 0.001 | [57] | |
| Reduced disease-free interval | 0.027 | 3.48 | ||||||
| Reduced overall survival | 0.004 | 9.19 | ||||||
| DKK3 | FF | Hyper | 153 primary invasive cancers, 19 normal | MSP | Reduced overall survival | 0.011 | 14.4 | [58] |
| Reduced disease-free survival | 0.047 | 2.5 | ||||||
| ELK1 | FF | Hyper | 130 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.005 | 3.53 | [56] |
| ESR2 (ER-B) | FF | Hyper | 55 cancers | MSP | Increased incidence of relapse | 0.016 | [59] | |
| FGF12 | FF | Hyper | 113 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.004 | 3.31 | [56] |
| FGF4 | FF | Hyper | 241 patients with breast cancer | MethyLight | Reduced time to distant metastasis | 0.029 | [51] | |
| FOXH1 | FF | Hyper | 129 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.00007 | 5.09 | [56] |
| FOXL2 | FF | Hyper | 241 patients with breast cancer | MethyLight | Reduced time to distant metastasis | 0.02 | [51] | |
| GSTP1 | FF | Hyper | 176 invasive tumors (Japanese cohort) | MSP | Reduced relapse-free survival | <0.01 | [60] | |
| Poor prognosis | <0.05 | 2.77 | ||||||
| Poor prognosis | <0.01 | 7.13 | ||||||
| FFPE | Hyper | 974 primary in situ or invasive breast cancers | MethyLight | Increased breast cancer-specific mortality | NR | 1.71 | [61] | |
| FFPE | Hyper | 50 breast tumors | MSP | High Nottingham Prognostic Index | 0.0017 | [62] | ||
| HOXB13 | FF | Hyper | 57 ER-α+ tumors | QM-PCR | Reduced disease-free survival | 0.029 | 3.25 | [36] |
| ID4 | FF | Hyper | 171 tumors and match normal | MSP | Reduced recurrence-free survival | 0.036 | [63] | |
| ITIH5 | FF | Hyper | 109 tumors | MSP | Reduced overall survival | 0.008 | [64] | |
| ITR | NR | Hyper | 59 ductal carcinomas, 24 matched normal | IA/CoBRA | Reduced relapse-free survival | 0.0041 | [50] | |
| KLK10 | FFPE | Hyper | 128 breast carcinomas, 10 breast carcinomas with paired adjacent normal, 10 breast fibroadenomas, and 11 normal | MSP | Reduced disease-free interval Reduced overall survival Increased incidence of relapse | 0.0025 0.003 0.026 |
/ / 3.49 |
[65] |
| LHX5 | FF | Hyper | 125 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.032 | 2.94 | [56] |
| MLH1 | FF | Hyper | 86 primary breast cancer tissues (Tunisian cohort) | MSP | Reduced overall survival | 0.015 | [54] | |
| NR2E1 | FF | Hyper | 241 patients with breast cancer | MethyLight | Reduced time to distant metastasis | 0.02 | [51] | |
| OLIG2 | FF | Hyper | 115 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.023 | 2.56 | [56] |
| ONECUT1 | FF | Hyper | 128 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.023 | 2.8 | [56] |
| P16 | Serum | Hyper | 105 tumors, 20 unmatched normal | MSP | Poor prognosis | 0.001 | 5.5 | [53] |
| PITX2 | FFPE | Hyper | 427 invasive cancers | QM-PCR | Reduced time to distant metastasis | 0.004 | 2.75 | [66] |
| Reduced time to distant metastasis | 0.013 | 2.35 | ||||||
| Reduced metastasis-free survival | 0.032 | 2.69 | ||||||
| FF | Hyper | 241 patients with breast cancer | MethyLight | High risk of distant recurrence | 0.026 | [51] | ||
| Reduced time to distant metastasis | <0.001 | |||||||
| Reduced disease-free survival | 0.0084 | |||||||
| Reduced overall survival | 0.0003 | |||||||
| FF | Hyper | 236 node-negative tumors | Array/QM-PCR | Reduced metastasis-free survival | <0.00045 | >2.1 | [67] | |
| FF | Hyper | 416 tumors | QM-PCR | Reduced time to distant metastasis | <0.01 | 1.71 | [68] | |
| Reduced overall survival | <0.01 | 1.71 | ||||||
| Reduced metastasis-free survival | <0.01 | 1.74 | ||||||
| Reduced overall survival | 0.02 | 1.46 | ||||||
| PITX2/BMP4/c20orf55/fgf5 | FF | Hyper | 241 patients with breast cancer | MethyLight | Increased risk of distant recurrence Increased risk of distant recurrence | <0.01 <0.01 |
[51] | |
| RARB | FFPE | Hyper | 967 primary in situ or invasive breast cancers | MethyLight | Increased breast cancer-specific mortality | NR | 1.78 | [61] |
| RASSF1A | FF | Hyper | 80 tumors (Tunisian cohort) | MSP | Poor survival | 0.014 | [69] | |
| FFPE | Hyper | 93 carcinomas, 10 carcinomas with adjacent normal, 10 fibroadenomas, and 11 normal | MSP | Increased incidence of relapse Reduced disease-free survival | 0.011 0.028 |
[70] | ||
| FNA | Hyper | 237 patients with suspicious palpable lesions taken prior to surgery | QM-PCR | Reduced disease-free survival | 0.031 | OR = 2.53 | [71] | |
| RECK | NR | Hyper | 59 ductal carcinomas, 24 matched normal | IA/CoBRA | Reduced relapse-free survival | 0.0001 | [50] | |
| SFRP1 | FF | Hyper | 131 tumors, 26 matched normal | MSP | Reduced overall survival | 0.045 | [46] | |
| SFRP2 | NR | Hyper | 59 ductal carcinomas, 24 matched normal | IA/CoBRA | Reduced relapse-free survival | 0.0001 | [50] | |
| SFRP5 | FF | Hyper | 14 matched tumors and normal, 155 unmatched tumors | MSP | Reduced overall survival | 0.049 | 4.55 | [72] |
| SYNM | FF/FFPE | Hyper | 195 breast cancers | MSP | Reduced recurrence-free survival | 0.0282 | 2.94 | [73] |
| TDGF1 | FF | Hyper | 109 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.0009 | 4.08 | [56] |
| TLX3 | FF | Hyper | 241 patients with breast cancer | MethyLight | Reduced time to distant metastasis | 0.008 | [51] | |
| TUBB3 | FF | Hyper | 121 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.035 | 3.19 | [56] |
| TWIST1 | FFPE | Hyper | 973 primary in situ or invasive breast cancers | MethyLight | Increased breast cancer-specific mortality | NR | 1.67 | [61] |
| UAP1L1 | NR | Hyper | 59 ductal carcinomas, 24 matched normal | IA/CoBRA | Reduced relapse-free survival | 0.0005 | [50] | |
| UGT3A1 | NR | Hyper | 59 ductal carcinomas, 24 matched normal | IA/CoBRA | Reduced relapse-free survival | 0.0018 | [50] | |
| UNC5A | FF | Hyper | 111 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.027 | 2.74 | [56] |
| ZNF1A1 | FF | Hyper | 241 patients with breast cancer | MethyLight | Reduced time to distant metastasis | 0.044 | [51] | |
| BTG1 | FF | Hypo | 124 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.013 | 2.65 | [56] |
| GSC | FF | Hypo | 132 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.002 | 3.69 | [56] |
| HDAC4 | FF | Hypo | 117 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.016 | 2.62 | [56] |
| JUN | FF | Hypo | 131 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.025 | 2.44 | [56] |
| MKI67 (KI-67) | FF | Hypo | 116 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.004 | 3.43 | [56] |
| KIF2C | FF | Hypo | 118 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.008 | 2.65 | [56] |
| KLF4 | FF | Hypo | 114 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.009 | 2.63 | [56] |
| KLF5 | FF | Hypo | 123 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.004 | 3.56 | [56] |
| LHX2 | FF | Hypo | 126 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.028 | 2.32 | [56] |
| MAPK12 | FF | Hypo | 120 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.001 | 3.51 | [56] |
| MRD1 | FF/serum | Hypo | 100 invasive ductal carcinomas with matched normal and blood | MSP | Reduced overall survival | <0.01 | [74] | |
| ONECUT2 | FF | Hypo | 127 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.029 | 2.74 | [56] |
| SPRY1 | FF | Hypo | 112 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.002 | 4.0 | [56] |
| TOP1 | FF | Hypo | 108 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.0005 | 3.68 | [56] |
| UBE2C | FF | Hypo | 119 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.0009 | 3.57 | [56] |
| VEGF | FF | Hypo | 122 tumors, 11 normal (Indian cohort) | MOMA | Increased likelihood of relapse | 0.007 | 3.01 | [56] |
aHazard ratio given where reported. FF, fresh frozen; FFPE, formalin-fixed paraffin-embedded; FNA, fine-needle aspirate; HR, hazard ratio; Hyper, hypermethylation; Hypo, hypomethylation; IA/CoBRA, infinium array/combined bisulfite restriction enzyme analysis; MOMA, methylation oligonucleotide analysis; MSP, methylation-specific polymerase chain reaction; NR, not reported; OR, odds ratio; Q-BSSeq, quantitative bisulphite sequencing; QM-PCR, quantitative methylation-specific polymerase chain reaction.