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Table 2 Prognostic and predictive methylated ctDNA in colorectal cancer patients

From: Methylated circulating tumor DNA as a biomarker for colorectal cancer diagnosis, prognosis, and prediction

Gene Country Type of study No. of cases Time of sample collection Cases characteristics FU duration Sample type Technology used Hypermethylation reported association with HR (p-value) References
HPP1 Germany Prospective 77 Pretherapy UICC I (10), II (24)
III (27), IV (15)
5 Y Serum MethyLight Higher risk of death 5.1 (0.001) [77]
HLTF   3 (0.008)  
HPP1 and/or HLTF   HR (uni) = 4.2 (< 0.001), HR (multi) = 3.4 (0.007)  
HLTF Germany Prospective 103 Pretherapy UICC IV 6 Y Serum MSP Worse OS in stage IV 1.8 (0.0438) [76]
HPP1 Germany Prospective 103 Pretherapy UICC IV 6 Y Serum MSP Worse OS in stage IV 1.6 (0.0495) [76]
HLTF Germany Prospective 259 Pretherapy I (51), II (68), III (51), IV (89) 10 Y Serum MethyLight Shorter OS (p = 0.0008) esp. in stage IV (p = 0.0081)   [78]
HPP1 Germany Prospective 259 Pretherapy I (51), II (68), III (51), IV (89) 10 Y Serum MethyLight Shorter OS (p < 0.0001) esp. in stage IV (p = 0.0005)   [78]
HPP1 Germany Prospective 467 Pretherapy and after first cycle mCRC on combination of a fluoropyrimidine, oxaliplatin and bevacizumab 24 W Plasma MethyLight At baseline with worse OS, after the first cycle with high risk of progression HR baseline = 1.86 (0.0001), HR during treatment = 2.13 (0.0001) [79]
HLTF Germany   106 Pretherapy UICC I–III 5 Y Serum MethyLight Increased risk of recurrence HRuni = 2.7 (0.014), HRmulti = 2.5 (0.023) [80]
SEPT9 Singapore Prospective 150 Preoprative, 6 M-FU and 1Y-FU I–III; 1 neoadjuvant treatment and 45 adjuvant chemo and radiotherapy 7 Y Serum MSP 1Y-FU with poor DFS and CSS; dynamic change from 6 M to 1Y and from baseline and 1Y with recurrence HR (1Y-FU; CSS) = 2.69 (< 0.05); HR (1Y-FU;DFS) = 3.50 (0.001); HR (6 M-FU to 1Y-FU;DFS) = 2.58 (0.05), HR (baseline to 1Y-FU;DFS) = 3.35 (0.01) [81]
SEPT9 China Prospective 98 Preoperative and at 3 M intervals Performed surgery 28 M Plasma MSP Postoperative with higher mortality rate (p = 0.024) and presence of mets (p = 0.013) and lower OS (p = 0.014)   [18]
SEPT9 China Retrospective 300 from china, 330 from TCGA Preoperative Absent 30 M for Chinese people, 125 M for TCGA Plasma MSP Shorter PFS (p = 0.019) and OS (p = 0.008)   [83]
SEPT9 China Prospective 82 Preoperative and 1 and 7 days postoperative I (14), II (40), III (45) 21 M Plasma MSP Higher risk of death post-surgery HR (OS) = 2.51 (0.036) [82]
SEPT9 (10 subregions) China Prospective 82 Postoperative (within 2 W)   3Y Plasma MSP Poor RFS HR (RFS) = 4.20 (0.0005) [29]
SEPT9 (10 subregions) China Prospective 19 Serial postoperative   3Y Plasma MSP Poor RFS; better in recurrence prediction than single detection HR (RFS) = 7.49 (0.01) [29]
NPY Denmark Prospective 97 Pretherapy, 2 W of treatment and before every new cycle mCRC receiving regorafenib as last-line treatment Every second week for 2 months and then monthly if stable Plasma MSP ddPCR Baseline with shorter OS (p < 0.001)   [86]
NPY Denmark and Canada Prospective 146 Pretherapy Locally advanced rectal cancer taking Neoadjuvant Chemoradiotherapy 5 Y Serum MSP ddPCR Higher risk of death and distant disease progression HR (OS) = 2.08 (0.007), HR (distant mets) = 2.20 (0.01) [88]
NPY Denmark Prospective 123 Pretherapy mCRC taking 5-FU, oxaliplatin, and bevacizumab 7.5 Y Plasma MSP ddPCR Shorter PFS and OS HR (PFS) = 0.48 (0.0005), HR (OS) = 0.50 (0.0001) [89]
RASSF1A Greece Prospective 155 Preoperative Early operable (88), mets (67) 8 Y Serum MSP Worse survival in early and mets; more pronounced in mets HR (early; OS) = 3.06 (0.038), HR (mets; OS) = 5.76 (0.001) [93]
RASSF1A China Prospective 108 CRC, 78 healthy Pretherapy and after two cycles II–III receiving oxaliplatin-based chemo 3 Y Blood MSP Shorter PFS and OS HR = 2.471 (0.02) [92]
BCAT1 and IKZF1 Australia and New Zealand Prospective 172 12 M post-surgery Invasive CRC requiring surgery 12 M Plasma MSP Increased risk of residual disease and recurrence HR = 3.8 (0.004) [94]
BCAT1 and IKZF1 USA Prospective 322 Within 6 M post-therapy Stage II or III CRC   Plasma MSP (COLVERA) Increased recurrence   [97]
BCAT1 and IKZF2 Australia and New Zealand Prospective 144 Within 12 M in remission I (21), II (50), III (62), IV (11)   Plasma MSP (COLVERA) Increased recurrence   [96]
BCAT1 and IKZF3 Australia and New Zealand Prospective 122 3, 6, or 12 M in remission I (28), II (40), III (47), IV (4)   Plasma MSP Increased recurrence   [95]
SST Singapore Prospective 165 Preoperative Done surgery without neoadjuvent chemo 7 Y Serum MSP Higher risk of cancer-specific death esp stage III and risk of recurrence HR (OS) = 1.96 (0.031), HR (DFS) = 2.60 (0.003) [99]
TAC1 Singapore Prospective 150 Preoperative, 6 M-FU and 1Y-FU I–III; 1 neoadjuvant treatment and 45 adjuvant chemo- and radiotherapy 7 Y Serum MSP 6 M-FU with poor DFS and CSS; dynamic change from baseline to 6 M with recurrence HR (6 M-FU; CSS) = 4.12 (< 0.001), HR (6 M-FU, DFS) = 5.72 (< 0.001), HR (from baseline to 6 M-FU; DFS) = 4.71 (< 0.001) [81]
APC Greece Prospective 155 Preoperative Early operable (88), mets (67) 8 Y serum MSP Worse survival in early and mets; more pronounced in early operable HR (early; OS) = 7.88 (< 0.001), HR (mets; OS) = 3.47 (0.017) [93]
13 markers *** Minnesota, USA Prospective 40 recurrent, 60 healthy Post-surgery I (11), II (26), III (24), IV (23)   Plasma TELQAS detect recurrent/metastatic CRC with 90% sensitivity, 90% specificity, AUC = 0.96   [59]
MYO1G, CALML4, GCET2, KLF3, ATXN1 China Prospective 528 Pretherapy Training cohort 26.6 M Plasma Deep sequencing of bis-DNA High cp-score associated with poor prognosis (OS) 2.24 (< 0.001) [57]
273 Validation cohort 26.6 M 2.21 (< 0.001)  
EYA4, GRIA4, ITGA4, MAP3K14-AS1, MSC Italy Retrospective 60 before and 62 during treatment Pretherapy and biweekly during regorafenib treatment mCRC patients who received regorafenib 5.5 M (1.25–56.5 M) Plasma Methyl-BEAMing Baseline with worse OS and shorter PFS, during treatment with shorter PFS HR baseline (OS) = 3.471 (0.0001), HR baseline (PFS) = 2.196 (0.0015), HR during treatment (PFS) = 2.985 (< 0.0001), HR dynamic (PFS) = 1.78 (0.028) [101]
  1. ***(FER1L4, VAV3, CHST2, DTX1, PDGFD, SFMBT2, QKI, ZNF568, ANKRD13B, ZNF671, CNNM1, GRIN2D, JAM3)
  2. CECT, contrast enhanced computed tomography; Chemo, Chemotherapy; CSS, Cancer-specific survival; ddPCR, digital droplet PCR; DFS, Disease-free survival; FU, fluorouracil; MethyLight, fluorescence-based real time PCR; Mets, Mestastasis; M, month; MS-HRM, methylation‐sensitive high‐resolution melting assay; Multi, Multivariate; OS, Overall Survival; PFS, Progression-free survival; RFS, recurrence-free survival; TELQAS, target enrichment long-probe quantitative-amplified signal TA, tubular adenoma; 1FU, 1-year follow-up; 6MFU, 6-month follow-up; Uni, univariate; Y, year