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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