Table 1.
An overview of the sensitivity and specificity for CRC detection of all ctDNA mutation, hypermethylation, and hypomethylation markers included in this review*
| Marker | Sensitivity |
Specificity | Concordance with primary tumor | ||||
|---|---|---|---|---|---|---|---|
| Stage I | Stage II | Stage III | Stage IV | Stage not reported | |||
| Mutation | |||||||
| APC (41–48) | 0–50% | 6–57% | 3–46% | 15–75% | 14–18% | NA | 16–100% |
| BRAF (34,35,42,45,48–53) | 50% | 0–9% | 33% | 3–29% | 2–12% | NA | 33–100% |
| ERBB2 (44,54) | NA | 5–9% | NA | NA | |||
| KRAS (32,34,35,41–46,48–53,55–64) | 0–67% | 3–46% | 5–50% | 5–73% | 8–71% | 70–100% | 25–100% |
| NRAS (35,52) | NA | 12% | NA | 100% | |||
| PIK3CA (44,45,48,49,51) | NA | 19% | 0–21% | NA | 0%–100% | ||
| tp53 (41–46,48) | 0–25% | 22–30% | 17–49% | 38–67% | 6–50% | 100% | 14–100% |
| Hypermethylation | |||||||
| AKAP12 (65) | NA | 48% | 92.0% | NA | |||
| ALX4 (66–70) | 75% | 83% | 82% | 100% | 29–83% | 66–99% | NA |
| 30% | 60% | ||||||
| APC (67,71–74) | 24% | 60% | 54% | 20–57% | 68–100% | 50% | |
| BCAT1 (31,75) | 21% | 62% | 68% | 81% | 57–65% | 95–97% | NA |
| BMP3 (67) | NA | 29% | 89% | NA | |||
| BNC1 (67) | NA | 12% | 87% | NA | |||
| BRCA1 (67) | NA | 25% | 78% | NA | |||
| CDH1 (72) | NA | 60% | 84% | NA | |||
| CDH4 (76) | NA | 70% | 100% | 83% | |||
| CDKN2A (55,67,71,77–79) | 15% | 50–67% | 50–67% | 10–75% | 9–61% | 70%–96% | 70–82% |
| CRABP1 (75,80) | NA | 50% | NA | NA | |||
| DAPK1 (72) | 50.0% | NA | 74% | 80% | |||
| DLC1 (81) | 36% | 48% | 42% | 91% | NA | ||
| ERCC1 (82) | 60% | NA | NA | 93% | 90% | ||
| EYA4 (80) | NA | 50% | NA | NA | |||
| FBN2 (83) | 9% | 7% | 8% | NA | 9% | NA | 8% |
| FGF5 (75) | NA | 85% | 83% | NA | |||
| FHIT (72,74) | NA | 20–50% | 84% | 40% | |||
| GATA5 (84) | 46% | 83% | 61% | NA | NA | ||
| GRASP (75) | NA | 54% | 93% | NA | |||
| HIC1 (67) | 6% | 99% | NA | ||||
| HLTF (67,85–89) | 8–20% | 15–16% | 9–16% | 24–47% | 11–30% | 96–100% | 41–42% |
| hMLH1 (67,77,89) | 27% | 0–24% | 25–27% | 12–40% | 16–29% | 100% | 33% |
| HPP1 (85,87–90) | 3–7% | 0–6% | 5–9% | 52–53% | 13–72% | NA | 56% |
| IKZF1 (31,75) | 28% | 41% | 55% | 94% | 48–68% | 95–99% | NA |
| IRF4 (75) | NA | 59% | 96% | NA | |||
| ITGA4 (84) | 24% | 54% | 37% | 81% | NA | ||
| LRR3CB (74) | NA | 15% | NA | 23% | |||
| MAL (80) | 50% | NA | NA | ||||
| MGMT (67,82) | 58% | NA | 6% | 95–99% | 94% | ||
| MLH1 (67,77,89,91) | NA | 45% | 57% | 33% | |||
| NELL1 (80) | NA | 33% | NA | NA | |||
| NDRG4 (67,92) | 54% | 56% | 9–55% | NA | NA | ||
| NEUROG1 (67,87) | 31% | 28% | 26% | 20% | 21–26% | NA | NA |
| NGFR (93) | 20% | 25% | 36% | 36% | 38% | 91.4% | NA |
| NPTX2 (67) | NA | 70% | 41% | NA | |||
| OSMR (67,94) | 74% | 77% | 11–75% | 86–93% | 79% | ||
| p73 (77) | NA | 25% | NA | NA | |||
| PCDH10 (36) | 71% | 54% | 63% | NA | 67% | ||
| PDX1 (75) | NA | 45% | 70% | NA | |||
| PHACTR3 (67) | NA | 15% | 94% | NA | |||
| PPENK (67) | NA | 10% | 96% | NA | |||
| RAR-β (67) | 25% | 30% | |||||
| RASSF1A (67,73) | 14% | 47% | 45% | 11–34% | 84–100% | NA | |
| RUNX3 (95) | 33% | 50% | 42% | 100% | NA | ||
| SDC2 (67,75) | NA | 24–59% | 84–94% | NA | |||
| SEPT9 (25,29,30,32,33,66,67,75, 80,93,94,96–107) | 14–84% | 50–100% | 38–100% | 68–100% | 24–96% | 73–97% | 80–88% |
| 20–57% | 52–70% | ||||||
| 64% | NA | ||||||
| SFRP1 (67) | 22% | 93% | |||||
| SFRP2 (67,84) | 42% | 71% | 20–54% | 72–82% | NA | ||
| SHOX2 (103) | NA | 44% | 21% | NA | NA | ||
| SMAD4 (72) | NA | 52% | 64% | NA | |||
| SOX21 (75) | NA | 80% | 50% | NA | |||
| SPG20 (67) | NA | 16% | 82% | NA | |||
| SST (67,80) | NA | 30–50% | 69% | NA | |||
| TAC1 (67,80) | NA | 50–53% | 53% | NA | |||
| TFPI1 (108) | NA | 7% | 98% | NA | |||
| TFPI2 (67) | 0% | 10% | 13% | 58% | 18% | 100% | NA |
| THBD (67) | NA | 10% | 99% | NA | |||
| TMEFF2 (66,93) | 5% | 22% | 47% | 45% | 30–71% | 90–95% | NA |
| VIM (67,109,110) | 50–52% | 55–67% | 40% | 86% | 18–71% | 60–93% | 78% |
| WIF1 (67) | NA | 10% | 96% | NA | |||
| WNT5A (67) | NA | 6% | 95% | NA | |||
| Hypomethylation | |||||||
| CBS (111) | NA | 56% | NA | NA | |||
| LINE-1 (112) | 63% | 68% | 66% | 90% | NA | ||
| Panels | |||||||
| Hypermethylation: ALX4 + BMP3 + NPTX2 + RARB + SDC2 + SEPT9 + VIM + female sex + age>66 (67) | 89% | NA | 91% | 73% | NA | ||
| Mutations: sequencing panel including TP53 + APC + KRAS (45) | NA | 100% | NA | NA | |||
| Mutations: APC + KRAS + TP53 (46) | 0% | 22% | 49% | 67% | 35% | 100% | 46% |
| Hypermethylation: APC + MGMT + RASSF2A + Wif-1 (86) | 87% | NA | 92% | NA | |||
| Hypermethylation: BCAT1 + IKZF1 (38) | 41% | 76% | 59% | 71% | 62% | 92% | NA |
| Hypermethylation: ALX4 + SEPT 9 + TMEFF 2 (66) | NA | 84% | 88% | NA | |||
*
The number of studies reporting a specific marker is represented next to the target gene. If possible, the sensitivity was presented separately for each disease stage. Concordance was defined as the percentage of agreement between ctDNA analysis and mutation or methylation analysis in the primary tumor. CRC = colorectal cancer; ctDNA = circulating tumor DNA; NA = not available, for when no data were available in a specific category.