DNA Methylation in Urine and Feces Indicative of Eight Major Human Cancer Types Globally
Abstract
:1. Introduction
2. Materials and Methods
2.1. Literature Sources
2.2. PRISMA Criteria
2.3. Geographic Analysis
2.4. Statistical Analysis
3. Results
3.1. PRISMA Literature Review
3.2. Sensitivity and Specificity of Epigenetic Biomarkers Utilized in Clinical Screening of Urine and Feces
3.3. Geographic Locations of Patient Cohorts Clinically Analyzed for Epigenetic Biomarkers in Urine and Feces Compared to Cancer Hotspots Globally
4. Discussion
4.1. Performance of Epigenetic Biomarker Panels
4.2. Geographic Considerations for Epigenetic Biomarker Panels
4.3. Translation to Clinic
4.4. Applications of Population Epigenetics for Public Health
4.5. Potential Confounding Results
4.6. Literature Search Window Extension
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Glossary
biomarker | biological compound produced in the body indicating disease |
epigenetic | marks and changes (e.g., methylation, acetylation) to genetic machinery by environmental stimuli; not mutation |
incidence | the rate of individuals diagnosed with a disease at a given time |
liquid biopsy | analysis of bodily fluids to detect biomarkers of disease |
sensitivity | ability for a test to indicate individuals with disease |
specificity | ability for a test to indicate individuals without a disease |
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Disease | Liquid Biopsy Specimen | Biomarker Panel | Epigenetic Marker Type | Sensitivity (Disease as Positive) | Specificity (Control as Negative) | Threshold Score * | Source |
---|---|---|---|---|---|---|---|
bladder cancer | urine | hyper: SOX1, TJP2, MYOD, HOXA9_1, HOXA9_2 hypo: VAMP8, CASP8, SPP1, IFNG, CAPG, HLADPA1, RIPK3 | methylation | 100.0 | 100.0 | 2.0 | [12] |
bladder cancer | urine | TBX2 | methylation | 100.0 | 80.0 | 1.8 | [28] |
bladder cancer | urine | p14ARF, RUNX3, RARβ, DAPK, and HPP1 | methylation | 98.2 | 88.9 | 1.9 | [29] |
bladder cancer | urine | 150 CpG loci | methylation | 98.0 | 97.0 | 2.0 | [30] |
bladder cancer | urine | HS3ST2, SLIT2 and SEPTIN9 | methylation | 97.6 | 84.8 | 1.8 | [31] |
bladder cancer | urine | ZNF671, IRF8 and sFRP1 | methylation | 96.2 | 90.9 | 1.9 | [32] |
bladder cancer | urine | CFTR, SALL3, and TWIST1 | methylation | 96.0 | 40.0 | 1.4 | [33] |
bladder cancer | urine | GDF15, TMEFF2, and VIM CpG island-containing genes | methylation | 94.0 | 90.0 | 1.8 | [13] |
bladder cancer | urine | cfDNA | methylation | 93.5 | 95.8 | 1.9 | [34] |
bladder cancer | urine | 3 BC-specific genes2 internal control genes | methylation | 93.5 | 92.6 | 1.9 | [35] |
bladder cancer | urine | CADM1, FAM19A4, GHSR, MAL, PHACTR3, PRDM14, SST, ZIC1, miR-124-2, miR-129, miR-137, miR-148, miR-181 and miR-935 | methylation | 92.0 | 85.0 | 1.8 | [36] |
bladder cancer | urine | SALL3, CFTR, ABCC6, HPR1, RASSF1A, MT1A, RUNX3, ITGA4, BCL2, ALX4, MYOD1, DRM, CDH13, BMP3B, CCNA1, RPRM, MINT1, and BRCA1 | methylation | 91.7 | 87.0 | 1.8 | [37] |
bladder cancer | urine | GDF15, TMEFF2 and VIM promoter | methylation | 91.0 | 100.0 | 1.9 | [14] |
bladder cancer | urine | CDH1, SALL3, THBS1, MEFF2, VIM, and GDF15: 0.89, and with cytology | methylation | 91.0 | 92.0 | 1.8 | [38] |
bladder cancer | urine | p14ARF, p16INK4A, RASSF1A, DAPK, and APC promoters | methylation | 91.0 | 0.9 | [39] | |
bladder cancer | urine | PCDH17 and POU4F2 | methylation | 90.0 | 94.0 | 1.8 | [40] |
bladder cancer | urine | TWIST1 and NID2 | methylation | 90.0 | 93.0 | 1.8 | [22] |
bladder cancer | urine | 15 (proprietary) | methylation | 88.9 | 88.0 | 1.8 | [15] |
bladder cancer | urine | miR-129-2 and miR-663a promoters | methylation | 87.7 | 84.0 | 1.7 | [41] |
bladder cancer | urine | TWIST1 and NID2 | methylation | 87.5 | 95.8 | 1.8 | [23] |
bladder cancer | urine | sFRP-5 | methylation | 87.0 | 37.0 | 1.2 | [42] |
bladder cancer | urine | DAPK, IRF8, p14, RASSF1A and SFRP1 | methylation | 86.7 | 94.7 | 1.8 | [43] |
bladder cancer | urine | SOX1, IRAK3, andL1-MET | methylation | 86.0 | 89.0 | 1.8 | [44] |
bladder cancer | urine | EOMES, HOXA9, POU4F2, TWIST1, VIM, and ZNF154 | methylation | 85.5 | 97.0 | 1.8 | [45] |
bladder cancer | urine | MYO3A, CA10, NKX6-2, DBC1, and SOX11 or PENK | methylation | 85.0 | 95.0 | 1.8 | [46] |
bladder cancer | urine | ZNF154, POU4F2, HOXA9, and EOMES | methylation | 84.0 | 96.0 | 1.8 | [47] |
bladder cancer | urine | E-cadherin, p16, p14, and RASSF1A | methylation | 83.0 | 100.0 | 1.8 | [48] |
bladder cancer | urine | VIM, CDH1, SALL3, TMEFF2, RASSF1A, BRCA1, GDF15, and ABCC6 | methylation | 83.0 | 60.0 | 1.4 | [38] |
bladder cancer | urine | CDH1, HSPA2, RASSF1A, TMEFF2, VIM, and GDF15 | methylation | 82.0 | 68.0 | 1.5 | [38] |
bladder cancer | urine | VIM, RASSF1A, GDF15, and TMEFF2 | methylation | 82.0 | 53.0 | 1.4 | [38] |
bladder cancer | urine | DAPK, BCL-2, and H-TERT | methylation | 81.1 | 100.0 | 1.8 | [49] |
bladder cancer | urine | MYO3A, CA10, NKX6-2, and DBC1 or SOX11 | methylation | 81.0 | 97.0 | 1.8 | [46] |
bladder cancer | urine | miR-137, miR-124-2, miR-124-3, and miR-9-3 | methylation | 81.0 | 89.0 | 1.7 | [50] |
bladder cancer | urine | BCL2, CDKN2A and NID2 | methylation | 80.9 | 86.4 | 1.7 | [51] |
bladder cancer | urine | TWIST1 and NID2 | methylation | 79.0 | 63.0 | 1.4 | [21] |
bladder cancer | urine | TWIST1 and NID2 | methylation | 76.2 | 83.3 | 1.6 | [26] |
bladder cancer | urine | BCL2 and hTERT promoters | methylation | 76.0 | 98.0 | 1.7 | [52] |
bladder cancer | urine | sFRP-1 | methylation | 75.9 | 53.7 | 1.3 | [42] |
bladder cancer | urine | BCL2, EOMES, HOXA9, VIM2, CCNA1, POU4F2, and SALL3 | methylation | 75.0 | 0.8 | [53] | |
bladder cancer | urine | OTX1, MEIS1, ONECUT2, SIM2, FOXA1, ZNF503, HOXA9, and OSR1 | methylation | 74.0 | 90.0 | 1.6 | [28] |
bladder cancer | urine | p14ARF promoter | methylation | 72.1 | 63.6 | 1.4 | [54] |
bladder cancer | urine | SFRP5 | methylation | 70.0 | 100.0 | 1.7 | [55] |
bladder cancer | urine | RASSF1a, APC and E-cad promoters | methylation | 69.0 | 60.0 | 1.3 | [56] |
bladder cancer | urine | APC, ARF, CDH1, GSTP1, MGMT, CDKN2A, RARβ2, RASSF1A, and TIMP3 promoters | methylation | 69.0 | 10.0 | 0.8 | [57] |
bladder cancer | urine | 15 (proprietary) | methylation | 68.2 | 88.0 | 1.6 | [17] |
bladder cancer | urine | CCNA1 promoter | methylation | 68.0 | 83.0 | 1.5 | [58] |
bladder cancer | urine | CDH1 promoter | methylation | 67.4 | 93.9 | 1.6 | [54] |
bladder cancer | urine | TWIST1 and NID2 | methylation | 67.0 | 69.0 | 1.4 | [24] |
bladder cancer | urine | RAR-β2 | methylation | 65.0 | 89.7 | 1.5 | [59] |
bladder cancer | urine | CALCA promoter | methylation | 63.5 | 71.5 | 1.4 | [58] |
bladder cancer | urine | Wif-1 | methylation | 63.0 | 72.2 | 1.4 | [42] |
bladder cancer | urine | sFRP-2 | methylation | 63.0 | 57.4 | 1.2 | [42] |
bladder cancer | urine | 15 (proprietary) | methylation | 62.3 | 86.3 | 1.5 | [16] |
bladder cancer | urine | APC, RASSF1A and SFRP2 | methylation | 62.0 | 100.0 | 1.6 | [60] |
bladder cancer | urine | TCF21 and PCDH17 promoters | methylation | 60.0 | 100.0 | 1.6 | [61] |
bladder cancer | urine | DLX1, ITGA4, SOX17, ASTN1, RXFP3, and ZNF671 | methylation | 60.0 | 96.7 | 1.6 | [62] |
bladder cancer | urine | TWIST1 and NID2 | methylation | 57.0 | 72.0 | 1.3 | [25] |
bladder cancer | urine | RBBP8 | methylation | 52.0 | 91.0 | 1.4 | [63] |
bladder cancer | urine | VGF | methylation | 40.0 | 1.0 | 0.4 | [64] |
bladder cancer | urine | Dkk-3 | methylation | 38.9 | 92.6 | 1.3 | [42] |
bladder cancer | urine | sFRP-4 | methylation | 38.9 | 87.0 | 1.3 | [42] |
bladder cancer | urine | SFRP1 | methylation | 36.7 | 93.3 | 1.3 | [65] |
bladder cancer | urine | TCF21 and PCDH17 promoters | methylation | 32.0 | 100.0 | 1.3 | [61] |
bladder cancer | urine | CCND2 promoter | methylation | 26.0 | 100.0 | 1.3 | [58] |
bladder cancer | urine | TCF21 and PCDH17 promoters | methylation | 26.0 | 100.0 | 1.3 | [61] |
cervical cancer | urine | SFRP4 and ZAR1 promoters | methylation | 45.2 | 83.3 | 1.3 | [66] |
colorectal cancer | feces | BMP3 and NDRG4 | methylation | 98.0 | 90.0 | 1.9 | [18] |
colorectal cancer | feces | SFRP2, GATA4/5, NDRG4 and VIM | methylation | 96.4 | 65.0 | 1.6 | [67] |
colorectal cancer | feces | BMP3 and NDRG4 | methylation | 92.3 | 86.6 | 1.8 | [8] |
colorectal cancer | feces | SDC2 | methylation | 90.2 | 90.2 | 1.8 | [68] |
colorectal cancer | feces | SDC2 | methylation | 90.0 | 90.9 | 1.8 | [69] |
colorectal cancer | feces | GRIA4 and VIPR2 | methylation | 90.0 | 0.9 | [70] | |
colorectal cancer | feces | BMP3, NDRG4, vimentin, and TFPI2 plus mutant KRAS | methylation | 87.0 | 90.0 | 1.8 | [71] |
colorectal cancer | feces | SFRP2 promoter | methylation | 87.0 | 0.9 | [72] | |
colorectal cancer | feces | SEPT9 | methylation | 83.3 | 92.1 | 1.8 | [20] |
colorectal cancer | feces | VIM | methylation | 83.0 | 82.0 | 1.7 | [73] |
colorectal cancer | feces | NDRG4 | methylation | 76.2 | 0.8 | [74] | |
colorectal cancer | feces | TFPI2 | methylation | 76.0 | 93.0 | 1.7 | [75] |
colorectal cancer | feces | APC, ATM, hMLH1, sFRP2, HLTF, MGMT, and GSTP1 | methylation | 75.0 | 90.0 | 1.7 | [76] |
colorectal cancer | fecal occult blood | SEPT9 | methylation | 73.0 | 94.5 | 1.7 | [19] |
colorectal cancer | urine | NDRG4 | methylation | 72.6 | 0.7 | [74] | |
colorectal cancer | feces | VIM and HLTF | methylation | 72.5 | 86.9 | 1.6 | [77] |
colorectal cancer | feces | BMP3 and NDRG4 | methylation | 69.2 | 86.6 | 1.6 | [8] |
colorectal cancer | feces | APC, ATM, hMLH1, sFRP2, HLTF, MGMT, and GSTP1 | methylation | 68.0 | 90.0 | 1.6 | [76] |
colorectal cancer | feces | SFRP2 promoter | methylation | 61.8 | 0.6 | [72] | |
colorectal cancer | feces | VIM | methylation | 60.0 | 100.0 | 1.6 | [78] |
colorectal cancer | feces | GATA4 and GATA5 promoters | methylation | 51.0 | 93.0 | 1.4 | [79] |
colorectal cancer | feces | Vimentin exon 1 | methylation | 46.0 | 90.0 | 1.4 | [80] |
colorectal cancer | feces | EN1, SCTR, INHBB CpG Islands | methylation | 44.0 | 97.0 | 1.4 | [81] |
colorectal cancer | feces | SFRP2 promoter | methylation | 42.3 | 76.8 | 1.2 | [72] |
colorectal cancer | feces | OSMR CpGs | methylation | 38.0 | 95.0 | 1.3 | [82] |
colorectal cancer | feces | NPY, Wif1, and NPY | methylation | 29.2 | 89.7 | 1.2 | [83] |
colorectal cancer | feces | TFPI2 | methylation | 21.0 | 93.0 | 1.1 | [75] |
colorectal cancer | urine | SEPT9, TMEFF2, SDC2, NDRG4, VIM and ALX4 | methylation | 86.0 | 0.9 | [84] | |
hematuria | urine | TWIST1, ONECUT2, and OTX1 | methylation | 97.0 | 83.0 | 1.8 | [85] |
hematuria | urine | OTX1, ONECUT2 and TWIST1 | methylation | 93.0 | 86.0 | 1.8 | [86] |
hematuria | urine | HOXA9, PCDH17, POU4F2, and ONECUT2 | methylation | 90.5 | 73.2 | 1.6 | [87] |
kidney cancer | urine | VHL, p16/CDKN2a, p14ARF, APC, RASSF1A, and Timp-3 | methylation | 88.0 | 100.0 | 1.9 | [10] |
kidney cancer | urine | TCF21 | methylation | 79.0 | 100.0 | 1.8 | [88] |
kidney cancer | urine | RASSF1A promoter | methylation | 65.0 | 89.0 | 1.5 | [89] |
kidney cancer | urine | microRNA-30a-5p: two CpGs | methylation | 63.0 | 67.0 | 1.3 | [90] |
kidney cancer | urine | TIMP3 promoter | methylation | 46.0 | 91.0 | 1.4 | [89] |
kidney cancer | urine | APC promoter | methylation | 38.0 | 96.0 | 1.3 | [89] |
kidney cancer | urine | CDH1 promoter | methylation | 38.0 | 95.0 | 1.3 | [89] |
kidney cancer | urine | p16 promoter | methylation | 35.0 | 100.0 | 1.4 | [89] |
kidney cancer | urine | ARF promoter | methylation | 31.0 | 100.0 | 1.3 | [89] |
kidney cancer | urine | RAR-β2 promoter | methylation | 31.0 | 91.0 | 1.2 | [89] |
kidney cancer | urine | GSTP1 promoter | methylation | 15.0 | 100.0 | 1.2 | [89] |
kidney cancer | urine | MGMT promoter | methylation | 8.0 | 100.0 | 1.1 | [89] |
lung cancer | urine | CDO1, TAC1, HOXA7, HOXA9, SOX17, and ZFP42 promoters | methylation | 73.0 | 92.0 | 1.7 | [91] |
prostate cancer | urine | singleplex-miR-34b/c and miR-193b;multiplex-APC, GSTP1, and RARβ2 promoters | methylation | 94.3 | 84.4 | 1.8 | [27] |
prostate cancer | urine | PLA2G16 CpG adjacent loci | methylation | 92.0 | 35.0 | 1.3 | [92] |
prostate cancer | urine | GSTP1, SFRP2, IGFBP3, IGFBP7, APC, and PTSG2 | methylation | 90.0 | 0.9 | [93] | |
prostate cancer | urine | miR-130a promoter | methylation | 83.5 | 82.3 | 1.7 | [94] |
prostate cancer | urine | miR-24, miR-30c and CRIP3 | methylation | 81.0 | 59.7 | 1.4 | [95] |
prostate cancer | urine | GSTP1, APC, RASSF1A, PITX2 and C1orf114 p | methylation | 81.0 | 0.8 | [96] | |
prostate cancer | urine | GSTP1, SFRP2, IGFBP3, IGFBP7, APC, and PTGS2 | methylation | 73.0 | 76.0 | 1.5 | [97] |
prostate cancer | urine | GSTP1, RARB, and APC | methylation | 55.0 | 80.0 | 1.4 | [98] |
prostate cancer | urine | GSTP1, RARB, and APC | methylation | 53.0 | 76.0 | 1.3 | [98] |
prostate cancer | urine | DLEC1 | methylation | 36.7 | 0.4 | [99] | |
prostate cancer | urine | HOXD3 and GSTP1 | methylation | 31.6 | 88.1 | 1.2 | [7] |
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Newell, M.E.; Babbrah, A.; Aravindan, A.; Rathnam, R.; Halden, R.U. DNA Methylation in Urine and Feces Indicative of Eight Major Human Cancer Types Globally. Life 2025, 15, 482. https://doi.org/10.3390/life15030482
Newell ME, Babbrah A, Aravindan A, Rathnam R, Halden RU. DNA Methylation in Urine and Feces Indicative of Eight Major Human Cancer Types Globally. Life. 2025; 15(3):482. https://doi.org/10.3390/life15030482
Chicago/Turabian StyleNewell, Melanie Engstrom, Ayesha Babbrah, Anumitha Aravindan, Raj Rathnam, and Rolf U. Halden. 2025. "DNA Methylation in Urine and Feces Indicative of Eight Major Human Cancer Types Globally" Life 15, no. 3: 482. https://doi.org/10.3390/life15030482
APA StyleNewell, M. E., Babbrah, A., Aravindan, A., Rathnam, R., & Halden, R. U. (2025). DNA Methylation in Urine and Feces Indicative of Eight Major Human Cancer Types Globally. Life, 15(3), 482. https://doi.org/10.3390/life15030482