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| mtDNA biomarkers | Human cancers | Findings | References |
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| Large-scale deletions | | | |
| 3.4 kb (3379 bp) | Breast and prostate | (i) Patented kit for cancer detection, Prostate Core Mitomic Test kit; deletion was detected in proximal benign tissues (field-effect or cancerization), suggesting early tumorigenesis.
(ii) Deletion was suggested as cancer predictor with 100% sensitivity and 90% specificity. | [97–100, 102] |
| 4977 bp | Breast | (i) Deletion was higher in cancer patients, suggesting it as a potential noninvasive biomarker for breast cancer detection (China).
(ii) Higher deletion in control samples than cancerous tissues (Argentina, Vietnam). | [108–110] |
| Colorectal; gastric | (i) Higher deletion in control samples than cancerous tissues (Sweden; Brazil).
(ii) Deletion was higher in cancerous tissues (China). | [111, 113, 112, 114] |
| Hepatocellular | (i) First mtDNA4977 study, with higher detection in adjacent tissues (Japan).
(ii) Common deletion was responsible for cancer development and progression. | [115, 116] |
| Oral | (i) Associated betel quid chewing with increased mtDNA mutations, suggesting cytochrome P450 2E1 gene polymorphism as coexist factor. | [117, 118] |
| Brain; hepatocellular | (i) Deletion was detected only in cancerous tissues (Malaysia; China). | [119, 120] |
| Skin; lung; endometrial | (i) Higher deletion detected in adjacent tissues (Germany; China; Poland). | [121–123] |
| 3895 bp | Skin | (i) Deletion was patented in 2011 for cancer detection and diagnosis.
(ii) Higher deletion frequency in sun-exposed skin with predominant nonmelanoma cancer; mtDNA4977 detection was 50% lower. | [124, 126, 127] |
| 4576 bp | Breast | (i) Deletion in 77% of cancerous tissues with no deletion in normal subjects; suggested as breast cancer screening tool. | [128] |
|
| mtDNA copy number | Hepatocellular; breast | (i) Reduced copy number was correlated to D-loop mutations. | [132–134] |
| Breast | (i) Associated copy number with breast cancer risk, development, and neoplastic transformation.
(ii) Reduced copy number significantly induced breast cancer stem cells and metastatic characteristics.
(iii) Copy number changes determined chemotherapy response; low copy number shows higher chances of disease-free survival.
(iv) mtDNA depletion correlated with lower chances of disease-free survival and higher tumor grades. | [134–136, 71, 141, 134] |
| Prostate; colorectal | (i) Genomic heterogeneity altered mtDNA content. | [137, 138] |
| Colorectal | (i) Low copy number reduced 3-year survival and correlated with lymph node metastasis.
(ii) Increased copy number worsen the overall survival and relapse-free survival. | [139, 140] |
|
| Circulating cell-free mtDNA (cf-mtDNA) | Hepatocellular | (i) Suggested as noninvasive biomarker and predictor for cancer risk in hepatitis C patients. | [152] |
| Lung | (i) Predictor for diagnosis and prognosis of cancer. | [154] |
| Head and neck | (i) Significantly higher levels observed in cancer patients than controls; increased levels with cancer progression, associated with lymph node metastasis and predictive with cancer survival; suggested as diagnostic biomarker due to high association with smoke and smokeless tobacco, alcohol, and betel quid chewing. | [155–157] |
| Epithelial ovarian | (i) Showed significantly higher levels in cancer patients which was suggested as diagnostic and prognostic biomarker. | [158, 159] |
| Endometrial; prostate; brain | (i) Evaluated as a biomarker. | [160–162] |
| Breast | (i) Lower levels in cancerous samples than controls.
(ii) Higher levels in cancerous samples than controls. | [163, 164, 135, 136, 165] |
|
| mtMSI | | | |
| D310 | Breast; gallbladder | (i) Mutations detected in both cancerous and normal adjacent tissues. | [179, 180] |
| Brain; rectal and colorectal; tongue squamous cell | (i) Detected in cancerous patients (12%, 34%, 38%, and 25%). | [176, 181, 193] |
| D16184 | Gastric; endometrial; acute myeloid leukemia | (i) Detected in cancerous patients (16.1%, 14%, and 70.3%) | [183–184] |
|
| Somatic mtDNA alterations | | | |
| A12308G, tRNALeu (CUN) | Prostate and renal | (i) Mitochondrial predisposition factor in North American white individuals. | [189] |
| Breast | (i) 12% changes detected among studied population in Poland and closely associated with neoplastic process.
(ii) Increased the risk of cancer development. | [187, 191] |
| Colorectal | (i) Potential diagnostic tool for cancer and pathogenic when combined with other mtDNA alterations. | [190] |
| Oral | (i) Increased the risk of cancer. | [186] |
| A10398G | Oral | (i) Increased the risk of cancer. | [186] |
| Breast | (i) Increased the risk of cancer development. | [191] |
| Tongue squamous cell | (i) Detected in 62.5% of cancerous tissues. | [193] |
| Non-small cell lung | (i) Suggested as a poor prognosis marker. | [194] |
|
| Methylation | | | |
| mtDNA | Liver and breast | (i) Bisulphite sequencing detected higher levels of CpG and non-CpG in liver cancerous cell lines compare to noncancerous, while higher levels in normal cells than breast cancerous cells. | [198] |
| Breast | (i) Positively correlated D-loop methylation with cancer risk which is maternally inherited; displayed familial-specific methylation pattern. | [199] |
| Head and neck | (i) Higher CpG and CpH levels detected in cancerous tissues than noncancerous using nanopore sequencing that prevents bisulphite and PCR bias. | [200] |
| Glioblastoma and osteosarcoma | (i) Decreased 5mC levels detected while mtDNA copy number increased which regulates transcription process. | [91] |
| Cervix; adenoma | (i) Low mtDNA methylation detected in cancerous tissues. | [202, 203] |
| mtRNA | Kidney renal clear cell | (i) Predicted poor prognosis of cancer patients. | [205] |
| Oral squamous cell | (i) Observed hypermethylation of MT-COI and MT-CYB with concomitant high expression levels in cancer cell lines. | [207] |
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