Identification of Somatic Mitochondrial DNA Mutations, Heteroplasmy, and Increased Levels of Catenanes in Tumor Specimens Obtained from Three Endometrial Cancer Patients
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients and Tissue Specimens
2.2. DNA Extraction from Normal and Tumor Tissue
2.3. mtDNA Next-Generation Sequencing and Data Analysis
2.4. Determination of Relative mtDNA Copy Number
2.5. Characterization of mtDNA Topoisomers
3. Results
3.1. mtDNA Mutations and Heteroplasmy Identified in Patient 1
3.2. mtDNA Mutations and Heteroplasmy Identified in Patient 2
3.3. mtDNA Mutations and Heteroplasmy Identified in Patient 3
3.4. Tumor DNA Extracts from Patients 2 and 3 Harbor Altered mtDNA Copy Number
3.5. Endometrial Cancer Tumors Have Striking Differences in mtDNA Topoisomer Molecules
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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MtDNA nt change a | Location b | Coverage c | %Variant d | Remarks e |
---|---|---|---|---|
C5899CC | NC5, adjacent OL and TRNY | 714 | 26 | Insertion of C, potential effect on DNA rep. initiation? |
T6481C | COX1/V193A | 794 | 71 | Missense variant, deleterious (1.0) f; pathogenic (0.56) g; functional impact medium (2.34) h; associated with LAML, BRCA/Breast AdenoCA [31,33] |
T9179C | ATP6/V218A | 767 | 69 | Missense variant, deleterious (0.99) f; neutral (0.4) g; functional impact medium (2.91) h; associated with CLL, Panc-AdenoCA [33] |
G15995A | TRNP | 756 | 64 | Likely pathogenic (MitoTIP80%) i, mitochondrial cytopathy [41]; associated with BRCA/Breast-AdenoCA [31,33] |
C16327T | ATT, CR:HVS1,7S | 489 | 64 | Potential effect on DNA rep. initiation? associated with STAD, CLL, PRAD, Panc-AdenoCA [31,33] |
MtDNA nt Change a | Location | Coverage | %Variant | Remarks |
---|---|---|---|---|
G12007A | ND4/W416W | 424 | 75 | Synonymous variant; significantly associated with SZ + BD b [54]; associated with PRAD [33] |
T13490C | ND5/F385S | 516 | 94 | Missense variant, deleterious (1.0) c; pathogenic (0.63) d; Functional impact medium (3.425) e; associated with CLL, RCC [33] |
MtDNA nt Change a | Location b | Coverage | %Variant | Remarks |
---|---|---|---|---|
G10401A | ND3/E115K | 556 | 66 | Missense variant, deleterious (0.99) c; neutral (0.31) d; associated with THCA, HCC, Ovary-AdenoCA [31,33] |
A10411T | TRNR | 540 | 63 | Assoc. w/cardiomyopathy [55]; possibly benign(MitoTIP26.4%) e |
G10644A | ND4L/V59M | 658 | 67 | Missense variant, neutral (0.45) c; neutral (0.3) d; conflicting interpretations of pathogenicity (NC_012920.1(MT-ND4L):m.10644G>A) f; associated with PRDA [33] |
Sample Index (See Supp. File 2 in [13]) | MtDNA nt Change a | Location b | %Variant | Remarks c |
---|---|---|---|---|
5128 | T5506C | ND2/I346T | 91 | Missense, neutral (0.77) d; neutral (0.45) e; Uterus-AdenoCA [33] |
5139 | T11875C | ND4/T372T | 92 | Synonymous, UCEC, Eso-AdenoCA [31,33] |
5139 | G13531A | ND5/A399T | 93 | Missense, neutral (0.52) d; neutral (0.29) e; UCEC, Panc-Endorine, Soft Tissue-Liposarc, HCC [31,33] |
5150 | G4308A | TRNI | 46 | Confirmed pathogenic (MitoTIP82.1%) f, UCEC, Breast AdenoCA, Kidney-ChRCC [31,33] |
5155 | G14410A | ND6/V88V | 35 | Synonymous, UCEC [31] |
5157 | C14112T | ND5/F592F | 96 | Synonymous, UCEC/Uterus-AdenoCA [31,33] |
5160 | T152C | ATT, CR: HVS2, 7S, OH | 88 | LGG, LUAD/ Lung-AdenoCA, SARC, SKCM, THCA, BLCA/ Bladder-TCC, BRCA/Breast-AdenoCA, ESCA, PRAD/Prost-AdenoCA, STAD, UCEC, Lymph-CLL, Panc-AdenoCA, Soft Tissue-Liposarc, skin melanoma [31,33] |
5160 | G1642A | TRNV | 80 | Possibly pathogenic (MitoTIP74.3%) f, HNSC, UCEC, Head-SCC, Panc-AdenoCA, Thy-AdenoCA, HCC [31,33] |
5160 | G13417A | ND5/G361TERM | 51 | Nonsense mutation, LUAD, UCEC, HNSC [31] |
5161 | G5560A | TRNW | 12 | Possibly pathogenic (MitoTIP62.3%) f, THCA/Thy-AdenoCA, Kidney-ChRCC, Ovary-AdenoCA [31,33] |
5163 | T9062C | ATP6/L179P | 14 | Missense, neutral (0.92) d; neutral (0.25) e; UCEC/Uterus-AdenoCA [31,33] |
5165 | G529A | CR: HVS3, TFH | 99 | |
5165 | G2553A | RNR2 | 17 | UCEC, Panc-AdenoCA, Prost-AdenoCA [31,33] |
5165 | G5753A | OL | 98 | HCC, Uterus-AdenoCA [33] |
5165 | G14453A | ND6/A74V | 98 | Missense, deleterious (1.0) d; pathogenic (0.81) e; Kidney-ChRCC, Ovary-AdenoCA, CNS-Medullo, HCC, Biliary-AdenoCA [33] |
5167 | T14325C | ND6/N117D | 94 | Missense, neutral (0.56) d; pathogenic (0.54) e; UCEC [31] |
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Young, M.J.; Sachidanandam, R.; Hales, D.B.; Brard, L.; Robinson, K.; Rahman, M.M.; Khadka, P.; Groesch, K.; Young, C.K.J. Identification of Somatic Mitochondrial DNA Mutations, Heteroplasmy, and Increased Levels of Catenanes in Tumor Specimens Obtained from Three Endometrial Cancer Patients. Life 2022, 12, 562. https://doi.org/10.3390/life12040562
Young MJ, Sachidanandam R, Hales DB, Brard L, Robinson K, Rahman MM, Khadka P, Groesch K, Young CKJ. Identification of Somatic Mitochondrial DNA Mutations, Heteroplasmy, and Increased Levels of Catenanes in Tumor Specimens Obtained from Three Endometrial Cancer Patients. Life. 2022; 12(4):562. https://doi.org/10.3390/life12040562
Chicago/Turabian StyleYoung, Matthew J., Ravi Sachidanandam, Dale B. Hales, Laurent Brard, Kathy Robinson, Md. Mostafijur Rahman, Pabitra Khadka, Kathleen Groesch, and Carolyn K. J. Young. 2022. "Identification of Somatic Mitochondrial DNA Mutations, Heteroplasmy, and Increased Levels of Catenanes in Tumor Specimens Obtained from Three Endometrial Cancer Patients" Life 12, no. 4: 562. https://doi.org/10.3390/life12040562