Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Mitochondrial DNA Copy Number Determination
2.2. Deep Targeted Sequencing
2.3. Whole-Genome and Whole-Exome Sequencing
2.4. RNA Expression Analysis
2.5. Statistical Analysis
3. Results
3.1. Patients with Newly Diagnosed MM and Relapsed Patients Have an Increased Mitochondrial DNA Copy Number Associated with Worse Prognosis
3.2. Mitochondrial DNA Copy Number Increases with the Progression of MM Disease
3.3. Mitochondrial Biogenesis Regulator Genes Are Overexpressed in Advance States of MM with Implications for Prognosis
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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MGUS (n = 17) | SMM (n = 20) | NDMM (n = 79) a | RRMM (n = 26) | ||
---|---|---|---|---|---|
Median age (range), years | 71 (48–87) | 78.5 (54–87) | 72 (62–85) | 67.5 (38–87) | |
Sex (%) | Male | 58.8 | 45 | 52.9 | 53.8 |
Female | 41.2 | 55 | 47.1 | 46.2 | |
PC BM, average % (range) | 6.8 (2–17) | 23.2 (10–55) | 43.9 (10–84) | 39.2 (4–88) | |
PPC MFC %, average (range) | 1 (0.1–2.9) | 6.1 (0.98–24) | 11.2 (0.2–30) | 14.8 (0.01–79) | |
Type of Ig heavy chain (serum) | Non-detected | 5.9 | 0 | 0 | 0 |
IgG | 52.9 | 60 | 64.7 | 69.2 | |
IgA | 35.3 | 40 | 23.5 | 15.4 | |
IgM | 5.9 | 0 | 5.9 | 15.4 | |
IgD | 0 | 0 | 0 | 0 | |
Biclonal | 0 | 0 | 0 | 0 | |
Type of Ig light chain (serum) | Non-detected | 5.9 | 0 | 0 | 3.8 |
Kappa | 52.9 | 55 | 76.5 | 61.5 | |
Lambda | 41.2 | 45 | 23.5 | 30.8 | |
Biclonal | 0 | 0 | 0 | 3.8 | |
Serum M-spike, ≥3 gr/dL (%) | 0 | 10 | 82.4 | 23.1 | |
Urine M-spike, detected (%) | 20 | 29.4 | 70.6 | 53.8 | |
Kappa (%) | ≥19.4 mg/L | 57.1 | 66.7 | 100 | 66.7 |
Lambda (%) | ≥26.3 mg/L | 50 | 41.7 | 33.3 | 33.3 |
Free kappa/lambda ratio (%) | <0.26 mg/L | 14.3 | 23.1 | 0 | 26.7 |
≥0.26 < 1.65 mg/L | 42.9 | 38.5 | 22.2 | 6.7 | |
≥1.65 mg/L | 42.9 | 38.5 | 77.8 | 66.7 | |
Creatinine (%) | ≥1.3 mg/dL | 29.4 | 25 | 47.1 | 19.2 |
Serum calcium (%) | ≥11 mg/dL | 0 | 0 | 11.1 | 11.5 |
LDH (%) | ≥225 U/I | 5.9 | 14 | 11.8 | 38.5 |
Albúmina (%) | ≤3 g/dL | 0 | 5 | 11.8 | 3.8 |
Immunoparesis, yes (%) | 18.8 | 20 | 23.5 | 80.8 | |
Refractory, yes (%) | NA | NA | 5.9 | 40 | |
Type of prior treatment (%) | With PI | NA | 0 | 5.9 | 42.3 |
Without PI | NA | 100 | 94.1 | 57.7 | |
Type of following treatment (%) | With PI | NA | 25 | 88.2 | 42.3 |
Without PI | NA | 75 | 11.8 | 57.7 | |
Best response categories * (%) | VGPR | 0 | 0 | 17.6 | 0 |
PR | 0 | 30 | 58.8 | 34.6 | |
CR | 0 | 0 | 23.5 | 19.2 | |
CR MRD+ | 0 | 0 | 0 | 0 | |
CR MRD- | 0 | 0 | 0 | 0 | |
SD | 0 | 5 | 0 | 34.6 | |
NA | 100 | 65 | 0 | 11.5 | |
Performed analysis (methods) | Samples, n | 26 | 39 | 107 | 81 |
WGS | 0 | 10 | 10 | 0 | |
WES | 0 | 0 | 0 | 44 | |
mtDNA CN | 17 | 20 | 79 | 26 | |
Gene expression | 9 | 9 | 18 | 11 |
Coordinates | Codons | Protein | Substitution | Region | dbSNP ID | SNP Type | Mutated Sample | Prediction |
---|---|---|---|---|---|---|---|---|
15,89864181,1,T/C | AGT-gGT | POLG | S933G | EXON CDS | Novel | Nonsynonymous | SMM | DAMAGING |
15,89869943,1,C/A | GAG-tAG | POLG | E538X | EXON CDS | rs138413938:A | Nonsynonymous | RRMM | Damaging due to stop |
17,62492888,1,C/G | GAG-cAG | POLG2 | E67Q | EXON CDS | Novel | Nonsynonymous | RRMM | TOLERATED |
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Ruiz-Heredia, Y.; Ortiz-Ruiz, A.; Samur, M.K.; Garrido, V.; Rufian, L.; Sanchez, R.; Aguilar-Garrido, P.; Barrio, S.; Martín, M.A.; Bolli, N.; et al. Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma. Cancers 2021, 13, 3189. https://doi.org/10.3390/cancers13133189
Ruiz-Heredia Y, Ortiz-Ruiz A, Samur MK, Garrido V, Rufian L, Sanchez R, Aguilar-Garrido P, Barrio S, Martín MA, Bolli N, et al. Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma. Cancers. 2021; 13(13):3189. https://doi.org/10.3390/cancers13133189
Chicago/Turabian StyleRuiz-Heredia, Yanira, Alejandra Ortiz-Ruiz, Mehmet K. Samur, Vanesa Garrido, Laura Rufian, Ricardo Sanchez, Pedro Aguilar-Garrido, Santiago Barrio, Miguel A. Martín, Niccolò Bolli, and et al. 2021. "Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma" Cancers 13, no. 13: 3189. https://doi.org/10.3390/cancers13133189