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Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple‐negative breast cancer patients for potential biomarker development

Early detection and recurrence prediction are challenging in triple‐negative breast cancer (TNBC) patients. We aimed to develop mitochondrial DNA (mtDNA)‐based liquid biomarkers to improve TNBC management. Mitochondrial genome (MG) enrichment and next‐generation sequencing mapped the entire MG in 73...

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Autores principales: Vikramdeo, Kunwar Somesh, Anand, Shashi, Sudan, Sarabjeet Kour, Pramanik, Paramahansa, Singh, Seema, Godwin, Andrew K., Singh, Ajay Pratap, Dasgupta, Santanu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10551276/
https://www.ncbi.nlm.nih.gov/pubmed/37810173
http://dx.doi.org/10.1096/fba.2023-00070
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author Vikramdeo, Kunwar Somesh
Anand, Shashi
Sudan, Sarabjeet Kour
Pramanik, Paramahansa
Singh, Seema
Godwin, Andrew K.
Singh, Ajay Pratap
Dasgupta, Santanu
author_facet Vikramdeo, Kunwar Somesh
Anand, Shashi
Sudan, Sarabjeet Kour
Pramanik, Paramahansa
Singh, Seema
Godwin, Andrew K.
Singh, Ajay Pratap
Dasgupta, Santanu
author_sort Vikramdeo, Kunwar Somesh
collection PubMed
description Early detection and recurrence prediction are challenging in triple‐negative breast cancer (TNBC) patients. We aimed to develop mitochondrial DNA (mtDNA)‐based liquid biomarkers to improve TNBC management. Mitochondrial genome (MG) enrichment and next‐generation sequencing mapped the entire MG in 73 samples (64 tissues and 9 extracellular vesicles [EV] samples) from 32 metastatic TNBCs. We measured mtDNA and cardiolipin (CL) contents, NDUFB8, and SDHB protein expression in tumors and in corresponding circulating EVs. We identified 168 nonsynonymous mtDNA mutations, with 73% (123/186) coding and 27% (45/168) noncoding in nature. Twenty percent of mutations were nucleotide transversions. Respiratory complex I (RCI) was the key target, which harbored 44% (74/168) of the overall mtDNA mutations. A panel of 11 hotspot mtDNA mutations was identified among 19%–38% TNBCs, which were detectable in the serum‐derived EVs with 82% specificity. Overall, 38% of the metastatic tumor‐signature mtDNA mutations were traceable in the EVs. An appreciable number of mtDNA mutations were homoplasmic (18%, 31/168), novel (14%, 23/168), and potentially pathogenic (9%, 15/168). The overall and RCI‐specific mtDNA mutational load was higher in women with African compared to European ancestry accompanied by an exclusive abundance of respiratory complex (RC) protein NDUFB8 (RCI) and SDHB (RCII) therein. Increased mtDNA (p < 0.0001) content was recorded in both tumors and EVs along with an abundance of CL (p = 0.0001) content in the EVs. Aggressive tumor‐signature mtDNA mutation detection and measurement of mtDNA and CL contents in the EVs bear the potential to formulate noninvasive early detection and recurrence prediction strategies.
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spelling pubmed-105512762023-10-06 Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple‐negative breast cancer patients for potential biomarker development Vikramdeo, Kunwar Somesh Anand, Shashi Sudan, Sarabjeet Kour Pramanik, Paramahansa Singh, Seema Godwin, Andrew K. Singh, Ajay Pratap Dasgupta, Santanu FASEB Bioadv Research Articles Early detection and recurrence prediction are challenging in triple‐negative breast cancer (TNBC) patients. We aimed to develop mitochondrial DNA (mtDNA)‐based liquid biomarkers to improve TNBC management. Mitochondrial genome (MG) enrichment and next‐generation sequencing mapped the entire MG in 73 samples (64 tissues and 9 extracellular vesicles [EV] samples) from 32 metastatic TNBCs. We measured mtDNA and cardiolipin (CL) contents, NDUFB8, and SDHB protein expression in tumors and in corresponding circulating EVs. We identified 168 nonsynonymous mtDNA mutations, with 73% (123/186) coding and 27% (45/168) noncoding in nature. Twenty percent of mutations were nucleotide transversions. Respiratory complex I (RCI) was the key target, which harbored 44% (74/168) of the overall mtDNA mutations. A panel of 11 hotspot mtDNA mutations was identified among 19%–38% TNBCs, which were detectable in the serum‐derived EVs with 82% specificity. Overall, 38% of the metastatic tumor‐signature mtDNA mutations were traceable in the EVs. An appreciable number of mtDNA mutations were homoplasmic (18%, 31/168), novel (14%, 23/168), and potentially pathogenic (9%, 15/168). The overall and RCI‐specific mtDNA mutational load was higher in women with African compared to European ancestry accompanied by an exclusive abundance of respiratory complex (RC) protein NDUFB8 (RCI) and SDHB (RCII) therein. Increased mtDNA (p < 0.0001) content was recorded in both tumors and EVs along with an abundance of CL (p = 0.0001) content in the EVs. Aggressive tumor‐signature mtDNA mutation detection and measurement of mtDNA and CL contents in the EVs bear the potential to formulate noninvasive early detection and recurrence prediction strategies. John Wiley and Sons Inc. 2023-09-08 /pmc/articles/PMC10551276/ /pubmed/37810173 http://dx.doi.org/10.1096/fba.2023-00070 Text en ©2023 The Authors FASEB BioAdvances published by The Federation of American Societies for Experimental Biology. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Vikramdeo, Kunwar Somesh
Anand, Shashi
Sudan, Sarabjeet Kour
Pramanik, Paramahansa
Singh, Seema
Godwin, Andrew K.
Singh, Ajay Pratap
Dasgupta, Santanu
Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple‐negative breast cancer patients for potential biomarker development
title Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple‐negative breast cancer patients for potential biomarker development
title_full Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple‐negative breast cancer patients for potential biomarker development
title_fullStr Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple‐negative breast cancer patients for potential biomarker development
title_full_unstemmed Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple‐negative breast cancer patients for potential biomarker development
title_short Profiling mitochondrial DNA mutations in tumors and circulating extracellular vesicles of triple‐negative breast cancer patients for potential biomarker development
title_sort profiling mitochondrial dna mutations in tumors and circulating extracellular vesicles of triple‐negative breast cancer patients for potential biomarker development
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10551276/
https://www.ncbi.nlm.nih.gov/pubmed/37810173
http://dx.doi.org/10.1096/fba.2023-00070
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