Detection of mitochondrial DNA mutations in circulating mitochondria-originated extracellular vesicles for potential diagnostic applications in pancreatic adenocarcinoma.
Detection of mitochondrial DNA mutations in circulating mitochondria-originated extracellular vesicles for potential diagnostic applications in pancreatic adenocarcinoma.
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DOI：
10.1038/s41598-022-22006-5
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发表时间：
2022-11-02
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
早期胰腺导管腺癌（PDAC）诊断完全缺乏高度敏感和特异性的生物标志物，限制了多模式治疗的选择。线粒体DNA （mtDNA）因其在肿瘤细胞中的高拷贝数和高突变频率而成为发现生物标志物的极好资源。我们研究了mtDNA突变是否可以在PDAC患者的循环细胞外囊泡（EVs）中检测到，并用于区分癌症和非癌症受试者。PDAC患者（n = 20）比非癌症（NC）患者（n = 10）获得更高的循环ev产量（约1.4倍，p = 0.002）。pdac - ev的总DNA含量高于nc - ev(~ 5.5倍，p = 0.0001)， mtDNA的富集程度高于nc - ev（~ 14.02倍，p = 0.0001）。pdac - ev也有较高水平的心磷脂（线粒体内膜磷脂），提示其线粒体起源。所有pdac - ev的mtDNA突变都是独特的，并且频率显著较高。pdac - ev中mtDNA突变最多（41.5%）发生在呼吸复合体i (RCI) (ND1-ND6)，其次是RCIII基因（CYTB, 11.2%）。在非编码基因中，D-Loop和RNR2突变最多，各占15.2%。总之，我们的研究首次确定了mtDNA突变可以在循环ev中检测到，并可能作为可靠的PDAC诊断工具。
There is a complete lack of highly sensitive and specific biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis, limiting multi-modal therapeutic options. Mitochondrial DNA (mtDNA) is an excellent resource for biomarker discovery because of its high copy number and increased mutational frequency in cancer cells. We examined if mtDNA mutations can be detected in circulating extracellular vesicles (EVs) of PDAC patients and used for discerning between cancer and non-cancer subjects. A greater yield of circulating EVs (~ 1.4 fold; p = 0.002) was obtained in PDAC patients (n = 20) than non-cancer (NC) individuals (n = 10). PDAC-EVs contained a higher quantity of total DNA (~ 5.5 folds; p = 0.0001) than NC-EVs and had greater enrichment of mtDNA (~ 14.02-fold; p = 0.0001). PDAC-EVs also had higher levels of cardiolipin (a mitochondrial inner-membrane phospholipid), suggestive of their mitochondrial origin. All mtDNA mutations in PDAC-EVs were unique and frequency was remarkably higher. Most mtDNA mutations (41.5%) in PDAC-EVs were in the respiratory complex-I (RCI) (ND1-ND6), followed by the RCIII gene (CYTB; 11.2%). Among the non-coding genes, D-Loop and RNR2 exhibited the most mutations (15.2% each). Altogether, our study establishes, for the first time, that mtDNA mutations can be detected in circulating EVs and potentially serve as a tool for reliable PDAC diagnosis.
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DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
DOI：
10.1158/1940-6207.capr-10-0326
发表时间：
2011-05
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Chatterjee A;Dasgupta S;Sidransky D
通讯作者：
Sidransky D
影响因子：
5.5
作者：
Amintas S;Vendrely V;Dupin C;Buscail L;Laurent C;Bournet B;Merlio JP;Bedel A;Moreau-Gaudry F;Boutin J;Dabernat S;Buscail E
通讯作者：
Buscail E
影响因子：
32.4
作者：
Iyer SS;He Q;Janczy JR;Elliott EI;Zhong Z;Olivier AK;Sadler JJ;Knepper-Adrian V;Han R;Qiao L;Eisenbarth SC;Nauseef WM;Cassel SL;Sutterwala FS
通讯作者：
Sutterwala FS
影响因子：
5.6
作者：
Genovese I;Carinci M;Modesti L;Aguiari G;Pinton P;Giorgi C
通讯作者：
Giorgi C