Identification of Somatic Mitochondrial DNA Mutations, Heteroplasmy, and Increased Levels of Catenanes in Tumor Specimens Obtained from Three Endometrial Cancer Patients.
Identification of Somatic Mitochondrial DNA Mutations, Heteroplasmy, and Increased Levels of Catenanes in Tumor Specimens Obtained from Three Endometrial Cancer Patients.
复制标题
鉴定体细胞线粒体DNA突变，异质性，和增加水平的肿瘤标本从三个子宫内膜癌患者。
DOI：
10.3390/life12040562
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发表时间：
2022-04-09
期刊：
影响因子：
3.2
通讯作者：
Young, Carolyn K. J.
中科院分区：
文献类型：
--
作者：
Young, Matthew J.;Sachidanandam, Ravi;Hales, Dale B.;Brard, Laurent;Robinson, Kathy;Rahman, Md Mostafijur;Khadka, Pabitra;Groesch, Kathleen;Young, Carolyn K. J.
关键词：
子宫内膜癌（EC）是最常见的妇科恶性上皮性肿瘤，在过去的20年中，这种疾病的死亡率翻了一番。线粒体为癌细胞提供必要的合成代谢构件，如氨基酸、脂质和核苷酸，并且EC样品已显示出增加线粒体生物合成。在癌症中，线粒体DNA（mtDNA）异质性研究表明异质性变体编码预测的致病蛋白。我们调查了正常和肿瘤标本中的mtDNA基因型，这些标本来自三个诊断为EC的个体。正常组织和肿瘤组织的DNA提取物用于mtDNA特异性下一代测序和mtDNA含量和拓扑异构体分析。这三种肿瘤具有异质性体细胞突变，并且预测每种癌中至少有一种突变会有害地改变mtDNA编码的蛋白质。在不同的肿瘤中发现了与两个mtDNA tRNA基因相关的体细胞异质性，在单个EC肿瘤中发现了两个异质性非编码变体。虽然有两个肿瘤改变了mtDNA含量，但所有三个肿瘤都显示mtDNA链烷增加。我们的研究结果支持EC细胞需要野生型mtDNA，但异质性突变可能会改变线粒体代谢，以帮助促进癌细胞的生长和增殖。
Endometrial carcinoma (EC) is the most common type of gynecologic malignant epithelial tumor, with the death rate from this disease doubling over the past 20 years. Mitochondria provide cancer cells with necessary anabolic building blocks such as amino acids, lipids, and nucleotides, and EC samples have been shown to increase mitochondrial biogenesis. In cancer, mitochondrial DNA (mtDNA) heteroplasmy studies suggest that heteroplasmic variants encode predicted pathogenic proteins. We investigated the mtDNA genotypes within peri-normal and tumor specimens obtained from three individuals diagnosed with EC. DNA extracts from peri-normal and tumor tissues were used for mtDNA-specific next-generation sequencing and analyses of mtDNA content and topoisomers. The three tumors harbor heteroplasmic somatic mutations, and at least one mutation in each carcinoma is predicted to deleteriously alter a mtDNA-encoded protein. Somatic heteroplasmy linked to two mtDNA tRNA genes was found in separate tumors, and two heteroplasmic non-coding variants were identified in a single EC tumor. While two tumors had altered mtDNA content, all three displayed increased mtDNA catenanes. Our findings support that EC cells require wild-type mtDNA, but heteroplasmic mutations may alter mitochondrial metabolism to help promote cancer cell growth and proliferation.
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影响因子：
7.7
作者：
Ju YS;Alexandrov LB;Gerstung M;Martincorena I;Nik-Zainal S;Ramakrishna M;Davies HR;Papaemmanuil E;Gundem G;Shlien A;Bolli N;Behjati S;Tarpey PS;Nangalia J;Massie CE;Butler AP;Teague JW;Vassiliou GS;Green AR;Du MQ;Unnikrishnan A;Pimanda JE;Teh BT;Munshi N;Greaves M;Vyas P;El-Naggar AK;Santarius T;Collins VP;Grundy R;Taylor JA;Hayes DN;Malkin D;ICGC Breast Cancer Group;ICGC Chronic Myeloid Disorders Group;ICGC Prostate Cancer Group;Foster CS;Warren AY;Whitaker HC;Brewer D;Eeles R;Cooper C;Neal D;Visakorpi T;Isaacs WB;Bova GS;Flanagan AM;Futreal PA;Lynch AG;Chinnery PF;McDermott U;Stratton MR;Campbell PJ
通讯作者：
Campbell PJ
影响因子：
56.9
作者：
Ishikawa, Kaori;Takenaga, Keizo;Hayashi, Jun-Ichi
通讯作者：
Hayashi, Jun-Ichi
影响因子：
3.5
作者：
Guerra, Flora;Kurelac, Ivana;Gasparre, Giuseppe
通讯作者：
Gasparre, Giuseppe
影响因子：
1.2
作者：
Hardarson, Hordur Alexander;Heidemann, Lene Nyhoj;dePont Christensen, Rene;Mogensen, Ole;Jochumsen, Kirsten M
通讯作者：
Jochumsen, Kirsten M
影响因子：
20.8
作者：
Gorelick, Alexander N.;Kim, Minsoo;Chatila, Walid K.;La, Konnor;Hakimi, A. Ari;Berger, Michael F.;Taylor, Barry S.;Gammage, Payam A.;Reznik, Ed
通讯作者：
Reznik, Ed