Mitochondrial DNA Mutations are Associated with Ulcerative Colitis Preneoplasia but Tend to be Negatively Selected in Cancer
Mitochondrial DNA Mutations are Associated with Ulcerative Colitis Preneoplasia but Tend to be Negatively Selected in Cancer
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DOI：
10.1158/1541-7786.mcr-18-0520
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发表时间：
2019-02-01
影响因子：
5.2
通讯作者：
Risques, Rosa Ana
中科院分区：
文献类型：
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作者：
Baker, Kathryn T.;Nachmanson, Daniela;Risques, Rosa Ana
线粒体DNA（mtDNA）突变在癌症中的作用仍然存在争议。溃疡性结肠炎是一种炎症性肠病，可增加结直肠癌的风险，并涉及线粒体功能障碍，使其成为研究mtDNA在肿瘤发生中作用的理想模型。我们的目标是使用双链测序（一种超精确的下一代测序方法）全面表征溃疡性结肠炎肿瘤发生中的mtDNA突变。我们分析了46例非溃疡性结肠炎对照患者和溃疡性结肠炎伴或不伴癌症患者的结肠活检，包括异型增生进展各个阶段的活检。mtDNA测序的中位深度为1，364 x。通过突变等位基因频率对突变进行分类：克隆> 0.95，亚克隆0.01-0.95，和极低频（VLF）< 0.01。我们确定了208个克隆和亚克隆突变以及56，764个VLF突变。突变在线粒体基因组中随机分布。克隆和亚克隆突变的数量和致病性在早期异型增生增加，但在癌症的数量和致病性下降。大多数克隆、亚克隆和VLF突变都是线粒体DNA重链中的C>T转变，这可能是由DNA复制错误引起的。VLF突变的一个子集是C>A颠换，这可能是由于氧化损伤。VLF转换和插入缺失在非D环区不太丰富，并随着进展而减少。我们的研究结果表明，mtDNA突变是频繁的溃疡性结肠炎癌前病变，但消极选择cancer.Implications：虽然mtDNA突变可能有助于早期溃疡性结肠炎肿瘤的发生，他们似乎是选择对癌症，这表明功能性线粒体可能需要在溃疡性结肠炎的恶性转化。
The role of mitochondrial DNA (mtDNA) mutations in cancer remains controversial. Ulcerative colitis is an inflammatory bowel disease that increases the risk of colorectal cancer and involves mitochondrial dysfunction, making it an ideal model to study the role of mtDNA in tumorigenesis. Our goal was to comprehensively characterize mtDNA mutations in ulcerative colitis tumorigenesis using Duplex Sequencing, an ultra-accurate next-generation sequencing method. We analyzed 46 colon biopsies from non-ulcerative colitis control patients and ulcerative colitis patients with and without cancer, including biopsies at all stages of dysplastic progression. mtDNA was sequenced at a median depth of 1,364x. Mutations were classified by mutant allele frequency: clonal > 0.95, subclonal 0.01-0.95, and very low frequency (VLF) < 0.01. We identified 208 clonal and subclonal mutations and 56,764 VLF mutations. Mutations were randomly distributed across the mitochondrial genome. Clonal and subclonal mutations increased in number and pathogenicity in early dysplasia, but decreased in number and pathogenicity in cancer. Most clonal, subclonal, and VLF mutations were C>T transitions in the heavy strand of mtDNA, which likely arise from DNA replication errors. A subset of VLF mutations were C>A transversions, which are probably due to oxidative damage. VLF transitions and indels were less abundant in the non-D-loop region and decreased with progression. Our results indicate that mtDNA mutations are frequent in ulcerative colitis preneoplasia but negatively selected in cancers.Implications: While mtDNA mutations might contribute to early ulcerative colitis tumorigenesis, they appear to be selected against in cancer, suggesting that functional mitochondria might be required for malignant transformation in ulcerative colitis.