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首页> 外文期刊>Neoplasia: an international journal for oncology research >Widespread Non-Canonical Epigenetic Modifications in MMTV-NeuT Breast Cancer
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Widespread Non-Canonical Epigenetic Modifications in MMTV-NeuT Breast Cancer

机译：MMTV - 乳腺癌中的广泛非规范表观遗传修饰

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Breast tumors in (FVB × BALB-NeuT) F1 mice have characteristic loss of chromosome 4 and sporadic loss or gain of other chromosomes. We employed the Illumina GoldenGate genotyping platform to quantitate loss of heterozygosity (LOH) across the genome of primary tumors, revealing strong biases favoring chromosome 4 alleles from the FVB parent. While allelic bias was not observed on other chromosomes, many tumors showed concerted LOH (C-LOH) of all alleles of one or the other parent on sporadic chromosomes, a pattern consistent with cytogenetic observations. Surprisingly, comparison of LOH in tumor samples relative to normal unaffected tissues from these animals revealed significant variegated (stochastic) deviations from heterozygosity (V-LOH) in every tumor genome. Sequence analysis showed expected changes in the allelic frequency of single nucleotide polymorphisms (SNPs) in cases of C-LOH. However, no evidence of LOH due to mutations, small deletions, or gene conversion at the affected SNPs or surrounding DNA was found at loci with V-LOH. Postulating an epigenetic mechanism contributing to V-LOH, we tested whether methylation of template DNA impacts allele detection efficiency using synthetic oligonucleotide templates in an assay mimicking the GoldenGate genotyping format. Methylated templates were systematically over-scored, suggesting that the observed patterns of V-LOH may represent extensive epigenetic DNA modifications across the tumor genomes. As most of the SNPs queried do not contain standard (CpG) methylation targets, we propose that widespread, non-canonical DNA modifications occur during Her2/neuT-driven tumorigenesis.
机译：乳腺肿瘤（FVB×BALB-NEGRE）F1小鼠具有染色体4的特征丧失，以及其他染色体的散发性损失或增益。我们使用Illumina Goldengate基因分型平台来定量原发性肿瘤基因组的杂合性（LOH）的损失，揭示了来自FVB父母的染色体4个等位基因的强偏差。虽然在其他染色体上未观察到等位基因偏差，但许多肿瘤显示出散发染色体上的一种或另一个母体等位基因的齐节（C-LOH），其具有与细胞遗传学观察一致的模式。令人惊讶的是，肿瘤样品相对于来自这些动物的正常未受影响的组织的LOH在肿瘤样品中的比较显示出在每个肿瘤基因组中的杂合子（V-LOH）的显着差异（随机）偏差。序列分析显示C-LOH病例中单核苷酸多态性（SNP）的等位基因频率的预期变化。然而，在具有V-LOH的基因座上发现了由于受影响的SNP或受影响的SNP或周围DNA的突变或基因转化导致的LOH的证据。假设有助于V-LOH的表观遗传机制，我们测试了模板DNA的甲基化是否在模拟核心基因分型格式的测定中使用合成寡核苷酸模板对等位基因检测效率产生影响。系统地过度评分甲基化模板，表明V-LOH的观察模式可以在肿瘤基因组上表示广泛的表观遗传DNA修饰。由于大多数疑问的SNP不含标准（CPG）甲基化靶标，我们提出了在HER2 / Neut驱动的肿瘤内发生期间发生的广泛的非规范性DNA修饰。

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