Analysis of recurrently protected genomic regions in cell-free DNA found in urine.
Analysis of recurrently protected genomic regions in cell-free DNA found in urine.
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DOI：
10.1126/scitranslmed.aaz3088
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发表时间：
2021-02-17
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
尿液中的游离 DNA (cfDNA) 是一种很有前景的无创诊断分析物。然而，尿液 cfDNA 高度碎片化。这些片段的特征是否反映了潜在的基因组结构尚不清楚。在这里，我们使用全基因组测序来表征尿液 cfDNA 的碎片模式。尿液 cfDNA 片段的大小分布显示出 40 bp 至 120 bp 之间的多个强峰，众数大小为 81 bp，周期性为 10 bp，表明存在短暂的保护，免于完全降解。这些特性对于分析前的扰动（例如家庭收集和处理延迟）具有鲁棒性。尿液 cfDNA 片段的全基因组测序覆盖揭示了个体间保守的循环保护区域 (RPR)，与从血浆 cfDNA 推断的核小体定位图部分重叠。 cfDNA 片段的末端聚集在 RPR 的上游和下游，片段末端的核苷酸频率表明尿液 cfDNA 的酶消化。与血浆相比，尿液 cfDNA 的碎片模式与泌尿道上皮细胞的基因表达和染色质可及性具有更大的相关性。我们确定肿瘤来源的尿液 cfDNA 表现出较高频率的以 RPR 结尾的异常片段。通过比较异常片段的比例和片段末端的核苷酸频率，我们确定了曲线下面积为 0.89 的癌症患者的尿液样本。我们的结果揭示了尿液 cfDNA 片段的非随机基因组定位，并表明对反复受保护的基因组位点的片段模式进行分析可以作为癌症诊断。健康人和癌症患者尿液中游离 DNA 的断裂模式有所不同。
Cell-free DNA (cfDNA) in urine is a promising analyte for noninvasive diagnostics. However, urine cfDNA is highly fragmented. Whether characteristics of these fragments reflect underlying genomic architecture is unknown. Here, we characterized fragmentation patterns in urine cfDNA using whole genome sequencing. Size distribution of urine cfDNA fragments showed multiple strong peaks between 40 bp and 120 bp with a modal size of 81 bp and sharp 10 bp periodicity, suggesting transient protection from complete degradation. These properties were robust to pre-analytical perturbations, such as at-home collection and delay in processing. Genome-wide sequencing coverage of urine cfDNA fragments revealed recurrently protected regions (RPRs) conserved across individuals, with partial overlap with nucleosome positioning maps inferred from plasma cfDNA. The ends of cfDNA fragments clustered upstream and downstream of RPRs, and nucleotide frequencies of fragment ends indicated enzymatic digestion of urine cfDNA. Compared to plasma, fragmentation patterns in urine cfDNA showed greater correlation with gene expression and chromatin accessibility in epithelial cells of the urinary tract. We determined that tumor-derived urine cfDNA exhibits a higher frequency of aberrant fragments that end within RPRs. By comparing the fraction of aberrant fragments and nucleotide frequencies of fragment ends, we identified urine samples from cancer patients with an area under the curve of 0.89. Our results revealed non-random genomic positioning of urine cfDNA fragments and suggested that analysis of fragmentation patterns across recurrently protected genomic loci may serve as a cancer diagnostic. Fragmentation patterns of cell-free DNA from urine differ between healthy individuals and those with cancer.
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DOI：
10.1093/annonc/mdu479
发表时间：
2015-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Favero F;Joshi T;Marquard AM;Birkbak NJ;Krzystanek M;Li Q;Szallasi Z;Eklund AC
通讯作者：
Eklund AC
DOI：
10.1093/bioinformatics/btq033
发表时间：
2010-03-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Quinlan AR;Hall IM
通讯作者：
Hall IM
影响因子：
4.6
作者：
Markus H;Contente-Cuomo T;Farooq M;Liang WS;Borad MJ;Sivakumar S;Gollins S;Tran NL;Dhruv HD;Berens ME;Bryce A;Sekulic A;Ribas A;Trent JM;LoRusso PM;Murtaza M
通讯作者：
Murtaza M
影响因子：
8.3
作者：
Burnham, Philip;Khush, Kiran;De Vlaminck, Iwijn
通讯作者：
De Vlaminck, Iwijn
DOI：
10.1126/science.1222794
发表时间：
2012-09-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Maurano MT;Humbert R;Rynes E;Thurman RE;Haugen E;Wang H;Reynolds AP;Sandstrom R;Qu H;Brody J;Shafer A;Neri F;Lee K;Kutyavin T;Stehling-Sun S;Johnson AK;Canfield TK;Giste E;Diegel M;Bates D;Hansen RS;Neph S;Sabo PJ;Heimfeld S;Raubitschek A;Ziegler S;Cotsapas C;Sotoodehnia N;Glass I;Sunyaev SR;Kaul R;Stamatoyannopoulos JA
通讯作者：
Stamatoyannopoulos JA