Genome-wide analysis of aberrant position and sequence of plasma DNA fragment ends in patients with cancer.
Genome-wide analysis of aberrant position and sequence of plasma DNA fragment ends in patients with cancer.
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癌症患者的血浆DNA片段异常位置和序列的基因组分析。
DOI：
10.1126/scitranslmed.abm6863
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发表时间：
2023-01-11
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
由于细胞类型间染色质可及性的变化，血浆中无细胞DNA（cfDNA）的全基因组片段化模式受到细胞起源的强烈影响。健康细胞和癌细胞之间的这种差异为开发新的癌症诊断提供了机会。在这里，我们研究了cfDNA片段末端位置及其周围DNA序列的分析是否揭示了血液中肿瘤来源DNA的存在。我们对521个样本的cfDNA进行了全基因组分析，并分析了另外2,147个样本的测序数据，包括健康个体和11种不同癌症类型的患者。我们开发了一种基于全基因组片段定位差异的指标，通过片段长度和GC含量（异常片段的信息加权分数，iwFAF）进行加权。我们观察到iwFAF与肿瘤分数密切相关，对于携带体细胞点突变的DNA片段更高，并且在受拷贝数扩增影响的基因组区域内更高。我们还计算了在跨越片段末端的基因组位置处观察到的核苷酸频率的样品水平平均值。使用iwFAF和来自片段末端周围3个位置的9个核苷酸频率的组合，我们开发了一个机器学习模型来区分健康个体和癌症患者。我们观察到，对于检测任何阶段的癌症，接受者操作特征曲线（AUC）下的面积为0.91，对于检测I期癌症患者样品，AUC为0.87。我们的研究结果仍然稳健，每个样本分析的片段少至100万个，这表明片段末端分析可以成为癌症检测和监测的一种具有成本效益和可访问的方法。分析血浆DNA片段末端的定位和核苷酸频率可以改善癌症检测。
Genome-wide fragmentation patterns in cell-free DNA (cfDNA) in plasma are strongly influenced by cellular origin due to variation in chromatin accessibility across cell types. Such differences between healthy and cancer cells provide the opportunity for development of novel cancer diagnostics. Here, we investigated whether analysis of cfDNA fragment end positions and their surrounding DNA sequences reveals the presence of tumor-derived DNA in blood. We performed genome-wide analysis of cfDNA from 521 samples and analyzed sequencing data from an additional 2,147 samples, including healthy individuals and patients with 11 different cancer types. We developed a metric based on genome-wide differences in fragment positioning, weighted by fragment length and GC-content (information-weighted fraction of aberrant fragments, iwFAF). We observed that iwFAF strongly correlated with tumor fraction, was higher for DNA fragments carrying somatic point mutations, and was higher within genomic regions affected by copy number amplifications. We also calculated sample-level means of nucleotide frequencies observed at genomic positions spanning fragment ends. Using a combination of iwFAF and 9 nucleotide frequencies from 3 positions surrounding fragment ends, we developed a machine-learning model to differentiate healthy individuals from cancer patients. We observed an area under the receiver operative characteristic curve (AUC) of 0.91 for detection of cancer at any stage and an AUC of 0.87 for detection of stage I cancer patient samples. Our findings remained robust with as few as 1 million fragments analyzed per sample, demonstrating that analysis of fragment ends can become a cost-effective and accessible approach for cancer detection and monitoring. Analyzing the positioning and nucleotide frequency at plasma DNA fragment ends can improve cancer detection.
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DOI：
10.1016/j.annonc.2020.02.011
发表时间：
2020-06
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Liu MC;Oxnard GR;Klein EA;Swanton C;Seiden MV;CCGA Consortium
通讯作者：
CCGA Consortium
核苷酸分辨率上杂合性丧失和单相表达的全基因组丧失的综合分析揭示了三阴性乳腺癌的途径中断。
影响因子：
7
作者：
Ha G;Roth A;Lai D;Bashashati A;Ding J;Goya R;Giuliany R;Rosner J;Oloumi A;Shumansky K;Chin SF;Turashvili G;Hirst M;Caldas C;Marra MA;Aparicio S;Shah SP
通讯作者：
Shah SP
影响因子：
3.7
作者：
LoRusso PM;Sekulic A;Sosman JA;Liang WS;Carpten J;Craig DW;Solit DB;Bryce AH;Kiefer JA;Aldrich J;Nasser S;Halperin R;Byron SA;Pilat MJ;Boerner SA;Durecki D;Hendricks WPD;Enriquez D;Izatt T;Keats J;Legendre C;Markovic SN;Weise A;Naveed F;Schmidt J;Basu GD;Sekar S;Adkins J;Tassone E;Sivaprakasam K;Zismann V;Calvert VS;Petricoin EF;Fecher LA;Lao C;Eder JP;Vogelzang NJ;Perlmutter J;Gorman M;Manica B;Fox L;Schork N;Zelterman D;DeVeaux M;Joseph RW;Cowey CL;Trent JM
通讯作者：
Trent JM
DOI：
10.1073/pnas.1500076112
发表时间：
2015-03-17
影响因子：
11.1
作者：
Jiang, Peiyong;Chan, Carol W. M.;Lo, Y. M. Dennis
通讯作者：
Lo, Y. M. Dennis
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