Fragmentation patterns and personalized sequencing of cell-free DNA in urine and plasma of glioma patients.
Fragmentation patterns and personalized sequencing of cell-free DNA in urine and plasma of glioma patients.
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神经胶质瘤患者尿液和血浆中游离DNA的片段化模式和个性化测序
DOI：
10.15252/emmm.202012881
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发表时间：
2021-08-09
影响因子：
11.1
通讯作者：
Mair R
中科院分区：
文献类型：
--
作者：
Mouliere F;Smith CG;Heider K;Su J;van der Pol Y;Thompson M;Morris J;Wan JCM;Chandrananda D;Hadfield J;Grzelak M;Hudecova I;Couturier DL;Cooper W;Zhao H;Gale D;Eldridge M;Watts C;Brindle K;Rosenfeld N;Mair R
胶质瘤来源的游离细胞DNA （cfDNA）在液体活检中检测具有挑战性，因为体液中的含量很低。我们在匹配肿瘤活检分析的指导下，利用个性化捕获面板测序，确定了患者脑脊液（CSF）、血浆和尿液样本中胶质瘤来源的DNA片段。通过对每个患者肿瘤中单独鉴定的数千个突变的cfDNA进行测序，我们在大多数脑脊液（7/8）、血浆（10/12）和尿液样本（10/16）中检测到肿瘤来源的DNA，中位肿瘤分数分别为6.4 × 10 - 3、3.1 × 10 - 5和4.7 × 10 - 5。我们发现这些体液中肿瘤来源的cfDNA片段的大小分布发生了变化。我们使用全基因组测序进一步分析了来自35名神经胶质瘤患者、27名非恶性脑部疾病患者和26名健康个体的尿液样本中的cfDNA片段大小。与非恶性脑疾病患者（P = 1.7 × 10−2）和健康个体（P = 5.2 × 10−9）相比，神经胶质瘤患者尿液中的cfDNA片段化程度更高。整合碎片长度的机器学习模型可以区分神经胶质瘤患者的尿液样本（AUC = 0.80-0.91），这表明了真正的非侵入性癌症检测的可能性。利用体液中肿瘤来源的无细胞DNA （cfDNA）检测胶质瘤具有挑战性。在这项研究中，开发了两种新的分析方法（肿瘤引导测序和sWGS）来探索使用血浆和尿液cfDNA作为这种恶性肿瘤的液体活检的潜力。
Glioma‐derived cell‐free DNA (cfDNA) is challenging to detect using liquid biopsy because quantities in body fluids are low. We determined the glioma‐derived DNA fraction in cerebrospinal fluid (CSF), plasma, and urine samples from patients using sequencing of personalized capture panels guided by analysis of matched tumor biopsies. By sequencing cfDNA across thousands of mutations, identified individually in each patient’s tumor, we detected tumor‐derived DNA in the majority of CSF (7/8), plasma (10/12), and urine samples (10/16), with a median tumor fraction of 6.4 × 10−3, 3.1 × 10−5, and 4.7 × 10−5, respectively. We identified a shift in the size distribution of tumor‐derived cfDNA fragments in these body fluids. We further analyzed cfDNA fragment sizes using whole‐genome sequencing, in urine samples from 35 glioma patients, 27 individuals with non‐malignant brain disorders, and 26 healthy individuals. cfDNA in urine of glioma patients was significantly more fragmented compared to urine from patients with non‐malignant brain disorders (P = 1.7 × 10−2) and healthy individuals (P = 5.2 × 10−9). Machine learning models integrating fragment length could differentiate urine samples from glioma patients (AUC = 0.80–0.91) suggesting possibilities for truly non‐invasive cancer detection. Gliomas are challenging to detect using tumor derived cell‐free DNA (cfDNA) in body fluids. In this study, two novel analysis methods (tumor‐guided sequencing and sWGS) were developed to explore the potential of using plasma and urine cfDNA as a liquid biopsy for this malignancy.
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影响因子：
9.3
作者：
Pan W;Gu W;Nagpal S;Gephart MH;Quake SR
通讯作者：
Quake SR
影响因子：
16.6
作者：
De Mattos-Arruda L;Mayor R;Ng CKY;Weigelt B;Martínez-Ricarte F;Torrejon D;Oliveira M;Arias A;Raventos C;Tang J;Guerini-Rocco E;Martínez-Sáez E;Lois S;Marín O;de la Cruz X;Piscuoglio S;Towers R;Vivancos A;Peg V;Ramon y Cajal S;Carles J;Rodon J;González-Cao M;Tabernero J;Felip E;Sahuquillo J;Berger MF;Cortes J;Reis-Filho JS;Seoane J
通讯作者：
Seoane J
影响因子：
82.9
作者：
Nassiri F;Chakravarthy A;Feng S;Shen SY;Nejad R;Zuccato JA;Voisin MR;Patil V;Horbinski C;Aldape K;Zadeh G;De Carvalho DD
通讯作者：
De Carvalho DD
影响因子：
50.3
作者：
Kim, Jinkuk;Lee, In-Hee;Nam, Do-Hyun
通讯作者：
Nam, Do-Hyun
通过碎片尺寸分析增强了循环肿瘤DNA的检测。
影响因子：
17.1
作者：
Mouliere F;Chandrananda D;Piskorz AM;Moore EK;Morris J;Ahlborn LB;Mair R;Goranova T;Marass F;Heider K;Wan JCM;Supernat A;Hudecova I;Gounaris I;Ros S;Jimenez-Linan M;Garcia-Corbacho J;Patel K;Østrup O;Murphy S;Eldridge MD;Gale D;Stewart GD;Burge J;Cooper WN;van der Heijden MS;Massie CE;Watts C;Corrie P;Pacey S;Brindle KM;Baird RD;Mau-Sørensen M;Parkinson CA;Smith CG;Brenton JD;Rosenfeld N
通讯作者：
Rosenfeld N