Multi-dimensional fragmentomic assay for ultrasensitive early detection of colorectal advanced adenoma and adenocarcinoma
Multi-dimensional fragmentomic assay for ultrasensitive early detection of colorectal advanced adenoma and adenocarcinoma
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DOI：
10.1186/s13045-021-01189-w
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Junjie Peng
中科院分区：
文献类型：
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作者：
Xiaoji Ma;Yikuan Chen;Wanxiangfu Tang;Hua Bao;Shaobo Mo;Rui Liu;Shuyu Wu;Hairong Bao;Yaqi Li;Long Zhang;Xue Wu;Sanjun Cai;Yang Shao;Fangqi Liu;Junjie Peng
AbstractPrevious studies on liquid biopsy-based early detection of advanced colorectal adenoma (advCRA) or adenocarcinoma (CRC) were limited by low sensitivity. We performed a prospective study to establish an integrated model using fragmentomic profiles of plasma cell-free DNA (cfDNA) for accurately and cost-effectively detecting early-stage CRC and advCRA. The training cohort enrolled 310 participants, including 149 early-stage CRC patients, 46 advCRA patients and 115 healthy controls. Plasma cfDNA samples were prepared for whole-genome sequencing. An ensemble stacked model differentiating healthy controls from advCRA/early-stage CRC patients was trained using five machine learning models and five cfDNA fragmentomic features based on the training cohort. The model was subsequently validated using an independent test cohort (N = 311; including 149 early-stage CRC, 46 advCRA and 116 healthy controls). Our model showed an area under the curve (AUC) of 0.988 for differentiating advCRA/early-stage CRC patients from healthy individuals in an independent test cohort. The model performed even better for identifying early-stage CRC (AUC 0.990) compared to advCRA (AUC 0.982). At 94.8% specificity, the sensitivities for detecting advCRA and early-stage CRC reached 95.7% and 98.0% (0: 94.1%; I: 98.5%), respectively. Promisingly, the detection sensitivity has reached 100% and 97.6% in early-stage CRC patients with negative fecal occult or CEA blood test results, respectively. Finally, our model maintained promising performances (AUC: 0.982, 94.4% sensitivity at 94.8% specificity) even when sequencing depth was down-sampled to 1X. Our integrated predictive model demonstrated an unprecedented detection sensitivity for advCRA and early-stage CRC, shedding light on more accurate noninvasive CRC screening in clinical practice.
