ctDNA检测相关的理论模型
1 cm3肿瘤释放到血液中的ctDNA比例为0.022%
肿瘤体积与hGE线性相关
By reanalyzing ctDNA sequencing data and tumor volumes of 176 patients with stage I to III non–small cell lung cancer of three cohorts (14, 22, 23), we found that haploid genome equivalents (hGE) per plasma ml indeed correlate with tumor volume with a slope of 0.9997 [95% confidence interval (CI), 0.78 to 1.2; R2 = 0.32; red line in Fig. 1B; Materials and Methods]. We found similar linear regression slopes and intercepts in the separated three cohorts (fig. S1).
Linear regression predicted 0.21 hGE per plasma ml for 1 cm3 of tumor volume(95% CI, 0.15 to 0.28; 95% prediction interval, 0.0033 to 13 hGE per plasma ml for a fixed slope of 1; fig. S2B). In other words, approximately 0.014% of a cancer cell’s genome is shed into the bloodstream after it undergoes apoptosis.
For a ctDNA half-life time of t1/2 = 30 min (16), we calculated a ctDNA elimination rate of ≈ 33 per day.
At a primary tumor size of 1 cm3 (~1 billion cells), we find, on average, 572 ctDNA hGE circulating in the bloodstream (Fig. 1D). A 15-ml blood sample contains approximately 1.7 ctDNA hGE (Fig. 1E). At a mean plasma DNA concentration of 6.3 ng per plasma ml (Materials and Methods), 0.21 ctDNA hGE per plasma ml correspond to a tumor fraction of 0.022% (assuming 6.6 pg per diploid genome).
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Factors influence ctDNA levels
In general, the tumor growth dynamics, the ctDNA half-life time, and the ctDNA shedding rate strongly influence ctDNA levels (fig. S3).
To further demonstrate the generality of this framework and the accuracy of our analytical results, we considered tumors with different sizes, growth rates, and cell turnover rates. As expected, a tumor with 0.5 billion cells leads to half the number of circulating biomarkers (C ≈ 286 hGE; Fig. 2A). More unexpectedly, a slowly growing lung cancer (r = 0.1%) leads to a substantially higher number of 585 hGE than a faster-growing cancer (r = 4%) with 502 hGE at the same size of 1 cm3, assuming that the faster growth is achieved by proportionally increased birth and decreased death rates (Fig. 2B).
1 cm3肿瘤血液中的ctDNA平均克隆突变VAF为0.008%
转换后的ctDNA平均克隆突变VAF与肿瘤体积线性相关
In ctDNA-positive patients, pathologic tumour size correlated with the mean plasma VAF of clonal SNVs (Spearman’s ρ=0.405, P=0.005, n=46, Extended Data Fig. 4b). Computed tomography (CT) scan volumetric analyses were evaluated in 37 out of 46 ctDNA-positive patients (see Extended Data Fig. 4c). Tumour volume from CT analyses correlated with mean clonal plasma VAF (Spearman’s ρ=0.63, P<0.001, n = 37, Fig. 3a).
A linear relationship between log-transformed volume and log-transformed mean clonal VAF values was observed (Fig. 3a). The line of best fit applied to the data was consistent with the line fitted to NSCLC volumetric data and ctDNA plasma VAFs that have been reported previously16 (Extended Data Fig. 4d).
Linear modelling based on the TRACERx data predicted that a primary tumour burden of 10 cm3 would result in a mean clonal plasma VAF of 0.1% (95% confidence interval, 0.06–0.18%) (Fig. 3b).
On the assumption that a cancer cell volume of 1 cm3 contains 9.4×107 cells, a plasma VAF of 0.1% would correspond to a primary NSCLC malignant burden of 302 million tumour cells
ctDNA可检测性与NSCLC病理分型相关
Centrally reviewed pathology data revealed that ctDNA detection was associated with histological subtype: 97% (30 out of 31) of lung squamous cell carcinomas (LUSCs) and 71% (5 out of 7) of other NSCLC subtypes were ctDNA-positive, compared with 19% (11 out of 58) of lung adenocarcinomas (LUADs) (Fig. 2a).
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ctDNA was detected in 94% (16 out of 17) of stage I LUSCs compared with 13% (5 out of 39) of stage I LUADs (Extended Data Fig. 3a).
参考资料
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Avanzini, Stefano et al. “A mathematical model of ctDNA shedding predicts tumor detection size.” Science advances vol. 6,50 eabc4308. 11 Dec. 2020, doi:10.1126/sciadv.abc4308
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Abbosh, Christopher et al. “Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.” Nature vol. 545,7655 (2017): 446-451. doi:10.1038/nature22364
