Abstract：
BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a promising tool for early cancer detection and minimal residual disease monitoring. However, the biology underlying ctDNA release and its variation across cancer types and histologies remains poorly understood. This study investigated the biology behind ctDNA shedding in colorectal cancer.
METHODS: The study included a local cohort of 747 stage I-III colorectal cancer patients. All patients had ctDNA measurement prior to treatment and extensive clinical data. Primary tumor RNA sequencing and whole exome sequencing was performed in 95 and 652 patients respectively. Additionally, the study evaluated 89 non-small cell lung cancer patients from the TRACERx cohort, comprising primary tumor RNA sequencing and ctDNA measurement.
RESULTS: We found tumor size and proliferative capacity to be key factors associated with ctDNA shedding in colorectal cancer. Furthermore, we found that the secretory and CMS3 colorectal cancer subtypes exhibited lower ctDNA shedding, while microsatellite instability (MSI) tumors had higher levels of ctDNA. Mutational analysis did not reveal any genes or pathways associated with ctDNA shedding in colorectal cancer. A comparison of transcriptomic profiles across multiple cancer types demonstrated that colorectal cancer and lung squamous cell carcinoma tumors shared a high-proliferative ctDNA shedding phenotype, while lung adenocarcinoma tumors displayed a distinct low-proliferative subgroup. Additionally, proliferation levels correlated with ctDNA detection sensitivity across multiple cancer types.
CONCLUSIONS: These findings suggest that tumor size and proliferative capacity are drivers of ctDNA release in colorectal cancer and provide insights into the biology of ctDNA shedding on a pan-cancer level.
METHODS: The study included a local cohort of 747 stage I-III colorectal cancer patients. All patients had ctDNA measurement prior to treatment and extensive clinical data. Primary tumor RNA sequencing and whole exome sequencing was performed in 95 and 652 patients respectively. Additionally, the study evaluated 89 non-small cell lung cancer patients from the TRACERx cohort, comprising primary tumor RNA sequencing and ctDNA measurement.
RESULTS: We found tumor size and proliferative capacity to be key factors associated with ctDNA shedding in colorectal cancer. Furthermore, we found that the secretory and CMS3 colorectal cancer subtypes exhibited lower ctDNA shedding, while microsatellite instability (MSI) tumors had higher levels of ctDNA. Mutational analysis did not reveal any genes or pathways associated with ctDNA shedding in colorectal cancer. A comparison of transcriptomic profiles across multiple cancer types demonstrated that colorectal cancer and lung squamous cell carcinoma tumors shared a high-proliferative ctDNA shedding phenotype, while lung adenocarcinoma tumors displayed a distinct low-proliferative subgroup. Additionally, proliferation levels correlated with ctDNA detection sensitivity across multiple cancer types.
CONCLUSIONS: These findings suggest that tumor size and proliferative capacity are drivers of ctDNA release in colorectal cancer and provide insights into the biology of ctDNA shedding on a pan-cancer level.
摘要：
背景：循环肿瘤DNA（ctDNA）已成为早期癌症检测和微小残留病监测的有希望的工具。然而,ctDNA释放的生物学基础及其在癌症类型和组织学之间的变化仍然知之甚少。这项研究调查了结直肠癌中ctDNA脱落背后的生物学行为。
方法：本研究纳入了747名I-III期结直肠癌患者的局部队列。所有患者在治疗前都有ctDNA测量和广泛的临床数据。分别对95例和652例患者进行了原发肿瘤RNA测序和全外显子组测序。此外,该研究评估了来自TRACERx队列的89例非小细胞肺癌患者，包括原发性肿瘤RNA测序和ctDNA测量。
结果：我们发现肿瘤大小和增殖能力是与结直肠癌ctDNA脱落相关的关键因素。此外，我们发现分泌型和CMS3型大肠癌亚型表现出较低的ctDNA脱落，而微卫星不稳定性（MSI）肿瘤的ctDNA水平较高。突变分析未发现与结直肠癌中ctDNA脱落相关的任何基因或途径。多种癌症类型的转录组学比较表明，结直肠癌和肺鳞状细胞癌肿瘤具有高增殖性ctDNA脱落表型，而肺腺癌肿瘤显示出明显的低增殖亚组。此外,增殖水平与多种癌症类型的ctDNA检测灵敏度相关。
结论：这些研究结果表明，肿瘤大小和增殖能力是结直肠癌中ctDNA释放的驱动因素，并在泛癌症水平上提供了对ctDNA脱落生物学的见解。
方法：本研究纳入了747名I-III期结直肠癌患者的局部队列。所有患者在治疗前都有ctDNA测量和广泛的临床数据。分别对95例和652例患者进行了原发肿瘤RNA测序和全外显子组测序。此外,该研究评估了来自TRACERx队列的89例非小细胞肺癌患者，包括原发性肿瘤RNA测序和ctDNA测量。
结果：我们发现肿瘤大小和增殖能力是与结直肠癌ctDNA脱落相关的关键因素。此外，我们发现分泌型和CMS3型大肠癌亚型表现出较低的ctDNA脱落，而微卫星不稳定性（MSI）肿瘤的ctDNA水平较高。突变分析未发现与结直肠癌中ctDNA脱落相关的任何基因或途径。多种癌症类型的转录组学比较表明，结直肠癌和肺鳞状细胞癌肿瘤具有高增殖性ctDNA脱落表型，而肺腺癌肿瘤显示出明显的低增殖亚组。此外,增殖水平与多种癌症类型的ctDNA检测灵敏度相关。
结论：这些研究结果表明，肿瘤大小和增殖能力是结直肠癌中ctDNA释放的驱动因素，并在泛癌症水平上提供了对ctDNA脱落生物学的见解。
