基于循环游离 DNA 甲基化测序的非侵入性多癌种检测（THUNDER）：开发和独立验证研究。

Unintrusive multi-cancer detection by circulating cell-free DNA methylation sequencing (THUNDER): development and independent validation studies.

机构信息

Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

Burning Rock Biotech, Guangzhou, China.

出版信息

Ann Oncol. 2023 May;34(5):486-495. doi: 10.1016/j.annonc.2023.02.010. Epub 2023 Feb 26.

DOI:10.1016/j.annonc.2023.02.010

PMID:36849097

Abstract

BACKGROUND

Early detection of cancer offers the opportunity to identify candidates when curative treatments are achievable. The THUNDER study (THe UNintrusive Detection of EaRly-stage cancers, NCT04820868) aimed to evaluate the performance of enhanced linear-splinter amplification sequencing, a previously described cell-free DNA (cfDNA) methylation-based technology, in the early detection and localization of six types of cancers in the colorectum, esophagus, liver, lung, ovary, and pancreas.

PATIENTS AND METHODS

A customized panel of 161 984 CpG sites was constructed and validated by public and in-house (cancer: n = 249; non-cancer: n = 288) methylome data, respectively. The cfDNA samples from 1693 participants (cancer: n = 735; non-cancer: n = 958) were retrospectively collected to train and validate two multi-cancer detection blood test (MCDBT-1/2) models for different clinical scenarios. The models were validated on a prospective and independent cohort of age-matched 1010 participants (cancer: n = 505; non-cancer: n = 505). Simulation using the cancer incidence in China was applied to infer stage shift and survival benefits to demonstrate the potential utility of the models in the real world.

RESULTS

MCDBT-1 yielded a sensitivity of 69.1% (64.8%-73.3%), a specificity of 98.9% (97.6%-99.7%), and tissue origin accuracy of 83.2% (78.7%-87.1%) in the independent validation set. For early-stage (I-III) patients, the sensitivity of MCDBT-1 was 59.8% (54.4%-65.0%). In the real-world simulation, MCDBT-1 achieved a sensitivity of 70.6% in detecting the six cancers, thus decreasing late-stage incidence by 38.7%-46.4%, and increasing 5-year survival rate by 33.1%-40.4%, respectively. In parallel, MCDBT-2 was generated at a slightly low specificity of 95.1% (92.8%-96.9%) but a higher sensitivity of 75.1% (71.9%-79.8%) than MCDBT-1 for populations at relatively high risk of cancers, and also had ideal performance.

CONCLUSION

In this large-scale clinical validation study, MCDBT-1/2 models showed high sensitivity, specificity, and accuracy of predicted origin in detecting six types of cancers.

摘要

背景

癌症的早期检测提供了在可行的治疗方法下识别候选者的机会。THUNDER 研究（THe UNintrusive Detection of EaRly-stage cancers，NCT04820868）旨在评估增强型线性分裂扩增测序的性能，这是一种以前描述的基于游离 DNA（cfDNA）甲基化的技术，用于早期检测和定位结直肠、食管、肝、肺、卵巢和胰腺的六种癌症。

患者和方法

通过公共和内部（癌症：n=249；非癌症：n=288）甲基组数据分别构建和验证了定制的 161984 个 CpG 位点的面板。从 1693 名参与者（癌症：n=735；非癌症：n=958）的 cfDNA 样本中回顾性收集数据，用于训练和验证两种用于不同临床场景的多癌种检测血液检测（MCDBT-1/2）模型。在年龄匹配的 1010 名参与者的前瞻性和独立队列中验证了模型（癌症：n=505；非癌症：n=505）。使用中国的癌症发病率进行模拟，以推断分期转移和生存获益，以证明模型在现实世界中的潜在效用。

结果

MCDBT-1 在独立验证集中的灵敏度为 69.1%（64.8%-73.3%），特异性为 98.9%（97.6%-99.7%），组织起源准确性为 83.2%（78.7%-87.1%）。对于早期（I-III 期）患者，MCDBT-1 的灵敏度为 59.8%（54.4%-65.0%）。在现实世界的模拟中，MCDBT-1 在检测六种癌症中的灵敏度为 70.6%，从而降低了晚期发病率 38.7%-46.4%，并分别提高了 5 年生存率 33.1%-40.4%。同时，MCDBT-2 的特异性略低，为 95.1%（92.8%-96.9%），但灵敏度为 75.1%（71.9%-79.8%），适用于癌症风险较高的人群，也具有理想的性能。