Diagnosis of malignant body fluids via cancer-universal methylation in cell-free DNA

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Abstract

BACKGROUND Differentiating malignant from nonmalignant body fluids remains a clinical challenge because of the unsatisfying performance of conventional cytology. We aimed to improve the sensitivity and ubiquity of cancer cell detection by assaying universal cancer–only methylation (UCOM) markers in supernatant cell-free DNA (cfDNA).METHODS An observational prospective cohort including 1,321 nonmalignant and malignant body fluids of multiple cancers was used to develop and validate a cfDNA UCOM methylation diagnostic assay. All samples were divided into 2 portions for cytology and supernatant cfDNA methylation analysis.RESULTS The significant hypermethylation of a potentially novel UCOM marker, TAGMe, together with the formerly reported PCDHGB7, was identified in the cfDNA of malignant body fluid samples. The combined model, cell-free cancer-universal methylation (CUE), was developed and validated in a prospective multicancer cohort with markedly elevated sensitivity and specificity, and was further verified in a set containing additional types of malignant body fluids and metastases. In addition, it remained hypersensitive in detecting cancer cells in cytologically negative malignant samples.CONCLUSION cfDNA methylation markers are robust in detecting tumor cells and are applicable to diverse body fluids and tumor types, providing a feasible complement to current cytology-based diagnostic analyses.TRIAL REGISTRATION This study was registered at Chictr.org.cn (ChiCTR2200060532).FUNDING National Natural Science Foundation of China (32270645, 31872814, 32000505, 82170088), the National Key R&D Program of Ningxia Hui Autonomous region (2022BEG01003), Shanghai Municipal Key Clinical Specialty (shslczdzk02201), Science and Technology Commission of Shanghai Municipality (20DZ2261200, 20DZ2254400), and Major Special Projects of Basic Research of Shanghai Science and Technology Commission (18JC1411101).

Authors

Zhanrui Mao, Shihua Dong, Yu Yan, Chengyang Wang, Wei Li, Lu Wang, Chengchen Qian, Yuanlin Song, Lin Tong, Wenqiang Yu