Comparative diagnostic value of a blood-based three-gene DNA methylation assay and a seven-autoantibody panel for differentiating pulmonary nodules.

Authors

Dong Rui, Xunsi Liang, Min Yi, Shaowei Zhan, Shui Xiang, Jifei Chen, Jiachen Hou, Xin Wu, Xuejun Qin, Zhougui Ling

Published in

The journal of liquid biopsy. Volume 14. Pages 100498. Epub Sep 10, 2026.

Abstract

Low-dose CT has increased pulmonary nodule detection, but noninvasively distinguishing benign from malignant nodules or early lung cancer remains difficult. Blood-based DNA methylation and tumour-associated autoantibody assays may complement imaging.
This combined prospective and retrospective study evaluated two blood-based strategies. The prospective methylation cohort (141 participants; May 2024-April 2026) comprised 91 malignant, 22 benign-nodule, and 28 high-risk individuals, with plasma SHOX2, RASSF1A, and PTGER4 methylation measured by multiplex fluorescence PCR. The retrospective cohort (446 participants; January 2023-April 2025) comprised 193 malignant, 118 benign-nodule, and 135 high-risk individuals, with serum conventional markers (CYFRA21-1, CEA, NSE, SCC) and seven autoantibodies (p53, GAGE7, PGP9.5, CAGE, MAGEA1, SOX2, GBU4-5) analysed. Performance was assessed by positive rate, sensitivity, specificity, AUC, and Youden index.
Positive rates in the malignant versus benign versus high-risk groups were 83.52% vs 45.45% vs 10.71% for the three-methylation panel and 63.20% vs 16.95% vs 10.37% for the seven-autoantibody panel (both P < 0.05). In early-stage (I-II) disease, the methylation panel had the highest positive rate (83.87%), exceeding the autoantibody panel (67.53%) and conventional markers (37.66%; P < 0.05), whereas conventional markers were highest in advanced (III-IV) disease (93.97%). Early-stage AUCs were 0.789 for methylation (sensitivity 83.87%, specificity 74.00%), 0.771 for autoantibodies (sensitivity 67.53%, specificity 86.56%), and 0.570 for conventional markers, rising to 0.851 in advanced disease. Combining the methylation and autoantibody panels raised early-stage sensitivity to 94.75% (AUC 0.794). As additional clinically oriented validation, the methylation panel yielded an overall positive predictive value of 85.39%, negative predictive value of 71.15%, accuracy of 80.14%, positive likelihood ratio of 3.21, and negative likelihood ratio of 0.22 for malignant disease versus all controls.
Both panels aided differentiation of malignant from benign pulmonary nodules; methylation gave the strongest early-stage sensitivity and autoantibodies higher specificity, both outperforming conventional markers. Combined testing may improve sensitivity but requires multicentre validation.

PMID:
42825038
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.

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