What question did this study set out to answer?

The study aims to identify a common chromatin remodeling signature in advanced aerodigestive cancers using plasma cfDNA.

April 5, 2026

Abstract 3862: Convergent chromatin remodeling enables pan-aerodigestive detection of advanced malignancies in plasma cfDNA.

Key Points

The study aims to identify a common chromatin remodeling signature in advanced aerodigestive cancers using plasma cfDNA.
Performed whole-genome EM-seq on cfDNA from 120 patients with stage III/IV aerodigestive cancers and 60 controls.
Assessed four fragmentomic modalities including genome-wide fragmentation, NMF spectral components, end motifs, and nucleosome scores.
Utilized a nested cross-validation approach for random forest classifier training.
The multimodal classifier achieved a mean AUROC of 0.86 and AUPRC of 0.94 for cancer detection.
Nucleosome positioning emerged as a key indicator with AUROC of 0.85, while end motifs were less effective (AUROC 0.61).
Findings indicated significant nucleosome depletion at promoters of genes associated with cell proliferation in late-stage cancers.

Abstract

Abstract Background: Liquid biopsy approaches for cancer detection often rely on tissue-specific methylation or fragmentation features to infer tumor origin. However, a pan-aerodigestive cancer detection strategy is clinically valuable given shared risk exposures, field cancerization, and frequent diagnostic ambiguity among lung, esophageal, and head squamous and adenocarcinoma) and 60 age-matched controls. Four fragmentomic modalities were assessed: (1) genome-wide fragmentation in 5-Mb bins (DELFI-like), (2) NMF spectral components, (3) 4-mer end motifs, and (4) promoter-centric nucleosome scores (Griffin). All preprocessing occurred strictly within each training fold of a repeated stratified 10-fold CV (100 repeats) to prevent data leakage. No test-sample information was used in training. Hyperparameters were tuned only within training partitions. Random Forest classifiers were trained under this fully nested scheme. Results: The multimodal classifier robustly detected advanced aerodigestive malignancies with a mean AUROC 0.86 and AUPRC 0.94. However, modality dissection revealed a clear performance hierarchy: nucleosome positioning (Griffin) alone achieved AUROC 0.85 and AUPRC 0.93, nearly matching the full integrated model, whereas end motifs performed poorly (AUROC 0.61). Biological interpretation demonstrated prominent nucleosome depletion centered at promoters of proliferation-associated genes, indicating a convergent epigenetic state of promoter opening across late-stage aerodigestive malignancies. Conclusions: Advanced aerodigestive cancers exhibit a dominant, convergent chromatin remodeling signature detectable in plasma cfDNA, driven primarily by altered nucleosome positioning. In late-stage disease, this shared malignancy-associated fragmentomic signal outweighs tissue-of-origin-dependent patterns. These findings highlight the utility of nucleosome-based fragmentomics not merely for detection, but for resolving diagnostic ambiguity in patients with indeterminate masses and for monitoring total tumor burden in high-risk aerodigestive malignancies. Citation Format: Axel Misael Hidalgo, Ayesha Hashmi, Jeff Szymanski, Pradeep Chauhan, Lilli Greiner, Faridi Qaium, Daniel J. Ma, David M. Routman, Katie M. Van Abel, Aadel A. Chaudhuri.. Convergent chromatin remodeling enables pan-aerodigestive detection of advanced malignancies in plasma cfDNA abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3862.

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