Longitudinal TP53 dynamics in repeated tissue-based next-generation sequencing in non-small cell lung cancer: a real-world study with molecular lineage adjudication and sequential credibility verification.
- 1Department of Pathology, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
Abstract
Apparent TP53 gain or loss in repeated next-generation sequencing (NGS) may reflect technical noise, spatial heterogeneity, metachronous multiple primary tumors, or true clonal evolution. This study aimed to characterize TP53 longitudinal dynamics using a transparent verification framework. We analyzed 948 patients with non-small cell lung cancer undergoing at least two tissue-based NGS tests separated by ≥120 days (all specimens ≥20% tumor-cell content). Apparent TP53 flip events underwent two-step sequential verification: molecular lineage adjudication comparing complete variant spectra of sequential specimens, followed by an empirically anchored variant allele frequency (VAF) threshold (≥5%) derived from platform re-detection characteristics. Driver background and MET amplification were exploratory outcomes. TP53 status remained stable in 824 patients (86.9%); 124 (13.1%) showed apparent gain (n=75) or loss (n=49). Lineage adjudication excluded 54 patients (5.4% of 1,002 eligible) with fully discordant driver spectra, whose apparent flip rate was three-fold higher than concordant patients (29.6% vs. 9.6%). Sequential verification identified 92 high-confidence events (64 acquisitions, 28 losses), showing no driver enrichment (EGFR 65.2% vs. 65.4% in the cohort; P>0.99). MET amplification did not differ across trajectories (high-confidence acquired vs. persistent negative: 8.9% vs. 6.3%; P=0.52). TP53 alterations are largely stable during longitudinal monitoring. Many apparent flips reflect metachronous multiple primaries or near-detection-limit noise and are identifiable by a simple sequential framework. After artifact control, TP53 dynamics show no EGFR preference, and previously suggested MET associations were not confirmed under uniform ascertainment.
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BibTeX
@article{zhao2026longitudinal,
title = {{Longitudinal TP53 dynamics in repeated tissue-based next-generation sequencing in non-small cell lung cancer: a real-world study with molecular lineage adjudication and sequential credibility verification.}},
author = {Dan Zhao and Deyang Xie and Kun Li and Nana Zhang and Zichen Liu and Nanying Che},
journal = {Journal of thoracic disease},
year = {2026},
month = sep,
doi = {10.21037/jtd-2026-2138},
url = {https://europepmc.org/article/MED/42996924},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Longitudinal TP53 dynamics in repeated tissue-based next-generation sequencing in non-small cell lung cancer: a real-world study with molecular lineage adjudication and sequential credibility verification.
AU - Dan Zhao
AU - Deyang Xie
AU - Kun Li
AU - Nana Zhang
AU - Zichen Liu
AU - Nanying Che
PY - 2026
DA - 2026/09/28
JO - Journal of thoracic disease
DO - 10.21037/jtd-2026-2138
UR - https://europepmc.org/article/MED/42996924
AB - Apparent TP53 gain or loss in repeated next-generation sequencing (NGS) may reflect technical noise, spatial heterogeneity, metachronous multiple primary tumors, or true clonal evolution. This study aimed to characterize TP53 longitudinal dynamics using a transparent verification framework. We analyzed 948 patients with non-small cell lung cancer undergoing at least two tissue-based NGS tests separated by ≥120 days (all specimens ≥20% tumor-cell content). Apparent TP53 flip events underwent two-step sequential verification: molecular lineage adjudication comparing complete variant spectra of sequential specimens, followed by an empirically anchored variant allele frequency (VAF) threshold (≥5%) derived from platform re-detection characteristics. Driver background and MET amplification were exploratory outcomes. TP53 status remained stable in 824 patients (86.9%); 124 (13.1%) showed apparent gain (n=75) or loss (n=49). Lineage adjudication excluded 54 patients (5.4% of 1,002 eligible) with fully discordant driver spectra, whose apparent flip rate was three-fold higher than concordant patients (29.6% vs. 9.6%). Sequential verification identified 92 high-confidence events (64 acquisitions, 28 losses), showing no driver enrichment (EGFR 65.2% vs. 65.4% in the cohort; P>0.99). MET amplification did not differ across trajectories (high-confidence acquired vs. persistent negative: 8.9% vs. 6.3%; P=0.52). TP53 alterations are largely stable during longitudinal monitoring. Many apparent flips reflect metachronous multiple primaries or near-detection-limit noise and are identifiable by a simple sequential framework. After artifact control, TP53 dynamics show no EGFR preference, and previously suggested MET associations were not confirmed under uniform ascertainment.
SN - 2072-1439
SN - 2077-6624
ER -