SLC12A4 promoter methylation in plasma cell-free DNA as a candidate biomarker for thyroid cancer.

@article{wu2026slc12a4,
  title = {{SLC12A4 promoter methylation in plasma cell-free DNA as a candidate biomarker for thyroid cancer.}},
  author = {Wei Wu and Ye Wang and Ying Qu and Changan Han and Peng Xia and Bin Huang and Jie Liu and Lingxiang Wu and Ruohan Zhang and Qianghu Wang and Zhi Zhang},
  journal = {Translational cancer research},
  year = {2026},
  month = oct,
  doi = {10.21037/tcr-2026-2403},
  url = {https://europepmc.org/article/MED/42997709},
  note = {CC BY-NC-ND},
}

TY  - JOUR
TI  - SLC12A4 promoter methylation in plasma cell-free DNA as a candidate biomarker for thyroid cancer.
AU  - Wei Wu
AU  - Ye Wang
AU  - Ying Qu
AU  - Changan Han
AU  - Peng Xia
AU  - Bin Huang
AU  - Jie Liu
AU  - Lingxiang Wu
AU  - Ruohan Zhang
AU  - Qianghu Wang
AU  - Zhi Zhang
PY  - 2026
DA  - 2026/10/21
JO  - Translational cancer research
DO  - 10.21037/tcr-2026-2403
UR  - https://europepmc.org/article/MED/42997709
AB  - Plasma cell-free DNA (cfDNA) methylation has emerged as a promising non-invasive approach for cancer detection; however, methylation biomarkers for thyroid carcinoma (THCA) remain insufficiently defined. This study aimed to identify THCA-associated DNA methylation alterations and evaluate their potential diagnostic value in plasma cfDNA. Publicly available Illumina HumanMethylation450K data from The Cancer Genome Atlas (TCGA) were used to identify hypermethylated differentially methylated positions (DMPs) in matched THCA and adjacent non-tumor tissues, and the identified DMPs were subsequently evaluated in the independent Gene Expression Omnibus (GEO) dataset GSE97466. Promoter cytosine-phosphate-guanine (CpG) sites associated with survival were further screened using univariate Cox regression, followed by methylation-expression correlation analysis. The selected SLC12A4 promoter region (chr16:67997880-67998180) was evaluated by methyl-CpG binding domain sequencing (MBD-seq) in tissue and plasma samples. Exploratory plasma diagnostic analyses were performed in seven patients with papillary thyroid carcinoma (PTC), together with control and non-THCA comparator samples. A total of 1,963 hypermethylated DMPs were identified in the TCGA discovery cohort. Of these, 1,959 showed concordant hypermethylation in GSE97466, and 1,881 remained significant after multiple-testing correction (FDR<0.05). Five methylation site-gene pairs, including cg09117114-SLC12A4, showed significant inverse correlations between methylation and gene expression. MBD-seq showed increased SLC12A4 promoter methylation enrichment in THCA tissues, with a similar directional pattern observed in four of five matched tumor-adjacent pairs, and the methylation signal was detectable in plasma cfDNA. In the exploratory comparison of seven PTC plasma samples with 1,301 normal controls, the area under the curve (AUC) was 0.938 [95% confidence interval (CI): 0.879-0.997]. At the exploratory cut-off of 12.2093 fragments per kilobase of exon model per million mapped fragments (FPKM), sensitivity was 0.857 (95% CI: 0.421-0.996) and specificity was 0.925 (95% CI: 0.909-0.938). These estimates should be interpreted as exploratory and require confirmation in independent cohorts. Increased methylation enrichment at the SLC12A4 promoter region was observed in THCA tissue and was detectable in plasma cfDNA. These findings support SLC12A4 promoter methylation as a candidate plasma biomarker for further evaluation, particularly in PTC. Validation in larger independent cohorts, including clinically relevant benign thyroid disease controls, is warranted.
SN  - 2218-676X
SN  - 2219-6803
ER  -