Biomarker DLEC1 for cancer
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Publication Number
US-11746383-B2
Publication Date
2023-09-05
Expiration Date
Abstract
The present invention provides a method for diagnosing and determining prognosis of certain cancers (e.g., esophageal squamous cell carcinoma or ESCC) in a subject by detecting suppressed expression of the DLEC1 gene, which in some cases is due to elevated methylation level in the genomic sequence of this gene. A kit and device useful for such a method are also provided. In addition, the present invention provides a method for treating cancer by increasing DLEC1 gene expression or activity.
Core Innovation
The document identifies DLEC1 as a tumor suppressor and as a diagnostic and prognostic biomarker in cancers, with emphasis on esophageal squamous cell carcinoma (ESCC). It reports that DLEC1 promoter CpG islands are hypermethylated, leading to DLEC1 silencing at the mRNA and protein levels, and links the methylation status of the DLEC1 promoter CGI with ESCC risk assessment, diagnosis, and prognosis.
The document further describes that re-expression of DLEC1 inhibits cancer cell growth and suppresses migration and invasion. The reported effects include cell cycle arrest and apoptosis, along with repression of epithelial-mesenchymal transition (EMT) and reduced expression of cell stemness markers. In pathway terms, DLEC1 is reported to repress multiple oncogenic pathways, including JAK/STAT3, MAPK/ERK, AKT, and Wnt/β-catenin.
A method is disclosed for diagnosing and treating ESCC in a subject using methylation analysis of a defined genomic sequence. DNA from an esophageal epithelial tissue sample is treated with an agent that differentially modifies methylated and unmethylated DNA, and the number of methylated CpGs is determined for SEQ ID NO:5 or 6 or a fragment thereof comprising at least 10 CpGs, then compared with a non-ESCC sample.
The disclosed approach includes determining increased risk for ESCC when the subject sample contains more methylated CpGs than the non-ESCC sample, administering X-ray or CT scan to the subject, and confirming the presence of ESCC. After confirmation, the subject is administered surgery, chemotherapy, radiotherapy, immunotherapy, photodynamic therapy, or any combination thereof.
Claims Coverage
The independent claim coverage combines ESCC methylation-based diagnosis with confirmation and treatment, and includes multiple inventive features across the workflow. The claim set also includes DLEC1 methylation analysis, comparative CpG quantification, and downstream ESCC therapy administration.
Differential DNA modification for CpG methylation analysis
Treating DNA from an esophageal epithelial tissue sample with an agent that differentially modifies methylated and unmethylated DNA.
Quantifying methylated CpGs in a defined genomic sequence
Determining number of methylated CpGs in a genomic sequence, which is SEQ ID NO:5 or 6 or a fragment thereof comprising at least 10 CpGs.
Comparative CpG methylation-based ESCC risk determination
Comparing the number of methylated CpGs from the subject sample with the number of methylated CpGs in the genomic sequence from a non-ESCC sample processed through the same steps.
ESCC risk determination based on increased methylated CpGs versus non-ESCC
Determining the subject as having an increased risk for ESCC when the subject sample contains more methylated CpGs than the non-ESCC sample.
Imaging confirmation after increased ESCC risk
Administering X-ray or CT scan to the subject determined to have an increased risk for ESCC and confirming the presence of ESCC.
Therapeutic administration after ESCC confirmation
Administering to the subject confirmed to have ESCC surgery, chemotherapy, radiotherapy, immunotherapy, photodynamic therapy, or any combination thereof.
Overall, the claims define a methylation-based diagnostic approach using differential DNA modification and quantification of methylated CpGs in SEQ ID NO:5 or 6, comparison to a non-ESCC sample to determine increased ESCC risk, imaging confirmation, and administration of one or more ESCC therapies.
Stated Advantages
Enables diagnosing ESCC risk by determining increased risk based on a higher number of methylated CpGs compared with a non-ESCC sample and a healthy subject not diagnosed with ESCC.
Supports confirmation of the presence of ESCC using X-ray or CT scan.
Provides a basis for administering ESCC treatments after ESCC confirmation, using surgery, chemotherapy, radiotherapy, immunotherapy, photodynamic therapy, or combinations.
Documented Applications
ESCC risk assessment, diagnosis, and prognosis based on measuring DLEC1 promoter methylation and/or DLEC1 expression (protein and/or mRNA) and comparing methylated CpG counts to non-ESCC samples.
Diagnosing and treating esophageal squamous cell carcinoma (ESCC) in a subject using methylation analysis of methylated CpGs in a genomic sequence (SEQ ID NO:5 or 6) followed by X-ray or CT scan confirmation and ESCC therapy administration.
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