Hypermethylated GRIA4 , a potential biomarker for an early non-invasive detection of metastasis of clinically known colorectal cancer.

Autor:	Lukacova E; Department of Molecular Biology and Genomics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia., Burjanivova T; Department of Molecular Biology and Genomics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia., Podlesniy P; Centro Investigacion Biomedica en Red Enfermedades Neurodegenerativas (CiberNed), Madrid, Spain., Grendar M; Laboratory of Bioinformatics and Biostatistics, Biomedical Center Martin JFM CU, Commenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia., Turyova E; Department of Molecular Biology and Genomics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia., Kasubova I; Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia., Laca L; Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia., Mikolajcik P; Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia., Kudelova E; Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia., Vanochova A; Department of Molecular Biology and Genomics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia., Miklusica J; Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia., Mersakova S; Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia., Lasabova Z; Department of Molecular Biology and Genomics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2023 Jul 05; Vol. 13, pp. 1205791. Date of Electronic Publication: 2023 Jul 05 (Print Publication: 2023).
DOI:	10.3389/fonc.2023.1205791
Abstrakt:	Introduction: Colorectal cancer (CRC) can develop through several dysregulated molecular pathways, including the serrated pathway, characterized by CpG island methylator (CIMP) phenotype. Although the tumor tissue is a commonly tested material, sample types such as stool or plasma, bring a new, non-invasive approach. Several cancer-related methylated genes have been identified in CRC patients, including gene GRIA4 , showing promising diagnostic potential. The aim of our study was to develop a sensitive droplet digital PCR (ddPCR) assay to examine GRIA4 hypermethylation status in CRC patients and evaluate its diagnostic potential in tissue and liquid biopsy samples. Methods: In total, 23 patients participated in this study, 7 patients with primary CRC and 16 patients with liver metastasis of clinically known CRC. We obtained tumor and non-tumor tissues (N=17), blood samples pre- and post-surgery (N=22), and blood of five volunteers without a personal cancer history. We have developed and optimized a ddPCR assay for GRIA4 hypermethylation detection, from tissue and plasma samples. Results: We detected significantly increased GRIA4 methylation in tumor tissues compared to their adjacent non-tumor tissue, p<0.0001. Receiver operating characteristic (ROC) analysis defined cutoff values to separate primary tumors and metastases from non-tumor colon/rectum, specifically 36.85% for primary tumors and 34.81% for metastases. All primary tumors were above this threshold. When comparing the methylation levels of metastatic vs. non-tumor tissue, a smaller increase was observed in liver metastasis versus colon tissue (3.6× gain; p=0.001), then in liver metastasis versus adjacent liver tissue (17.4× gain; p<0.0001). On average, GRIA4 hypermethylation in primary tumor plasma was 2.8-fold higher (p=0.39), and in metastatic plasma, 16.4-fold higher (p=0.0011) compared to healthy individuals. Hypermethylation in metastatic plasma was on average 5.9 times higher (p=0.051) than in primary tumor plasma. After tumor removal surgery, average hypermethylation decrease in plasma was 1.6× for primary (p=0.037) and 4.5× for metastatic patients (p=0.023). Discussion: Based on our data, it can be inferred that GRIA4 serves as a tissue specific biomarker for the colon/rectum tissue, thus is suitable for cancer classification. This biomarker showed the potential to be an attractive target for early non-invasive detection of metastases of clinically known CRC, although additional analysis has to be performed. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Lukacova, Burjanivova, Podlesniy, Grendar, Turyova, Kasubova, Laca, Mikolajcik, Kudelova, Vanochova, Miklusica, Mersakova and Lasabova.)
Databáze:	MEDLINE
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