CIRCULATING PLASMA DNA METHYLATION STATUS OF TUMOR SUPPRESSOR GENES MAY BE A PREDICTIVE FACTOR OF LUNG METASTASIS IN COLORECTAL CANCER
Kiichi Sugimoto*, Kazuhiro Sakamoto, Jun Aoki, Yu Okazawa, Kosuke Mizukoshi, Masaya Kawai, Shinya Munakata, Shun Ishiyama, Hirohiko Kamiyama, Makoto Takahashi, Yutaka Kojima, Yuichi Tomiki
Juntendo University Faculty of Medicine, Tokyo, Japan
Introduction
Hypermethylation in tumor suppressor genes can lead to cancer development and progression due to gene silencing. A wide variety of methylated genes have been identified and investigated to look into the correlations between epigenetic signatures and colorectal diagnosis, staging, tendency to metastasis, prognosis and response to treatment. A liquid biopsy, which is defined as the sampling and analysis of non-solid biological tissue (primarily blood), is thought to be useful for monitoring diseases such as cancer, with the added benefit of being largely non-invasive. Our aim in the current study was to investigate the significance of circulating plasma p14 and CHFR gene DNA methylation in colorectal cancer.
Materials and Methods
Seventy patients, who had undergone resection of stage I-IV adenocarcinoma of the colon and rectum were enrolled in this study. Patients were ineligible if they had synchronous or metachronous multiple cancers or underwent preoperative treatment. The patient backgrounds, clinicopathological factors and gene promoter methylation status were analyzed. Quantitative methylation-specific PCR (qMSP) was performed using the bisulfite-modified DNA for p14 and CHFR gene promoter methylation. Relative Methylation Value (RMV) was used to evaluate the final quantification of DNA methylation.
Results
In univariate analysis, the patients with lung metastases had significantly higher RMVs of p14 gene compared with those without ling metastases (p=0.01). The patients with vascular invasion demonstrated a tendency towards higher RMVs of p14 gene compared with those without vascular invasion (p=0.07). Similarly, the patients with Stage IV demonstrated a tendency towards higher RMVs of p14 gene compared with those with Stage I, II, III (p=0.19). There were no statistically significant correlations between RMVs of gene p14 and the preoperative CEA values (R=0.02, p=0.86). On the other hand, in univariate analysis, statistically significant differences in RMVs of CHFR gene were recognized in vascular invasion (absence / presence; p=0.01), N factor (N0 / N1, 2; p=0.01), lung metastasis (absence / presence; p=0.02). The patients with Stage IV demonstrated a tendency towards higher RMVs of CHFR gene compared with those with Stage I-III (p=0.08). There were no statistically significant correlations between RMVs of CHFR gene and the preoperative CEA values (R=0.06, p=0.66).
Discussion
Our current study demonstrated the correlations between the promoter methylation status of tumor suppressor genes in cell-free DNA from plasma and hematogeneous metastasis, especially lung metastasis.
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