Prognostic role of APC and RASSF1A promoter methylation status in cell free circulating DNA of operable gastric cancer patients

Balgkouranidou, Ioanna; Matthaios, Dimitrios; Karayiannakis, Anastasios J.; Bolanaki, Helen; Michailidis, P.; Xenidis, Nikolaos; Amarantidis, Kyriakos; Chelis, Leonidas; Trypsianis, Grigorios; Chatzaki, Εkaterini; Lianidou, Evi; Kakolyris, Stylianos

doi:10.1016/j.mrfmmm.2015.05.002

Cited by 65 publications

(54 citation statements)

References 32 publications

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“…This higher incidence of RASSF1A methylation in metastatic disease may be indicative of a more aggressive tumor behavior, which may explain the association with poorer prognosis observed in the present study. In our previous study, we performed a similar analysis of RASSF1A methylation status in patients with operable gastric cancer (42). In that study, a methylation rate of 68.5% was detected, which underlines the difference in the biological behavior of gastric cancer in comparison with CRC.…”

Section: Discussionmentioning

confidence: 77%

Methylation status of the APC and RASSF1A promoter in cell-free circulating DNA and its prognostic role in patients with colorectal cancer

et al. 2016

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Abstract. DNA methylation is the most frequent epigenetic alteration. Using methylation-specific polymerase chain reaction (MSP), the methylation status of the adenomatous polyposis coli (APC) and Ras association domain family 1 isoform A (RASSF1A) genes was examined in cell-free circulating DNA from 155 plasma samples obtained from patients with early and advanced colorectal cancer (CRC). APC and RASSF1A hypermethylation was frequently observed in both early and advanced disease, and was significantly associated with a poorer disease outcome. The methylation status of the APC and RASSF1A promoters was investigated in cell-free DNA of patients with CRC. Using MSP, the promoter methylation status of APC and RASSF1A was examined in 155 blood samples obtained from patients with CRC, 88 of whom had operable CRC (oCRC) and 67 had metastatic CRC (mCRC). The frequency of APC methylation in patients with oCRC was 33%. Methylated APC promoter was significantly associated with older age (P= 0.012), higher stage (P= 0.014) and methylated RASSF1A status (P= 0.050). The frequency of APC methylation in patients with mCRC was 53.7%. In these patients, APC methylation was significantly associated with methylated RASSF1A status (P=0.016). The frequency of RASSF1A methylation in patients with oCRC was 25%. Methylated RASSF1A in oCRC was significantly associated with higher stage (P=0.021). The frequency of RASSF1A methylation in mCRC was 44.8%. Methylated RASSF1A in mCRC was associated with moderate differentiation (P=0.012), high levels of carcinoembryonic antigen (P=0.023) and methylated APC status (P=0.016). Patients with an unmethylated APC gene had better survival in both early (81±5 vs. 27±4 months, P<0.001) and advanced disease (37±7 vs. 15±3 months, P<0.001), compared with patients with methylated APC. Patients with an unmethylated RASSF1A gene had better survival in both early (71±6 vs. 46±8 months, P<0.001) and advanced disease (28±4 vs. 16±3 months, P<0.001) than patients with methylated RASSF1A. The observed significant correlations between APC and RASSF1A promoter methylation status and survival may be indicative of a prognostic role for these genes in CRC, which requires additional testing in larger studies.

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Section: Discussionmentioning

confidence: 77%

Methylation status of the APC and RASSF1A promoter in cell-free circulating DNA and its prognostic role in patients with colorectal cancer

et al. 2016

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“…Actually, our results showed the limitations of analyzing only the total ccfDNA levels, as focusing on tumor-specific ccfDNA might serve as a more adequate surrogate biomarker. For solid tumors, many studies have validated that genetic alterations detected in ctDNA correspond to the primary tumor and that the levels of ctDNA could assess the tumor response and even provide an earlier indication of disease progression [28–30]. Roschewski et al [31] reported that monitoring ctDNA could identify patients with DLBCL who are at risk of recurrence before the manifestation of clinical evidence of disease, and interim ctDNA may be a promising biomarker to identify patients at high risk of treatment failure.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the circulating cell-free DNA marker association with diagnosis and prognostic prediction in patients with lymphoma: a single-center experience

Mao

Jia

et al. 2017

Ann Hematol

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Circulating cell-free DNA (ccfDNA) has been shown to be associated with the clinical characteristics and prognosis of cancer patients. Our objective was to assess whether the concentration and integrity index of ccfDNA in plasma may be useful for diagnosing and monitoring the progression of patients with lymphoma. We included plasma samples from 174 lymphoma patients and 80 healthy individuals. The total concentration of ccfDNA was determined using a fluorometry method, and the DNA integrity index (DII), which is the ratio of longer to shorter DNA fragments, for the APP gene was detected using real-time quantitative PCR. The median levels of the ccfDNA concentration and the DII in patients with lymphoma were significantly higher than those in controls (both P < 0.0001). Increases in the ccfDNA concentration and the DII were associated with advanced stage disease, elevated lactate dehydrogenase levels, and a higher prognosis score. In patients with diffuse large B cell lymphoma (DLBCL), high levels of ccfDNA (both concentration and the DII) showed an inferior 2-year progression-free survival (PFS) (P = 0.001; P < 0.0001, respectively). Our study provides quantitative and qualitative evidence in favor of using ccfDNA analysis in lymphoma patients for diagnostic and prognostic assessments.

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“…However, the majority of these studies have focused on the total ccfDNA concentration in the blood or on the detection of genetic or epigenetic alterations (16)(17)(18)(19)(20). Moreover, the relationship between total ccfDNA concentration and outcome may be biased because an increase in the level of total ccfDNA might also be indicative of non-cancerous disease, such as inflammation or trauma (16).…”

Section: Introductionmentioning

confidence: 99%

Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care

Messaoudi

Moulière

Manoir

et al. 2016

Clinical Cancer Research

142

108

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Purpose: Circulating cell-free DNA (ccfDNA) is a valuable source of tumor material obtained from a simple blood sampling that enables noninvasive analysis of the tumor genome. Our goal was to carry out a multiparametric analysis of ccfDNA and evaluate its prognostic value by investigating the overall survival (OS) of 97 metastatic colorectal cancer patients (mCRC).Experimental Design: Qualitative parameters (determination of the main KRAS exon2 and BRAF V600E mutations) and quantitative parameters (total ccfDNA concentration, mutant ccfDNA concentration, the proportion of mutant ccfDNA, and ccfDNA integrity index) were determined simultaneously in a single run using a unique Q-PCR multimarker approach (100% success rate).Results: The median follow-up time was 36 months and median OS was 22 months. Patients showing high ccfDNA levels had significantly shorter OS (18.07 months vs. 28.5 months, P ¼ 0.0087). Moreover, multivariate analysis revealed that a high ccfDNA level is an independent prognostic factor (P ¼ 0.034). All ccfDNA parameters were of prognostic interest: patients with higher levels of mutant ccfDNA and higher mutation loads for the detected mutations had shorter OS (P ¼ 0.0089 and P ¼ 0.05, respectively). In addition, the level of ccfDNA fragmentation correlated positively with decreased OS in the exclusive KRAS/ BRAF-mutant cohort of patients (P ¼ 0.0052) and appeared as a strong independent prognostic factor (P ¼ 0.0072), whereas it was not significant in the exclusive KRAS/BRAF WT cohort of patients (P ¼ 0.67).Conclusions: Our data provide for the first time qualitative and quantitative evidence in favor of multiparametric ccfDNA analysis in mCRC patients for prognostic assessment.

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Prognostic role of APC and RASSF1A promoter methylation status in cell free circulating DNA of operable gastric cancer patients

Cited by 65 publications

References 32 publications

Methylation status of the APC and RASSF1A promoter in cell-free circulating DNA and its prognostic role in patients with colorectal cancer

Methylation status of the APC and RASSF1A promoter in cell-free circulating DNA and its prognostic role in patients with colorectal cancer

Assessment of the circulating cell-free DNA marker association with diagnosis and prognostic prediction in patients with lymphoma: a single-center experience

Circulating DNA as a Strong Multimarker Prognostic Tool for Metastatic Colorectal Cancer Patient Management Care

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