Aberrant DNA methylation of the p16INK4a gene in plasma DNA of breast cancer patients

Silva, J M; Domínguez, Gemma; Villanueva, María Jesús García; González, R. N.; García, José M.; Corbacho, C.; Provencio, Mariano; España, Pilar; Bonilla, Félix

doi:10.1038/sj.bjc.6690495

Cited by 115 publications

(59 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition to analysis of DNA extracted from cancer samples, free DNA in the plasma or serum is known to be present in cancer patients (Shapiro et al, 1983;Stroun et al, 1989). Taking advantage of the high sensitivity of MSP, aberrant methylation in the plasma or serum DNA is now being used in a variety of cancer diagnoses (Esteller et al, 1999;Silva et al, 1999;Kawakami et al, 2000). From the high incidence of 3-OST-2 methylation in the primary cancer samples, detection of the aberrant methylation in plasma or serum DNA is expected to be useful as a tumor marker.…”

Section: Discussionmentioning

confidence: 99%

Methylation-associated silencing of heparan sulfate D-glucosaminyl 3-O-sulfotransferase-2 (3-OST-2) in human breast, colon, lung and pancreatic cancers

et al. 2003

View full text Add to dashboard Cite

Aberrant CpG methylations play important roles in cancer development and progression. In this study, aberrant methylations in human breast cancer were searched for using methylation-sensitive representational difference analysis (MS-RDA). A CpG island (CGI) in the 5 0 region of the heparan sulfate d-glucosaminyl 3-Osulfotransferase-2 (3-OST-2) gene was found to be hypermethylated, while its exon 2 was hypomethylated. In seven breast cancer cell lines, hypermethylation of the 5 0 region and loss of 3-OST-2 expression were observed. Treatment with a demethylating agent, 5-aza-2 0 -deoxycytidine, removed the methylation of the CGI in the 5 0 region and restored its expression, demonstrating silencing of the 3-OST-2 gene. Methylation-specific PCR (MSP) analysis in 85 primary breast cancers showed that the hypermethylation of the CGI in the 5 0 region was present in 75 (88%) of them. Quantitative reverse transcriptase-PCR (RT-PCR) analysis in 37 primary breast cancers showed that the average expression level was decreased in them. Further, MSP analysis in primary colon, lung and pancreatic cancers showed that hypermethylation of the CGI in the 5 0 region was present in the colon (8/10, 80%), lung (7/10, 70%) and pancreatic (10/10, 100%) cancers. These results showed that silencing of 3-OST-2 was present in a wide range of human cancers. The 3-OST-2 gene encodes an enzyme involved in the final modification step of heparan sulfate proteoglycans (HSPGs), and its silencing is expected to result in abnormal modification of HSPGs and abnormal signal transduction. From the high incidence, silencing of the 3-OST-2 gene is expected to have high diagnostic, and potentially therapeutic, values.

show abstract

Section: Discussionmentioning

confidence: 99%

Methylation-associated silencing of heparan sulfate D-glucosaminyl 3-O-sulfotransferase-2 (3-OST-2) in human breast, colon, lung and pancreatic cancers

et al. 2003

View full text Add to dashboard Cite

show abstract

“…It has therefore been proposed that analyses of free plasma DNA could be a useful tool for prognosis or the early diagnosis to detect subclinical disease recurrence [4]. Since the introduction of PCR-based techniques in the late 1980s, a large number of tumorspecific alterations have been identified in free plasma DNA, such as K-ras mutations in patients with colorectal cancer [5], microsatellite alterations in patients with smallcell lung cancer [6], head and neck cancer [7], clear cell renal carcinoma [8] and melanoma [9], and finally aberrant promotor hypermethylation of tumor suppressor genes in patients with non-small-cell lung cancer [10], liver [11], and breast cancer [12]. Whereas the majority of these studies examined patients with solid tumors, it has also been suggested that free plasma DNA can be used for the detection of molecular abnormalities in hematological malignancies [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Quantification of free total plasma DNA and minimal residual disease detection in the plasma of children with acute lymphoblastic leukemia

et al. 2009

View full text Add to dashboard Cite

The analysis of total plasma DNA and the monitoring of leukemic clone-specific immunoglobulin and/or T-cell receptor gene rearrangements for the evaluation of minimal residual disease (MRD) in the plasma may be useful tools for prognostic purposes or for early detection of subclinical disease recurrence in children with acute lymphoblastic leukemia (ALL). The aim of this paper is to establish reference ranges for total plasma DNA concentrations and to test the feasibility of MRD measurements employing plasma DNA from children with ALL by using real-time quantitative (RQ)-PCR. Despite wide interindividual variation, the median concentrations of total plasma DNA for 12 healthy donors (57 ng/ml), 21 children with ALL after day 4 of treatment initiation (62 ng/ml) and 13 children with other malignancies (76 ng/ml) were similar. However, ALL patients had significantly higher concentrations at diagnosis (277 ng/ml) and on treatment day 3 (248 ng/ml) before returning to normal afterwards. Early plasma DNA MRD kinetics could be established for 15 ALL patients and showed good concordance with bone marrow MRD. Plasma DNA was higher in children with ALL at diagnosis but returned to normal within the first four treatment days. Despite low concentrations of DNA, it is feasible to measure MRD kinetics in plasma DNA during ALL induction therapy by adapted real-time PCR methodologies.

show abstract

“…The discovery of circulating cell-free DNA in serum or plasma (15,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)) presents a new opportunity for identifying MGMT promoter methylation in tumor cells. There have been limited reports on the concordance between serum, plasma, or sputum and tumor methylation biomarkers in patients, such as APC promoter methylation in lung cancer (29); hMLH1 promoter methylation in CRC (23); p16 methylation in NSCLC, H&N, esophageal, breast, and hepatocellular cancers (15,24,28,30,32); and MGMT methylation in lung cancer (44).…”

Section: Discussionmentioning

confidence: 99%

“…There have been limited reports on the concordance between serum, plasma, or sputum and tumor methylation biomarkers in patients, such as APC promoter methylation in lung cancer (29); hMLH1 promoter methylation in CRC (23); p16 methylation in NSCLC, H&N, esophageal, breast, and hepatocellular cancers (15,24,28,30,32); and MGMT methylation in lung cancer (44). Although these reports used similar MSP analysis, the concordance between assays of tumor and surrogate tissue varied across different cancer types and biomarkers.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Phase II Study of Temozolomide in Patients with Advanced Aerodigestive Tract and Colorectal Cancers and Methylation of theO6-Methylguanine-DNA Methyltransferase Promoter

Hochhauser

Glynne‐Jones

Potter

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Responses of patients with gliomas to temozolomide are determined by O 6 -methylguanine-DNA methyltransferase (MGMT) and mismatch repair (MMR) pathways. This phase II study (NCT00423150) investigated whether MGMT promoter methylation predicts response in patients with advanced aerodigestive tract and colorectal cancers (CRC). Tumor and serum samples were screened for MGMT promoter methylation. In methylation-positive patients, 150 mg/m 2 temozolomide was administered daily on a seven-day-on, sevenday-off schedule for each 28-day cycle. The primary efficacy endpoint was response rate (RR). MMR status was determined by a microsatellite instability assay. Among 740 patients screened, 86 were positive for MGMT promoter methylation and enrolled. Nineteen percent of the screened population (137/740) had confirmed tissue and/or serum MGMT promoter methylation, including 25% (57 of 229) for CRC, 36% (55 of 154) for esophageal cancer, 11% (12 of 113) for head and neck cancer, and 5% (13 of 242) for non-small cell lung carcinoma. Among patients with valid methylation results in both tissue and serum samples, concordance was 81% (339 of 419). The majority of enrolled patients (69 of 86; 80%) had microsatellite stable cancer. Overall RR was 6% (5 of 86 partial responses); all responders had microsatellite stable cancer. Temozolomide resulted in low RRs in patients enriched for MGMT methylation. MGMT methylation status varied considerably in the patient population. Although serum methylation assay is an option for promoter methylation detection, tissue assay remains the standard for methylation detection. The low RR of this cohort of patients indicates that MGMT methylation as a biomarker is not applicable to heterogeneous tumor types, and tumor-specific factors may override validated biomarkers. Mol Cancer Ther; 12(5); 809-18. Ó2013 AACR.

show abstract

Aberrant DNA methylation of the p16INK4a gene in plasma DNA of breast cancer patients

Cited by 115 publications

References 24 publications

Methylation-associated silencing of heparan sulfate D-glucosaminyl 3-O-sulfotransferase-2 (3-OST-2) in human breast, colon, lung and pancreatic cancers

Methylation-associated silencing of heparan sulfate D-glucosaminyl 3-O-sulfotransferase-2 (3-OST-2) in human breast, colon, lung and pancreatic cancers

Quantification of free total plasma DNA and minimal residual disease detection in the plasma of children with acute lymphoblastic leukemia

A Phase II Study of Temozolomide in Patients with Advanced Aerodigestive Tract and Colorectal Cancers and Methylation of theO6-Methylguanine-DNA Methyltransferase Promoter

Contact Info

Product

Resources

About