Methylated RASSF1a Is the First Specific DNA Marker for Minimal Residual Disease Testing in Neuroblastoma

PCR-based detection of minimal residual disease (MRD) in neuroblastoma (NB) is presently based on NB-specific transcripts. However, the expression of these targets varies between patients and upon treatment, and only PHOX2B is truly specific. RASSF1a is methylated (RASSF1a(M)) in NB, and we investig...

Full description

Saved in:
Bibliographic Details
Published in:Clinical cancer research 2012-02, Vol.18 (3), p.808-814
Main Authors: STUTTERHEIM, Janine, AIT ICHOU, Fatima, DEN OUDEN, Emmy, VERSTEEG, Rogier, CARON, Huib N, TYTGAT, Godelieve A. M, DER SCHOOL, C. Ellen Van
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Biomarkers, Tumor - genetics
DNA Methylation
Genetic Markers
Humans
Kaplan-Meier Estimate
Medical sciences
Neoplasm Staging
Neoplasm, Residual - diagnosis
Neoplasm, Residual - genetics
Neoplasm, Residual - mortality
Neuroblastoma - diagnosis
Neuroblastoma - genetics
Neuroblastoma - mortality
Neurology
Pharmacology. Drug treatments
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Sensitivity and Specificity
Tumor Suppressor Proteins - analysis
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Tumors of the nervous system. Phacomatoses
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:PCR-based detection of minimal residual disease (MRD) in neuroblastoma (NB) is presently based on NB-specific transcripts. However, the expression of these targets varies between patients and upon treatment, and only PHOX2B is truly specific. RASSF1a is methylated (RASSF1a(M)) in NB, and we investigated whether it can serve as a specific and stable DNA MRD marker. The RASSF1a(M)-specific quantitative real-time PCR was tested on control bone marrow (BM; n = 50), on 71 NB tumors, and on 159 clinical BM samples at diagnosis and at follow-up of 77 patients. Results were compared with a panel of RNA markers and correlated with prognosis. RASSF1a(M) was present in all stage 4 and 4s tumors (n = 50) and in 86% stages 1 to 3 tumors (n = 21). The level of methylation in stage 4 NB was correlated with overall survival (P = 0.02). RASSF1a(M)-PCR was highly specific (only 1 amplification in 50 control samples tested in triplicate) and had a similar sensitivity as the RNA-based PCRs, as shown on clinical samples. Moreover, RASSF1a(M) enabled accurate quantification without need for the original tumor. RASSF1a(M) is a novel, highly specific DNA marker for MRD detection in NB, equal to PHOX2B in specificity and sensitivity, and better suitable for MRD quantification. We propose to include RASSF1a(M) in further prospective MRD studies in NB alongside RNA MRD markers. In addition, this assay might also be applicable for detection of circulating tumor cells in patients with other cancers withRASSF1a(M) such as breast or lung cancer.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-11-0849