Circulating methylated-DCR2 gene in serum as an indicator of prognosis and therapeutic efficacy in patients with MYCN nonamplified neuroblastoma.

Abstract

BACKGROUND:

MYCN amplification (MNA) in neuroblastoma is a strong indicator of poor prognosis. However, some MYCN nonamplified (non-MNA) cases show poor outcomes, and examining the status of the gene requires an operation, which may have surgical complications. Therefore, a new marker is needed to identify cases of non-MNA neuroblastomas with poor prognoses using less risky procedures. Aberrant hypermethylation of the DCR2 promoter has recently been associated with rapidly progressing neuroblastoma. We aimed to develop a noninvasive DCR2 methylation assay for patients with neuroblastoma using serum DNA, which predominantly originates from tumor-released DNA.

METHODS:

Using DNA-based real-time PCR, we simultaneously quantified a methylated-DCR2 specific sequence (M) and a reference sequence (R) located in the promoter region in serum DNA, and evaluated DCR2 methylation status as M/R ratios in 86 patients with neuroblastoma.

RESULTS:

Serum DCR2 M/R ratios were strongly correlated with those in the tumor (r=0.67; P=0.002). DCR2 methylation was associated with stage both in the whole neuroblastoma group and in the non-MNA group (P<0.001), and DCR2-methylated patients showed significantly poorer 5-year event-free survival in the whole neuroblastoma group (43% versus 84%; P<0.001), especially in the non-MNA group (12% versus 96%;P<0.001). Among five DCR2-methylated patients whose clinical courses were followed, serum M/R ratios were close to 0 in the patients in remission, whereas the ratios increased in patients who relapsed.

CONCLUSIONS:

Detection of methylated-DCR2 in serum DNA has promise as a noninvasive assay for predicting prognosis and therapeutic efficacy in neuroblastoma, especially in non-MNA cases. Furthermore, it might be a sensitive marker of tumor recurrence in DCR2-methylated cases.

• Authors: Shigeki Yagyu, Takahiro Gotoh, Tomoko Iehara, Mitsuru Miyachi, Yoshiki Katsumi, Satoko Tsubai-Shimizu, Ken Kikuchi, Shinichi Tamura, Kunihiko Tsuchiya, Toshihiko Imamura, Akiko Misawa-Furihata, Tohru Sugimoto, Tadashi Sawada, Hajime Hosoi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 21 Pg. 7011-9 (Nov 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18980997 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MYCN protein, human
• N-Myc Proto-Oncogene Protein
• Nuclear Proteins
• Oncogene Proteins
• TNFRSF10D protein, human
• Tumor Necrosis Factor Decoy Receptors

Topics

• DNA Methylation
• Female
• Gene Amplification
• Humans
• Infant
• Male
• N-Myc Proto-Oncogene Protein
• Neuroblastoma (blood, diagnosis, genetics, therapy)
• Nuclear Proteins (genetics)
• Oncogene Proteins (genetics)
• Prognosis
• Treatment Outcome
• Tumor Necrosis Factor Decoy Receptors (genetics)