This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Yagyu, S. Articles by Hosoi, H. Search for Related Content PubMed PubMed Citation Articles by Yagyu, S. Articles by Hosoi, H.

Circulating Methylated-DCR2 Gene in Serum as an Indicator of Prognosis and Therapeutic Efficacy in Patients with MYCN Nonamplified Neuroblastoma

Authors' Affiliations: ¹ Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; and ² Saiseikai Shiga Hospital, Shiga, Japan

Requests for reprints: Tomoko Iehara, Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi Hirokoji, Kamigyo-ku, Kyoto, Japan 602-8566. Phone: 81-75-251-5571; Fax: 81-75-252-1399; E-mail: iehara{at}koto.kpu-m.ac.jp.

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.