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In Reply:

Children's Hospital of Marburg, Pediatric Oncology and Hematology, Neuroblastoma Research Laboratory, Marburg, Germany

We thank Katleen De Preter and colleagues for re-evaluating their data with respect to our observations on patients with DDX1 coamplified, MYCN-amplified neuroblastoma tumors. They describe a discrepancy in survival data of their own cohort compared with data reported in our recent article.¹ Their data and argumentation reflect the difficulties in the interpretation of statistical findings in subgroups of patients with a prognosis unfavorable as patients with MYCN-amplified neuroblastoma.

Difficulties in investigating such a subgroup have been demonstrated by a number of previous studies, reporting on cohorts with small numbers of patients and with a low percentage of patients with a long-term (> 72 months after diagnosis) follow-up.^2-7 Large cohorts are needed to reach statistical significances including patients with a long-time follow-up, reflecting the relative incidence as found in our biologic neuroblastoma study performed from 1984 to 2004, on 1,679 neuroblastoma tumors at diagnosis.

Thus, a possible reason for the findings of De Preter and colleagues may be a relative under-representation of long-term surviving patients in their cohort. The overall survival probability in their investigated cohort is 10% to 15% (patients without and with DDX1 coamplification, respectively) and thus, is worse compared with the survival probability of patients with MYCN-amplified neuroblastoma in our biologic neuroblastoma study (20% to 25%, own results on 236 MYCN amplified neuroblastomas, data not published), indicating a bias toward patients with an unfavorable clinical outcome in the cohort of De Preter et al.

A direct comparison of survival data between different patient cohorts is generally impaired when different therapy strategies had been applied. Moreover, the cohort investigated by De Preter and collegues consists of samples collected in Ghent (Belgium), Lyon (France), and Newcastle (UK).⁶ Heterogeneity in diagnostics and resulting therapy strategies may be discussed as a problematic factor for interpretation and compareability of their data, too.

The significance of DDX1 coamplification as a prognostic marker in our report was strengthened by (A) focusing on an even more stringent subgroup (patients with a follow-up time of at least 72 months), (B) demonstration of the independency of DDX1 coamplification on age and stage (Cox-Regression analysis), and (C) confirmation of the coamplification data, with additional expression analyses.

Despite the discrepancies in the survival analyses, De Preter and colleagues conclude based on data of different studies (including their own and our reported data) that the coamplification of genes genomically localized in the vicinity of the MYCN locus occurs coincidentally. They argue that this coincidental coamplification would make a possible role for these genes in neuroblastoma development unlikely. We agree in part that reported data suggest a coincidental coamplification for the genes localized in the MYCN region, but a direct conclusion on the gene function in neuroblastoma development and/or response to therapy is not permitted in our opinion.

We and other investigators found the expression of DDX1 mRNA (and NAG, data not shown) to be significantly higher in coamplified tumors.^1,5 These data suggest that coamplified genes are actively transcribed, and thus, could also influence cellular processes. The function of DDX1 and NAG in MYCN amplified neuroblastomas is as yet unknown.

In general, information on DDX1 function is rare and the attribution of oncogenicity for DDX1 expression is mostly hypothetical. Even in case of oncogenicity of DDX1 expression it cannot be excluded that DDX1 coamplification serves as a favorable prognostic factor in the genetic background of MYCN amplified neuroblastomas. MYCN itself may serve as an example as, beyond controversy, it attributes oncogenic characteristics. On the other hand MYCN induces apoptosis and furthermore was found to sensitize cells for drug triggered apoptosis.⁸

Finally, we reported DDX1 gene coamplification to be found in the majority of long-time surviving patients with MYCN-amplified neuroblastoma. These data are in relative accordance to the survival data of De Preter and colleagues represented in their letter.

A direct implication of DDX1 in neuroblastoma genesis, development and/or response to therapy is not evidenced or abolished yet. As mentioned in our report¹ we agree with our colleagues from Belgium for the need of further confirmation of our correlational data by investigation of larger cohorts including representative numbers of long-time surviving MYCN amplified patients. Even more insights into the molecular functions of DDX1 are required to finally estimate its implications in neuroblastoma development.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Weber A, Imisch P, Bergmann E, et al: Coamplification of DDX1 correlates with an improved survival probability in children with MYCN-amplified human neuroblastoma. J Clin Oncol 22:2681-2690, 2004[Abstract/Free Full Text]

2. Squire JA, Thorner PS, Weitzman S, et al: Co-amplification of MYCN and a DEAD box gene (DDX1) in primary neuroblastoma. Oncogene 10:1417-1422, 1995[Medline]

3. George RE, Kenyon RM, McGuckin AG, et al: Investigation of co-amplification of the candidate genes ornithine decarboxylase, ribonucleotide reductase, syndecan-1 and a DEAD box gene, DDX1, with N-myc in neuroblastoma: United Kingdom Children's Cancer Study Group Oncogene 12:1583-1587, 1996

4. George RE, Kenyon R, McGuckin AG, et al: Analysis of candidate gene co-amplification with MYCN in neuroblastoma. Eur J Cancer 33:2037-2042, 1997

5. Manohar CF, Salwen HR, Brodeur GM, et al: Co-amplification and concomitant high levels of expression of a DEAD box gene with MYCN in human neuroblastoma. Genes Chromosomes Cancer 14:196-203, 1995[Medline]

6. De Preter K, Speleman F, Combaret V, et al: Quantification of MYCN, DDX1, and NAG gene copy number in neuroblastoma using a real-time quantitative PCR assay. Mod Pathol 15:159-166, 2002[CrossRef][Medline]

7. Scott DK, Board JR, Lu X, et al: The neuroblastoma amplified gene, NAG: Genomic structure and characterisation of the 7.3 kb transcript predominantly expressed in neuroblastoma. Gene 307:1-11, 2003[CrossRef][Medline]

8. Fulda S, Lutz W, Schwab M, et al: MYCN sensitizes neuroblastoma cells for drug triggered apoptosis. Med Pediatr Oncol 35:582-584, 2000[Medline]

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Related Correspondence

• No Evidence for Correlation of DDX1 Gene Amplification With Improved Survival Probability in Patients With MYCN-Amplified Neuroblastomas
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