PHOX2B Is a Novel and Specific Marker for Minimal Residual Disease Testing in Neuroblastoma

Author:

Stutterheim Janine1,Gerritsen Annemieke1,Zappeij-Kannegieter Lily1,Kleijn Ilona1,Dee Rob1,Hooft Lotty1,van Noesel Max M.1,Bierings Marc1,Berthold Frank1,Versteeg Rogier1,Caron Huib N.1,van der Schoot C. Ellen1,Tytgat Godelieve A.M.1

Affiliation:

1. From the Department of Pediatric Oncology, Emma Children's Hospital; Dutch Cochrane Centre; Department of Human Genetics, Academic Medical Center; Sanquin-AMC (Academic Medical Center) Landsteiner Laboratory, Amsterdam; Department of Pediatric Oncology/Hematology, Sophia Children's Hospital, Erasmus Medical Center, Rotterdam; Department of Pediatric Hematology, Wilhelmina Children's Hospital, Utrecht Medical Center, Utrecht, the Netherlands; and Department of Pediatric Oncology and Hematology, Children's...

Abstract

Purpose Polymerase chain reaction (PCR)–based detection of minimal residual disease (MRD) in neuroblastoma can be used to monitor therapy response and to evaluate stem cell harvests. Commonly used PCR markers, tyrosine hydroxylase (TH) and GD2 synthase, have expression in normal tissues, thus limiting MRD detection. To identify a more specific MRD marker, we tested PHOX2B. Patients and Methods To determine PHOX2B, TH, and GD2 synthase expression in normal tissues, it was measured by real-time quantitative PCR in samples of normal bone marrow (BM; n = 51), peripheral blood (PB; n = 37), and peripheral-blood stem cells (PBSCs; n = 24). Then, 289 samples of 101 Dutch patients and 47 samples of 43 German patients were tested for PHOX2B and TH; these samples included 52 tumor, 214 BM, 32 BM, and 38 PBSC harvests. Of the 214 BM samples, 167 were compared with cytology, and 47 BM samples were compared with immunocytology (IC). Results In contrast to TH and GD2 synthase, PHOX2B was not expressed in any of the normal samples. In patient samples, PHOX2B was detected in 32% cytology-negative and in 14% IC-negative samples and in 94% of cytology-positive and in 90% of IC-positive BM samples. Overall, PHOX2B was positive in 43% compared with 31% for TH. In 24% of all samples, TH expression was inconclusive, which is similar to expression found in normal tissues. In 42% of these samples, PHOX2B expression was positive. Conclusion PHOX2B is superior to TH and GD2 synthase in specificity and sensitivity for MRD detection of neuroblastoma by using real-time quantitative PCR. We propose to include PHOX2B in additional prospective MRD studies in neuroblastoma alongside TH and other MRD markers.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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