title: Heterogeneity of MYCN amplification in neuroblastoma at diagnosis, treatment, relapse, and metastasis.
abstract: Amplification of the MYCN gene in neuroblastoma is associated with a poor prognosis and is considered to remain unchanged in post-treatment specimens and metastases. While heterogeneity of MYCN copy number in tumor cells has been reported, serial samples have only been studied in a limited way, and the biologic relevance of this finding is not well understood. We used in situ hybridization on paraffin sections of 102 specimens from 30 patients with MYCN-amplified neuroblastoma to determine MYCN copy number in the primary tumor, pre- and post-treatment, and in metastatic samples. Nineteen cases (63%) showed diffuse MYCN amplification in all samples tested. Nine cases (30%) showed a reduction in MYCN copy number: five cases with diffuse amplification subsequently showed focal amplification, one case with diffuse MYCN amplification showed MYCN gain after treatment, and three focally amplified cases were non-amplified in later specimens. In two cases (7%), focal amplification became diffuse in subsequent samples. Histology was not predictive of the temporal or spatial pattern of MYCN amplification for a particular tumor. If extent of amplification (focal vs. diffuse) is not considered, 26/30 (87%) of cases were consistently MYCN-amplified. However, our data suggest that MYCN status can be heterogeneous between tumor sites, during tumor progression or following treatment, challenging the notion that MYCN copy number does not change for a particular neuroblastoma. Assessing the biologic significance of MYCN heterogeneity will require larger studies of clinically annotated tumor samples, and will depend on interpreting heterogeneity in MYCN status in combination with other genetic changes. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pediatric Laboratory Medicine, the Hospital for Sick Children, Toronto, Canada.
authors.forename: Paula
authors.initials: P
authors.lastname: Marrano
authors.affiliation: Department of Pediatrics, the Hospital for Sick Children, Toronto, Canada.|Department of Pediatrics, University of Toronto, Toronto, Canada.
authors.forename: Meredith S
authors.initials: MS
authors.lastname: Irwin
authors.affiliation: Department of Pediatric Laboratory Medicine, the Hospital for Sick Children, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Thorner
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D006801:Humans; D007223:Infant; D008297:Male; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein