Neuroblastoma cells undergo transcriptomic alterations upon dissemination into the bone marrow and subsequent tumor progression. Issue 2 (4th October 2017)

• Record Type: Journal Article
• Authors: Rifatbegovic, Fikret; Frech, Christian; Abbasi, M. Reza; Taschner‐Mandl, Sabine; Weiss, Tamara; Schmidt, Wolfgang M.; Schmidt, Iris; Ladenstein, Ruth; Ambros, Inge M.; Ambros, Peter F.
• Is Part Of: International journal of cancer. Volume 142:Issue 2(2018)
• Page Start: 297
• Page End: 307
• Publication Date: 2017-10-04
• Subjects: neuroblastoma -- disseminated tumor cells -- RNA‐Seq -- bone marrow; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31053
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Neuroblastoma is the most common extracranial solid tumor in childhood. The vast majority of metastatic (M) stage patients present with disseminated tumor cells (DTCs) in the bone marrow (BM) at diagnosis and relapse. Although these cells represent a major obstacle in the treatment of neuroblastoma patients, insights into their expression profile remained elusive. The present RNA‐Seq study of stage 4/M primary tumors, enriched BM‐derived diagnostic and relapse DTCs, as well as the corresponding BM‐derived mononuclear cells (MNCs) from 53 patients revealed 322 differentially expressed genes in DTCs as compared to the tumors ( q < 0.001, |log2 FC|>2). Particularly, the levels of transcripts encoded by mitochondrial DNA were elevated in DTCs, whereas, for example, genes involved in angiogenesis were downregulated. Furthermore, 224 genes were highly expressed in DTCs and only slightly, if at all, in MNCs ( q < 8 × 10 −75 log2 FC > 6). Interestingly, we found the transcriptome of relapse DTCs largely resembling those of diagnostic DTCs with only 113 differentially expressed genes under relaxed cut‐offs ( q < 0.01, |log2 FC|>0.5). Notably, relapse DTCs showed a positional enrichment of 31 downregulated genes on chromosome 19, including five tumor suppressor genes: SIRT6, BBC3 / PUMA, STK11, CADM4 and GLTSCR2 . This first RNA‐Seq analysis of neuroblastoma DTCs revealed their unique expression profile in comparison to the tumors and MNCs, and less pronounced differences between diagnostic and relapse DTCs. The latter preferentially affected downregulation of genes encoded by chromosome 19. As these alterations might be associated with treatment failure and disease relapse, further functional studies on DTCs should be considered. Abstract : What's new? More than 90% of patients diagnosed with stage 4 metastatic (4/M) neuroblastoma present with disseminated tumor cells (DTCs) in the bone marrow (BM). Despite treatment, a substantial fraction of these patients experience disease relapse. Here, sequencing analysis of tumor tissue, BM‐derived mononuclear cells (MNCs), and DTCs from stage 4/M neuroblastoma patients indicates that numerous genes are differentially expressed in DTCs but are not or are only slightly altered in tumors and MNCs. Moreover, DTCs exhibited significant downregulation of tumor suppressor genes specifically on chromosome 19. Further studies are needed to determine whether DTC transcriptomic alterations are associated with neuroblastoma relapse.