RNA-Seq provides insights into the gene expression profile of bone marrow-derived disseminated tumor cells in high-risk neuroblastoma patients

Introduction:

Neuroblastoma is the most common tumor diagnosed in the first year of life. The vast majority of stage 4/M patients present with disseminated tumor cells (DTCs) in the bone marrow (BM). Although these cells represent a major obstacle in the treatment of neuroblastoma patients, their gene expression profile was only poorly analyzed so far.

Results:

RNA-Seq of stage 4/M primary tumors, enriched BM-derived DTCs and corresponding non-tumor mononuclear cells (MNCs) revealed that DTCs largely retained the gene expression signature of primary tumors with 322 differentially expressed genes (q < 0.001, ((verbar))log₂FC((verbar))> 2). Particularly genes encoded by mitochondrial DNA were greatly up-regulated in DTCs. Furthermore, 224 genes were highly up-regulated in DTCs compared to MNCs (q < 8 × 10^-75 log₂FC > 6). Interestingly, we found only minor differences between diagnostic and relapse DTCs, with 113 differentially expressed genes (q < 0.01, ((verbar))log₂FC((verbar)) > 0.5) and, interestingly, a significant positional enrichment of 31 down-regulated genes on chromosome 19 including tumor suppressor genes SIRT6, BBC3/PUMA, STK11, CADM 4 and GLTSCR2.

Conclusion:

This first RNA-Seq analysis of neuroblastoma DTCs revealed their unique expression profile in comparison to tumors and corresponding MNCs, and less pronounced differences between diagnostic and relapse DTCs. The latter preferentially affected down-regulated 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.