Recent insights into the biology of neuroblastoma

Abstract

Neuroblastoma (NB) is an embryonal tumor of the sympathetic nervous system which accounts for 8-10% of pediatric cancers. It is characterized by a broad spectrum of clinical behaviors from spontaneous regression to fatal outcome despite aggressive therapies. Considerable progress has been made recently in the germline and somatic genetic characterization of patients and tumors. Indeed, predisposition genes that account for a significant proportion of familial and syndromic cases have been identified and genome-wide association studies have retrieved a number of susceptibility loci. In addition, genomewide sequencing, copy-number and expression studies have been conducted on tumors and have detected important gene modifications, profiles and signatures that have strong implications for the therapeutic stratification of patients. The identification of major players in NB oncogenesis, including MYCN, ALK, PHOX2B and LIN28B, has enabled the development of new animal models. Our review focuses on these recent advances, on the insights they provide on the mechanisms involved in NB development and their applications for the clinical management of patients.Neuroblastoma (NB) is the most common extracranial cancer of early childhood, with an estimated incidence of 1/8,000-10,000 births.1 In France, this cancer is diagnosed in 130-150 new patients every year, and accounts for approximately 15% of cancer-related deaths.2 Median age at diagnosis is 18 months, 40% of cases being diagnosed before 1 year of age. NB arises from embryonic cells that form the primitive neural crest, originating either in the adrenal medulla or in the paraspinal ganglia of the sympathetic nervous system. In case of metastases, these are most frequently observed in bone marrow, bone, lymph nodes, liver or subcutaneous tissue, other metastatic localizations occurring much rarer.The hallmark of NB is its wide range of clinical courses, with, on the one hand, a possibility of cellular maturation or spontaneous regression even in case of metastatic disease, or on the other hand, life-threatening tumor progression despite all treatment. Thus, prognostic factors have been sought for to identify risk groups and to stratify treatment approaches. The clinical parameters age and stage have been used, together with pathological features, to define different risk groups at the time of diagnosis.3 Children diagnosed with a NB before the age of 18 months have a better outcome than those diagnosed at a later age. 4 Patients with localized disease (INRG staging system L1 and L2; localized disease without or with image-defined risk factors precluding surgical resection) have a better prognosis than those with metastatic disease (INRG stage M), whose outcome remains dismal especially in older children. To date, different recurrent genetic markers have also been included in risk stratification schemes. It is likely that with the increase of knowledge about the underlying genetic features of NB, additional genetic information will be included for the definition of pro...

Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis

“…Genetic alterations in neuroblastoma at diagnosis mainly concern copy number alterations, with MYCN amplification in 20% to 25% of cases, and segmental copy number alterations involving more extensive chromosome regions (10)(11)(12)(13)(14). Genome sequencing studies of neuroblastoma at diagnosis have revealed a low mutation rate involving only few recurrently altered genes mainly involved in chromatin-remodeling or neuritogenesis (15)(16)(17).…”

Characterization of Chromosomal Aberrations in Neuroblastoma Formalin-Fixed Paraffin- Embedded Specimens with Standard ArrayCGH Procedure - Preliminary Experience

“…These diploid tumor's cells are more likely to harbor MYCN gene amplification or other SCAs. In contrast, neartriploid DNA content is most commonly found in infant tumors that remain localized and are associated with more favorable outcome [2][3][4][5][6][7][8][9]12].…”

“…Aggressive metastatic tumors are characterized by a high number of SCAs and a low number of Numerical Changes (NCAs). On the whole, genome-wide studies have demonstrated that critical chromosomal damages occur more frequently in older patients and that SCAs accumulate in an age-dependent manner, as supported by Schleiermacher and Coco [8][9][10][11][12].…”

“…The most unfavorable genetic factor in NB is MYCN oncogene amplification [2][3][4][5][6][7]. Moreover, tumor aggressiveness and progression is strongly associated with Segmental Chromosomal Aberrations (SCAs) observed in malignant cells [2,5,8]. Aggressive metastatic tumors are characterized by a high number of SCAs and a low number of Numerical Changes (NCAs).…”

Advances in ALK Targeted Therapy for Neuroblastoma

“…[3][4][5][6]. Next-generation sequencing-based genomic profiling identified the most frequent alterations including MYCN (26.5%), ALK (17.8%), ATRX (6.5%), CDKN2A (4.8%) and RPTOR (4.8%) in 230 neuroblastoma patient samples [7].…”