Ultrahigh-risk Group Within the High-risk Neuroblastoma Category

Abstract

Children with high-risk neuroblastoma (NBL) constitute a heterogenous group, but little attention has been paid to further subdivision of the high-risk group. Although the current therapies including multiple high-dose consolidations have neared their efficacy and tolerability limits, alternative therapies are needed. We wanted to define an ultrahigh-risk group among high-risk NBL patients, to be potential candidates for novel therapies given up-front. Children with high-risk NBL (n=59) treated at a single institution during 1987 to 2010 were evaluated for upfront prognostic factors at diagnosis and response to induction therapy. The overall outcome was not different during 1987 to 1994 versus 1995 to 2010. Therapy consisted of induction chemotherapy, surgery, and high dose-consolidation (single, tandem, or triple) with autologous stem cell rescue, followed by local irradiation and cis-retinoic acid. MYCN amplification and bone metastases were powerful upfront prognostic factors, and a combination of these determined an ultrahigh-risk group with a 5-year event-free survival of 0.125±0.083. The combination of MYCN amplification and bone metastases overruled the intensity of the therapy given and remained the only significant predictor (P<0.019) in a multiple step-wise forward Cox regression analysis. We conclude that high-risk NBL patients can be categorized into prognostic subgroups based on MYCN status and bone metastases. MYCN amplification and bone metastases combined determined an ultrahigh-risk group of patients being suitable candidates for novel alternative therapies.

Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

“…Mouse insertional mutagenesis experiments support CHD9 as cancer causing gene. °Gene found mutated with non-silent mutations in previous studies on primary neuroblastoma [8-11]. ^Gene found mutated with non-silent mutations in previous studies on relapsed neuroblastoma [12, 13].…”

“…The anticancer compounds targeting FAK are currently in preclinical and clinical trials. Moreover, current literature suggests FAK inhibition for tumor suppression and prevention or delay of metastasis in neuroblastoma [11]. We think that the found somatic mutations could activate the FAK protein, which thus could be a promising therapeutic target for clinically aggressive neuroblastoma.…”

“…Somatic mutations localized close to the well-known functional phosphorylation (Tyr576 and Tyr861) [11] sites were identified in PTK2 (also known as FAK) in 2 cases. During development and in various tumours including neuroblastoma, FAK promotes cell motility, survival and proliferation through kinase-dependent and kinase-independent mechanisms [19, 20].…”

“…Genome-wide association studies have identified multiple DNA polymorphisms influencing neuroblastoma susceptibility and clinical phenotype [3-7]. High-throughput sequencing-based studies have highlighted that recurrent mutations of single genes are infrequent in primary neuroblastoma with activating mutations in ALK and inactivating mutations in ATRX, and TERT rearrangements being the most frequent [8-11]. Two recent studies have shown a higher mutational load in relapsed neuroblastoma than in primary tumors with a relevant proportion of mutations in genes of the RAS-MAPK and YAP pathways [12, 13].…”

The challenge of defining “ultra‐high‐risk” neuroblastoma

“…In current usage, UHR may refer to disease characteristics at diagnosis, response to therapy, or potentially a combination of the two. Although some authors define UHR‐NBL as refractory disease (less than complete or very good partial response after induction chemotherapy), others use “death from disease within 18 months of diagnosis,” or patients with 5‐year EFS 10%–15% . The aim of this review is to outline a conceptual framework for UHR‐NBL, to discuss potential purpose‐specific definitions and to review progress to date in identifying subgroups of patients with HR‐NBL with inferior outcomes.…”