Multifocal primary neuroblastoma tumor heterogeneity in siblings with co‐occurring PHOX2B and NF1 genetic aberrations

Abstract

Neuroblastoma, the most common extracranial solid tumor of childhood, can present in multiple primary sites, but the extent of genetic heterogeneity among tumor foci, as well as the presence or absence of common oncogenic drivers, remains unknown. Although PHOX2B genetic aberrations can cause familial neuroblastoma, they demonstrate incomplete penetrance with respect to neuroblastoma pathogenesis, suggesting that additional undescribed oncogenic drivers are necessary for tumor development. We performed comprehensive molecular characterization of neuroblastoma tumors from two siblings affected by familial multifocal neuroblastoma, including whole exome sequencing and single‐nucleotide polymorphism (SNP) arrays of tumor and matched blood samples. Data were processed and analyzed using established bioinformatics algorithms to evaluate for germline and somatic mutations and copy number variations (CNVs). We confirmed the presence of a PHOX2B deletion and NF1 mutation across all tumor samples and the germline genome. Matched tumor‐blood whole exome sequencing also identified 365 genes that contained nonsilent coding mutations across all tumor samples, with no recurrent mutations across all tumors. SNP arrays also showed significant heterogeneity with respect to CNVs. The only common CNV across all tumors was 17q gain, with differing chromosomal coordinates across samples but a common region of overlap distal to 17q21.31, suggesting this adverse prognostic biomarker may offer insight about additional drivers for multifocal neuroblastoma in patients with germline PHOX2B or NF1 aberrations. Molecular characterization of all tumors from patients with multifocal primary neuroblastoma has potential to yield novel insights on neuroblastoma pathogenesis.

A review of the biological and clinical implications of RAS-MAPK pathway alterations in neuroblastoma

“…It has also been associated with other rare syndromic diseases, more particularly with those characterized by the presence of germline mutations located along the RAS-MAPK pathway. This group of diseases, also known as RASopathies, includes neurofibromatosis 1 (NF1 mutations), Costello syndrome (HRAS mutations), Noonan syndrome, and such Noonan-like syndromes as Noonan syndrome-like disorder with loose anagen hair and the LEOPARD syndrome (mutations in PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, MEK1, SHOC2, MEK2, RIT1, and CBL) [41,[45][46][47].…”

Intra-Tumour Genetic Heterogeneity and Prognosis in High-Risk Neuroblastoma

“…However, it should be noted that NB are frequently found in neonates and young children, in whom total surgical excision or representative biopsy collection are restricted options [40]. These difficulties in NB tumour sampling result in underdetection of genomic aberrations located in metastatic clones, forming small foci, nodules (such as ganglioneuroblastoma, nodular), or dispersed in an isolated tumour area that could lead to erroneous genetic diagnosis and inadequate treatment selection [41,42].…”

Key genetic disorders in the pathogenesis of neuroblastoma

“…В исследованиях Rybinski и соавт. делеция PHOX2B ассоциировалась с мутациями в NF1 и амплификацией дистального участка 17q [26], кодирующего ряд протоонкогенов (анти апоптотический белок BIRC5 -survivin, транскрипционный фактор TBX2) [27,28]. В настоящее время не имеется достоверных данных о взаимосвязи аберраций PHOX2B с общепризнанными прогностическими факторами НБ [9,25].…”