Neuroblastoma after Childhood: Prognostic Relevance of Segmental Chromosome Aberrations, ATRX Protein Status, and Immune Cell Infiltration

Abstract

Neuroblastoma (NB) is a common malignancy in children but rarely occurs during adolescence or adulthood. This subgroup is characterized by an indolent disease course, almost uniformly fatal, yet little is known about the biologic characteristics. The aim of this study was to identify differential features regarding DNA copy number alterations, α-thalassemia/mental retardation syndrome X-linked (ATRX) protein expression, and the presence of tumor-associated inflammatory cells. Thirty-one NB patients older than 10 years who were included in the Spanish NB Registry were considered for the current study; seven young and middle-aged adult patients (range 18-60 years) formed part of the cohort. We performed single nucleotide polymorphism arrays, immunohistochemistry for immune markers (CD4, CD8, CD20, CD11b, CD11c, and CD68), and ATRX protein expression. Assorted genetic profiles were found with a predominant presence of a segmental chromosome aberration (SCA) profile. Preadolescent and adolescent NB tumors showed a higher number of SCA, including 17q gain and 11q deletion. There was also a marked infiltration of immune cells, mainly high and heterogeneous, in young and middle-aged adult tumors. ATRX negative expression was present in the tumors. The characteristics of preadolescent, adolescent, young adult, and middle-aged adult NB tumors are different, not only from childhood NB tumors but also from each other. Similar examinations of a larger number of such tumor tissues from cooperative groups should lead to a better older age–dependent tumor pattern and to innovative, individual risk-adapted therapeutic approaches for these patients.

Treatment and outcome of adult‐onset neuroblastoma

“…Similar to other reports on adult-onset NB 7, 18, 19, 21 , none of our patients had MYCN -amplified NB. (Table 1) This is in contrast to pediatric NB where 20–25% of patients have MYCN -amplified NB 5, 22 .…”

“…ATRX is thought to play an essential role in maintaining chromosome stability by interacting with histones at telomeres and by regulating cell cycles. 19, 42 Adult malignancies, in general, have a much higher rate of somatic mutations which are thought to accumulate over time. 43 Similar to other adult-onset tumors, the development of NB could be related to the accumulation of somatic mutations with age.…”

“…5, 22 MYCN -amplified tumors have almost never been observed in adult-onset NB, with only one report in the literature of a patient ≥18 years at diagnosis. 19 Conversely, loss-of-function alpha thalassemia/mental retardation syndrome X linked ( ATRX ) mutations and deletions are more commonly observed in NB arising in patients ≥12 years old compared to the younger age group. 23 Although mechanisms of oncogenesis of ATRX mutations/deletions are unclear, they could be related to slower growth and chemoresistant phenotype of adolescent/adult NB.…”

Synthesis and Bioactivity of Natural Occurring Petasin-Like Derivatives as Antitumor Agents

“…Neuroblastoma (neuroblastoma, NB) [1] is the most common extracranial tumor in infants and young children. Recent clinical statistics show that the neuroblastoma has become the third most common cause of death after renal tumor and leukemia during the childhood [2] [3].…”

“…N-(1,8a-dimethyl-6-oxo-7-(propan-2-ylidene)-1,2,3,4,6,7,8,8a-octahydronaphthalen-2-yl)acetamide (8a).Yellow oil, yield 66%,1 H NMR (400 MHz, CDCl 3 ) δ 5.96 (s, 1H, NH), 5.75 (s, 1H, HC = C), 4.21 (m, 1H, CH), 2.87 (d, J = 14.4 Hz, 1H, CH 2 ), 2.44 (d, J = 14.6, Hz, 1H, CH 2 ), 2.24 -2.18 (d, J = 11.1 Hz, 1H, CH 2 ), 2.15 -2.04 (m, 2H, CH 2 ), 2.09 (s, 3H, CH 3 ), 2.02 (s, 3H, CH 3 ), 1.82 (s, 3H, CH 3 ), 1.75 -1.67 (d, J = 11.1 Hz, 1H, CH 2 ), 1.24 (m, 1H, CH), 1.03 (s, 3H, CH 3 ), 1.01 (d, J = 6.7 Hz, 3H, CH 3 ). 13 C NMR (100 MHz, CDCl 3 ) δ 191.44, 169.98, 165.75, 144.53, 127.17, 127.11, 49.39, 43.82, 41.67, 41.03, 30.95, 27.18, 23.77, 22.80, 22.31, 18.18, 12.02.…”