Comparative genetic study of intratumoral heterogenous MYCN amplified neuroblastoma versus aggressive genetic profile neuroblastic tumors

Abstract

Intratumoral heterogeneous MYCN amplification (hetMNA) is an unusual event in neuroblastoma with unascertained biological and clinical implications. Diagnosis is based on the detection of MYCN amplification surrounded by non-amplified tumor cells by fluorescence in situ hybridization (FISH). To better define the genetic features of hetMNA tumors, we studied the Spanish cohort of neuroblastic tumors by FISH and single nucleotide polymorphism arrays. We compared hetMNA tumors with homogeneous MNA (homMNA) and nonMNA tumors with 11q deletion (nonMNA w11q-). Of 1091 primary tumors, 28 were hetMNA by FISH. Intratumoral heterogeneity of 1p, 2p, 11q and 17q was closely associated with hetMNA tumors when analyzing different pieces for each case. For chromosome 2, 16 cases showed 2p intact, 4 focal gain at 2p24.3 and 8 MNA. The lengths of the smallest regions of overlap (SROs) for 2p gains and 1p deletions were between the SRO lengths observed in homMNA and nonMNA w11q- tumors. Co-occurrence of 11q- and +17q was frequently found with the largest SROs for both aberrations. The evidence for and frequency of different genetic subpopulations representing a hallmark of the hetMNA subgroup of NB indicates, on one hand, the presence of a considerable genetic instability with different SRO of either gains and losses compared with those of the other NB groups and highlights and, on the other hand, the need for multiple sampling from distant and macroscopically and microscopically distinct tumor areas. Narrowing down the different SRO for both deletions and gains in NB groups would be crucial to pinpointing the candidate gene(s) and the critical gene dosage with prognostic and therapeutic significance. This complexity of segmental chromosomal aberration patterns reinforces the necessity for a larger cohort study using FISH and pangenomic techniques to develop a suitable therapeutic strategy for these patients.

Genetic features of neuroblastic tumors associated with opsoclonus-myoclonus syndrome opens up the possibility for detection in peripheral blood

“…This frequency is different to that reported in the literature, and may be due to intratumoral heterogeneity, a well-known fact in NT, and as such would not affect the generalizability of the results with respect to the genetic findings [6,7,19]. All tumors were triploid.…”

“…SCA cases presented either heterogonous MNA (hetMNA, coexistence of amplified as well as nonamplified tumor cells in the same tumor) or no MNA (3 and 2, respectively) and with less than 4 large SCA. hetMNA is an infrequent event with unknown prognosis reported in only 2.6% (28 cases) of our total cohort of NT [19]. In one hetMNA tumor, two amplifications at chromosome region 1p34.2 and 1p31.2 were detected.…”

“…Of OMS patients with SCA tumors, 40% (2/5) were older than 18 months compared to 62.3% (104/167) in the NT control cohort. Of OMS patients with SCA tumors, 60% (3/5) were stage 1 versus 13.8% (22/160) in the NT control cohort [19]. SCA cases presented either heterogonous MNA (hetMNA, coexistence of amplified as well as nonamplified tumor cells in the same tumor) or no MNA (3 and 2, respectively) and with less than 4 large SCA.…”

11q deletion in neuroblastoma: a review of biological and clinical implications

“…In the particular subgroup of NBs occurring in adolescent and young adults [30], representing less than 5% of NBs and characterized by a high prevalence of SCA (35–85%) and very low incidence of MNA, the prevalence of 11q loss is high, ranging between 30 to 60% [37–39]. In this particular subgroup where ALK and ATRX alterations are also more frequent and the outcome very poor [37–40], ATRX mutated NBs showed a higher number of SCA including 11q deletions (Fig.…”

Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone

“…Despite the huge degree of intertumor genetic heterogeneity, studies on ITH in neuroblastoma have, thus far, mainly focused on MNA (16)(17)(18)(19)(20)(21). As a single biopsy likely fails to capture the genetic complexity of a heterogeneous tumor, the relapse-seeding subclone may be overlooked (14).…”