Abstract
Simple SummaryNeuroblastoma (NB) is the most common extra-cranial solid paediatric cancer and is responsible for 15% of childhood cancer deaths. Patients with NB are characterized by presenting a very heterogeneous clinic (inter-tumoural heterogeneity) and also both spatial and temporal intra-tumour heterogeneity (ITH) reflected in their genetic aberrations, which may be the consequence of the coexistence of different microenvironments within the tumour. Applying pangenomic techniques to detect genomic aberrations in different biopsies (solid and liquid) of high risk NB (HR-NB) we have detected spatial ITH in a surprisingly high percentage (almost 40%) of the studied cohort. Moreover, a positive association between this heterogeneity and survival has been found. Confirming these results, combining tumour material analysis in a large cohort of HR-NB will have a major impact in the genetic diagnosis routine procedure, and would also entail a revision of the prognosis of patients with ITH.Spatial ITH is defined by genomic and biological variations within a tumour acquired by tumour cell evolution under diverse microenvironments, and its role in NB patient prognosis is understudied. In this work, we applied pangenomic techniques to detect chromosomal aberrations in at least two different areas of each tumour and/or in simultaneously obtained solid and liquid biopsies, detecting ITH in the genomic profile of almost 40% of HR-NB. ITH was better detected when comparing one or more tumour pieces and liquid biopsy (50%) than between different tumour pieces (21%). Interestingly, we found that patients with ITH analysed by pangenomic techniques had a significantly better survival rate that those with non-heterogeneous tumours, especially in cases without MYCN amplification. Moreover, all patients in the studied cohort with high ITH (defined as 50% or more genomic aberration differences between areas of a tumour or simultaneously obtained samples) survived after 48 months. These results clearly support analysing at least two solid tumour areas (separately or mixed) and liquid samples to provide more accurate genomic diagnosis, prognosis and therapy options in HR-NB.
Highlights
In addition to genetic and clinical inter-tumour heterogeneity, which refers to variations found between different patients in tumours and/or behaviour, tumours can present with spatial and/or temporal intra-tumour heterogeneity (ITH)
Spatial genomic ITH is characterised by genomic variations within a tumour lesion, or between different tumours located in the patient at the same time point in the case of metastatic disease, and consists of multiple cells or sub-clones, each possessing different genomic profiles [1]
In a recent study we observed the dramatic impact of extracellular matrix (ECM) stiffness on ITH and clonal evolution of a MYCN amplification (MNA) NB cell line, in which dominant clones were selected when cultured in stiff 3D-bioprinted hydrogels and in xenograft tumours; these changes were not found in an ALK mutated NB cell-line [3,19]
Summary
In addition to genetic and clinical inter-tumour heterogeneity, which refers to variations found between different patients in tumours and/or behaviour, tumours can present with spatial and/or temporal intra-tumour heterogeneity (ITH). Temporal genomic ITH denotes genetic variation over the course of disease progression and has been observed mainly when comparing treatment-naïve and matched relapsed tumours [2] Both ITH types can be a result of clonal evolution due to natural selection among tumour cells, or in the absence of strong selection can emerge through the mechanism of genetic drift [2,3]. Tumour microenvironment (TME) and extracellular matrix (ECM) features are emerging as important factors contributing to tumour prognosis and heterogeneity [12,13] In this regard, our group has previously described a common aggressive pattern of rigid ECM in HR-NB [14], rich in cross-linked collagen III fibres, poor in glycosaminoglycans, supporting sinusoidal vascular structures (blood and lymphatic) and with a high amount of territorial vitronectin (located in cytoplasmic compartments and a thin layer around tumour cells) [15,16,17,18]. A continuous interplay exists between TME and genetics, tumour cell proliferation, aggressiveness and migration [20]
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