Genomic coamplification of CDK4/MDM2/FRS2 is associated with very poor prognosis and atypical clinical features in neuroblastoma patients

Amoroso, Loredana; Ognibene, Marzia; Morini, Martina; Conte, Massimo; Cataldo, Andrea Di; Tondo, Annalisa; D’Angelo, Paolo; Castellano, Aurora; Garaventa, Alberto; Lasorsa, Vito Alessandro; Podestà, Marina; Capasso, Mario; Pezzolo, Annalisa

doi:10.1002/gcc.22827

Cited by 22 publications

(32 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Various publications have also described a high presence of this aberration in NB, especially in stage four [57,58]. Although gain at 12q is understudied in the scientific literature, amplification (also present in three of the present cases; see Figures 1B and 2B) and overexpression of some of its genes, is correlated with poor prognosis [59,60]. In our cohort, gain of this region was most present in ITH cases, and preferentially in non-MNA and hetMNA tumours.…”

Section: Discussionsupporting

confidence: 62%

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

López-Carrasco

Berbegall

Martín-Vañó

et al. 2021

Cancers

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 62%

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

López-Carrasco

Berbegall

Martín-Vañó

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…In case patients have copy number unstable genomes and carry many gene fusions, the pathogenicity of individual fusions is difficult to assess. For example, the co-amplification and resulting overexpression of MDM2/CDK4/FRS2 in neuroblastoma patient M787AAA is clinically relevant [41], and the fusions originating from this amplification are more likely to be passenger events [27,42]. This shows that resolving the underlying SVs and copy number alterations (CNAs) can help to distinguish expression changes due to "catastrophic" genomic events from pathogenic fusions where 3' (onco)genes are upregulated due to fusion with an active promoter.…”

Section: Discussionmentioning

confidence: 99%

Systematic discovery of gene fusions in pediatric cancer by integrating RNA-seq and WGS

Belzen

Dan

Tuil

et al. 2021

Preprint

View full text Add to dashboard Cite

Background Gene fusions are important cancer drivers in pediatric cancer and their accurate detection is essential for diagnosis and treatment. Clinical decision-making requires high confidence and precision of detection. Recent developments show RNA sequencing (RNA-seq) is promising for genome-wide detection of fusion products, but hindered by many false positives that require extensive manual curation and impede discovery of pathogenic fusions. Results We developed Fusion-sq to detect tumor-specific gene fusions by integrating and 'fusing' evidence from RNA-seq and whole genome sequencing (WGS) using intron-exon gene structure. In a pediatric pan-cancer cohort of 130 patients, we identified 165 high confidence tumor-specific gene fusions and their underlying structural variants (SVs). This includes all clinically relevant fusions known to be present in this cohort (30 patients). Fusion-sq distinguishes healthy-occurring from tumor-specific fusions, and resolves fusions in amplified regions and copy number unstable genomes. A high gene fusion burden is associated with copy number instability. We identified 27 potentially pathogenic fusions involving oncogenes or tumor-suppressor genes characterised by underlying SVs or expression changes indicative of activating or disruptive effects. Conclusions Our results indicate how clinically relevant and potentially pathogenic gene fusions can be identified and their functional effects investigated by combining WGS and RNA-seq. Integrating RNA fusion predictions with underlying SVs advances fusion detection beyond extensive manual filtering. Taken together, we developed a method for identifying candidate fusions that is suitable for precision oncology applications. Our method provides multi-omics evidence for assessing the pathogenicity of tumor-specific fusions for future clinical decision making.

show abstract

“…Cytogenomic microarray analysis further clarified the copy number status of exons within ALK , and detected other unfavorable prognostic biomarkers including segmental gain of 17q and amplification within 12q. The latter harbors potential oncogenic target genes, including CKD4 and MDM2 [12].…”

Section: Discussionmentioning

confidence: 99%

5′ ALK Amplification in Neuroblastoma: A Case Report

et al. 2021

View full text Add to dashboard Cite

Neuroblastoma is the most common cancer in infants younger than 12 months of age, occurring with an incidence of 1 in 100,000 children. The clinical outcome of neuroblastoma ranges from spontaneous regression to treatment-resistant progression and/or metastasis, and accounts for 8–10% of childhood cancer deaths. Segmental chromosomal aberrations, as well as MYCN and ALK amplification, are among factors contributing to an unfavorable genomic profile and high-risk disease classification. Here, we describe a 5-year-old male who presented with a large right renal neuroblastoma tumor having lung and liver metastases. Fluorescence in situ hybridization analysis indicated the presence of >20 copies of the 5′ region of the ALK gene in 26% of cells examined. Subsequent copy number assessment did not confirm ALK amplification, but revealed a gain of exons 2–5 of ALK, consistent with increased copy number for the 5′ region of the ALK gene. Subsequent array analysis showed the presence of other unfavorable prognostic genomic features, including segmental gain of the 17q region and amplification of the long arm of chromosome 12 harboring CDK4 and MDM2, both reported to be poor prognostic indicators in patients with atypical clinical features in neuroblastoma. Taken together, this report illustrates the importance of careful interpretation of aberrant FISH findings and subsequent use of orthogonal methods to clarify the presence of genomic alterations to successfully determine potential treatment targets.

show abstract

Genomic coamplification of CDK4/MDM2/FRS2 is associated with very poor prognosis and atypical clinical features in neuroblastoma patients

Cited by 22 publications

References 44 publications

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

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

Systematic discovery of gene fusions in pediatric cancer by integrating RNA-seq and WGS

5′ <b><i>ALK</i></b> Amplification in Neuroblastoma: A Case Report

Contact Info

Product

Resources

About