Introduction: Genomic instability is common in cancer, driven by different mechanisms and often linked to disease stage and progression. Optical genome mapping (OGM) enables the detection of genome-wide balanced and unbalanced structural rearrangements (SRs), providing an overview of genomic complexity. Aims: To explore the utility of OGM in brain tumour characterisation, we conducted a pilot study on a well-characterised series of 43, mostly paediatric, cases encompassing different histotypes and enriched for gene fusion-positive neoplasms (30 cases). Results: SRs were observed in 37/43 samples and defined three genomic patterns based on their number and distribution across the chromosomes: SR-chromothripsis (11 cases), high SR-complexity (11 cases) and low SR-complexity (21 cases). Genomic complexity was also assessed according to the number of copy number alterations (CNA) and, to this end, in SR-chromothripsis samples, only CNAs affecting chromosomes not involved in chromothripsis were considered: absence of CNAs was found in 15 cases, 1–9 CNAs in 19 cases, 10–49 CNAs in three cases and ≥ 50 CNAs in six cases. When examining the relationship between SR and CNA, a positive correlation emerged between CNA burden and the number of chromosomes harbouring SR (Spearman's r = 0.588, p = 0.0001), while breakpoint number was weakly associated; chromothripsis occurred exclusively within low CNA-complexity groups (p = 0.0836). Genome complexity patterns correlated with tumour types, with diffuse high-grade gliomas exhibiting high complexity, whereas infant-type hemispheric gliomas, most low-grade gliomas and embryonal tumours showed low complexity profiles. Importantly, SR-chromothripsis cases corresponded to low/intermediate-grade fusion-driven tumours, with balanced/nearly balanced CNA profiles. OGM allowed the detection of gene fusions in 24/30 cases, failing in six. When integrated with RNA sequencing, OGM unveiled the mechanisms underlying gene fusion formation in all cases: chromothripsis (11 cases), isolated chromosomal abnormalities (12 cases) and genome-wide alterations (seven cases). Conclusions: OGM reveals distinct genomic complexity patterns and refines the definition of chromothripsis, improving insights into tumourigenic mechanisms.
Alesi, V., Genovese, S., Russo, S., Giovannoni, I., Barresi, S., Tancredi, C., Pedace, L., Arienzo, F., Lombardo, A., Bontempo, P., Agolini, E., Calacci, C., Morgia, A., Calvieri, G., Puggioni, C., Cardoni, A., Cacchione, A., Del Baldo, G., Colafati, G. S., Carai, A., Mastronuzzi, A., Miele, E., Abeni, D., Locatelli, F., Muda, A. O., Novelli, A., Alaggio, R., Rossi, S., Utility of Optical Genome Mapping in the Characterisation of the Global Genomic Architecture of Paediatric Central Nervous System Tumours: A Pilot Study, <<NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY>>, 2026; 52 (4): 1-22. [doi:10.1111/nan.70092] [https://hdl.handle.net/10807/344618]
Utility of Optical Genome Mapping in the Characterisation of the Global Genomic Architecture of Paediatric Central Nervous System Tumours: A Pilot Study
Carai, AndreaWriting – Review & Editing
;Mastronuzzi, AngelaWriting – Review & Editing
;Locatelli, FrancoWriting – Review & Editing
;
2026
Abstract
Introduction: Genomic instability is common in cancer, driven by different mechanisms and often linked to disease stage and progression. Optical genome mapping (OGM) enables the detection of genome-wide balanced and unbalanced structural rearrangements (SRs), providing an overview of genomic complexity. Aims: To explore the utility of OGM in brain tumour characterisation, we conducted a pilot study on a well-characterised series of 43, mostly paediatric, cases encompassing different histotypes and enriched for gene fusion-positive neoplasms (30 cases). Results: SRs were observed in 37/43 samples and defined three genomic patterns based on their number and distribution across the chromosomes: SR-chromothripsis (11 cases), high SR-complexity (11 cases) and low SR-complexity (21 cases). Genomic complexity was also assessed according to the number of copy number alterations (CNA) and, to this end, in SR-chromothripsis samples, only CNAs affecting chromosomes not involved in chromothripsis were considered: absence of CNAs was found in 15 cases, 1–9 CNAs in 19 cases, 10–49 CNAs in three cases and ≥ 50 CNAs in six cases. When examining the relationship between SR and CNA, a positive correlation emerged between CNA burden and the number of chromosomes harbouring SR (Spearman's r = 0.588, p = 0.0001), while breakpoint number was weakly associated; chromothripsis occurred exclusively within low CNA-complexity groups (p = 0.0836). Genome complexity patterns correlated with tumour types, with diffuse high-grade gliomas exhibiting high complexity, whereas infant-type hemispheric gliomas, most low-grade gliomas and embryonal tumours showed low complexity profiles. Importantly, SR-chromothripsis cases corresponded to low/intermediate-grade fusion-driven tumours, with balanced/nearly balanced CNA profiles. OGM allowed the detection of gene fusions in 24/30 cases, failing in six. When integrated with RNA sequencing, OGM unveiled the mechanisms underlying gene fusion formation in all cases: chromothripsis (11 cases), isolated chromosomal abnormalities (12 cases) and genome-wide alterations (seven cases). Conclusions: OGM reveals distinct genomic complexity patterns and refines the definition of chromothripsis, improving insights into tumourigenic mechanisms.
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