Intratumour diversity of chromosome copy numbers in neuroblastoma mediated by on-going chromosome loss from a polyploid state.

Neuroblastomas (NBs) are tumours of the sympathetic nervous system accounting for 8-10% of paediatric cancers. NBs exhibit extensive intertumour genetic heterogeneity, but their extent of intratumour genetic diversity has remained unexplored. We aimed to assess intratumour genetic variation in NBs w...

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Autores principales:	Gisela Lundberg, Yuesheng Jin, Daniel Sehic, Ingrid Øra, Rogier Versteeg, David Gisselsson
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4a7c17f326f54da09dbb2a3e5bae2ba5
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spelling	oai:doaj.org-article:4a7c17f326f54da09dbb2a3e5bae2ba52021-11-18T07:52:29ZIntratumour diversity of chromosome copy numbers in neuroblastoma mediated by on-going chromosome loss from a polyploid state.1932-620310.1371/journal.pone.0059268https://doaj.org/article/4a7c17f326f54da09dbb2a3e5bae2ba52013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23555645/?tool=EBIhttps://doaj.org/toc/1932-6203Neuroblastomas (NBs) are tumours of the sympathetic nervous system accounting for 8-10% of paediatric cancers. NBs exhibit extensive intertumour genetic heterogeneity, but their extent of intratumour genetic diversity has remained unexplored. We aimed to assess intratumour genetic variation in NBs with a focus on whole chromosome changes and their underlying mechanism. Allelic ratios obtained by SNP-array data from 30 aneuploid primary NBs and NB cell lines were used to quantify the size of clones harbouring specific genomic imbalances. In 13 cases, this was supplemented by fluorescence in situ hybridisation to assess copy number diversity in detail. Computer simulations of different mitotic segregation errors, single cell cloning, analysis of mitotic figures, and time lapse imaging of dividing NB cells were used to infer the most likely mechanism behind intratumour variation in chromosome number. Combined SNP array and FISH analyses showed that all cases exhibited higher inter-cellular copy number variation than non-neoplastic control tissue, with up to 75% of tumour cells showing non-modal chromosome copy numbers. Comparisons of copy number profiles, resulting from simulations of different segregation errors to genomic profiles of 120 NBs indicated that loss of chromosomes from a tetraploid state was more likely than other mechanisms to explain numerical aberrations in NB. This was supported by a high frequency of lagging chromosomes at anaphase and polyploidisation events in growing NB cells. The dynamic nature of numerical aberrations was corroborated further by detecting substantial copy number diversity in cell populations grown from single NB cells. We conclude that aneuploid NBs typically show extensive intratumour chromosome copy number diversity, and that this phenomenon is most likely explained by continuous loss of chromosomes from a polyploid state.Gisela LundbergYuesheng JinDaniel SehicIngrid ØraRogier VersteegDavid GisselssonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 3, p e59268 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gisela Lundberg Yuesheng Jin Daniel Sehic Ingrid Øra Rogier Versteeg David Gisselsson Intratumour diversity of chromosome copy numbers in neuroblastoma mediated by on-going chromosome loss from a polyploid state.
description	Neuroblastomas (NBs) are tumours of the sympathetic nervous system accounting for 8-10% of paediatric cancers. NBs exhibit extensive intertumour genetic heterogeneity, but their extent of intratumour genetic diversity has remained unexplored. We aimed to assess intratumour genetic variation in NBs with a focus on whole chromosome changes and their underlying mechanism. Allelic ratios obtained by SNP-array data from 30 aneuploid primary NBs and NB cell lines were used to quantify the size of clones harbouring specific genomic imbalances. In 13 cases, this was supplemented by fluorescence in situ hybridisation to assess copy number diversity in detail. Computer simulations of different mitotic segregation errors, single cell cloning, analysis of mitotic figures, and time lapse imaging of dividing NB cells were used to infer the most likely mechanism behind intratumour variation in chromosome number. Combined SNP array and FISH analyses showed that all cases exhibited higher inter-cellular copy number variation than non-neoplastic control tissue, with up to 75% of tumour cells showing non-modal chromosome copy numbers. Comparisons of copy number profiles, resulting from simulations of different segregation errors to genomic profiles of 120 NBs indicated that loss of chromosomes from a tetraploid state was more likely than other mechanisms to explain numerical aberrations in NB. This was supported by a high frequency of lagging chromosomes at anaphase and polyploidisation events in growing NB cells. The dynamic nature of numerical aberrations was corroborated further by detecting substantial copy number diversity in cell populations grown from single NB cells. We conclude that aneuploid NBs typically show extensive intratumour chromosome copy number diversity, and that this phenomenon is most likely explained by continuous loss of chromosomes from a polyploid state.
format	article
author	Gisela Lundberg Yuesheng Jin Daniel Sehic Ingrid Øra Rogier Versteeg David Gisselsson
author_facet	Gisela Lundberg Yuesheng Jin Daniel Sehic Ingrid Øra Rogier Versteeg David Gisselsson
author_sort	Gisela Lundberg
title	Intratumour diversity of chromosome copy numbers in neuroblastoma mediated by on-going chromosome loss from a polyploid state.
title_short	Intratumour diversity of chromosome copy numbers in neuroblastoma mediated by on-going chromosome loss from a polyploid state.
title_full	Intratumour diversity of chromosome copy numbers in neuroblastoma mediated by on-going chromosome loss from a polyploid state.
title_fullStr	Intratumour diversity of chromosome copy numbers in neuroblastoma mediated by on-going chromosome loss from a polyploid state.
title_full_unstemmed	Intratumour diversity of chromosome copy numbers in neuroblastoma mediated by on-going chromosome loss from a polyploid state.
title_sort	intratumour diversity of chromosome copy numbers in neuroblastoma mediated by on-going chromosome loss from a polyploid state.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/4a7c17f326f54da09dbb2a3e5bae2ba5
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Intratumour diversity of chromosome copy numbers in neuroblastoma mediated by on-going chromosome loss from a polyploid state.

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