The relative timing of mutations in a breast cancer genome.

Many tumors have highly rearranged genomes, but a major unknown is the relative importance and timing of genome rearrangements compared to sequence-level mutation. Chromosome instability might arise early, be a late event contributing little to cancer development, or happen as a single catastrophic...

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Autores principales:	Scott Newman, Karen D Howarth, Chris D Greenman, Graham R Bignell, Simon Tavaré, Paul A W Edwards
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b8a9b8d7fde040cb8298a7c71a5609f6
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spelling	oai:doaj.org-article:b8a9b8d7fde040cb8298a7c71a5609f62021-11-18T07:42:30ZThe relative timing of mutations in a breast cancer genome.1932-620310.1371/journal.pone.0064991https://doaj.org/article/b8a9b8d7fde040cb8298a7c71a5609f62013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23762276/?tool=EBIhttps://doaj.org/toc/1932-6203Many tumors have highly rearranged genomes, but a major unknown is the relative importance and timing of genome rearrangements compared to sequence-level mutation. Chromosome instability might arise early, be a late event contributing little to cancer development, or happen as a single catastrophic event. Another unknown is which of the point mutations and rearrangements are selected. To address these questions we show, using the breast cancer cell line HCC1187 as a model, that we can reconstruct the likely history of a breast cancer genome. We assembled probably the most complete map to date of a cancer genome, by combining molecular cytogenetic analysis with sequence data. In particular, we assigned most sequence-level mutations to individual chromosomes by sequencing of flow sorted chromosomes. The parent of origin of each chromosome was assigned from SNP arrays. We were then able to classify most of the mutations as earlier or later according to whether they occurred before or after a landmark event in the evolution of the genome, endoreduplication (duplication of its entire genome). Genome rearrangements and sequence-level mutations were fairly evenly divided earlier and later, suggesting that genetic instability was relatively constant throughout the life of this tumor, and chromosome instability was not a late event. Mutations that caused chromosome instability would be in the earlier set. Strikingly, the great majority of inactivating mutations and in-frame gene fusions happened earlier. The non-random timing of some of the mutations may be evidence that they were selected.Scott NewmanKaren D HowarthChris D GreenmanGraham R BignellSimon TavaréPaul A W EdwardsPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e64991 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Scott Newman Karen D Howarth Chris D Greenman Graham R Bignell Simon Tavaré Paul A W Edwards The relative timing of mutations in a breast cancer genome.
description	Many tumors have highly rearranged genomes, but a major unknown is the relative importance and timing of genome rearrangements compared to sequence-level mutation. Chromosome instability might arise early, be a late event contributing little to cancer development, or happen as a single catastrophic event. Another unknown is which of the point mutations and rearrangements are selected. To address these questions we show, using the breast cancer cell line HCC1187 as a model, that we can reconstruct the likely history of a breast cancer genome. We assembled probably the most complete map to date of a cancer genome, by combining molecular cytogenetic analysis with sequence data. In particular, we assigned most sequence-level mutations to individual chromosomes by sequencing of flow sorted chromosomes. The parent of origin of each chromosome was assigned from SNP arrays. We were then able to classify most of the mutations as earlier or later according to whether they occurred before or after a landmark event in the evolution of the genome, endoreduplication (duplication of its entire genome). Genome rearrangements and sequence-level mutations were fairly evenly divided earlier and later, suggesting that genetic instability was relatively constant throughout the life of this tumor, and chromosome instability was not a late event. Mutations that caused chromosome instability would be in the earlier set. Strikingly, the great majority of inactivating mutations and in-frame gene fusions happened earlier. The non-random timing of some of the mutations may be evidence that they were selected.
format	article
author	Scott Newman Karen D Howarth Chris D Greenman Graham R Bignell Simon Tavaré Paul A W Edwards
author_facet	Scott Newman Karen D Howarth Chris D Greenman Graham R Bignell Simon Tavaré Paul A W Edwards
author_sort	Scott Newman
title	The relative timing of mutations in a breast cancer genome.
title_short	The relative timing of mutations in a breast cancer genome.
title_full	The relative timing of mutations in a breast cancer genome.
title_fullStr	The relative timing of mutations in a breast cancer genome.
title_full_unstemmed	The relative timing of mutations in a breast cancer genome.
title_sort	relative timing of mutations in a breast cancer genome.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/b8a9b8d7fde040cb8298a7c71a5609f6
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The relative timing of mutations in a breast cancer genome.

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