Handle URI:
http://hdl.handle.net/10754/598405
Title:
Genome evolution during progression to breast cancer
Authors:
Newburger, D. E.; Kashef-Haghighi, D.; Weng, Z.; Salari, R.; Sweeney, R. T.; Brunner, A. L.; Zhu, S. X.; Guo, X.; Varma, S.; Troxell, M. L.; West, R. B.; Batzoglou, S.; Sidow, A.
Abstract:
Cancer evolution involves cycles of genomic damage, epigenetic deregulation, and increased cellular proliferation that eventually culminate in the carcinoma phenotype. Early neoplasias, which are often found concurrently with carcinomas and are histologically distinguishable from normal breast tissue, are less advanced in phenotype than carcinomas and are thought to represent precursor stages. To elucidate their role in cancer evolution we performed comparative whole-genome sequencing of early neoplasias, matched normal tissue, and carcinomas from six patients, for a total of 31 samples. By using somatic mutations as lineage markers we built trees that relate the tissue samples within each patient. On the basis of these lineage trees we inferred the order, timing, and rates of genomic events. In four out of six cases, an early neoplasia and the carcinoma share a mutated common ancestor with recurring aneuploidies, and in all six cases evolution accelerated in the carcinoma lineage. Transition spectra of somatic mutations are stable and consistent across cases, suggesting that accumulation of somatic mutations is a result of increased ancestral cell division rather than specific mutational mechanisms. In contrast to highly advanced tumors that are the focus of much of the current cancer genome sequencing, neither the early neoplasia genomes nor the carcinomas are enriched with potentially functional somatic point mutations. Aneuploidies that occur in common ancestors of neoplastic and tumor cells are the earliest events that affect a large number of genes and may predispose breast tissue to eventual development of invasive carcinoma.
Citation:
Newburger DE, Kashef-Haghighi D, Weng Z, Salari R, Sweeney RT, et al. (2013) Genome evolution during progression to breast cancer. Genome Research 23: 1097–1108. Available: http://dx.doi.org/10.1101/gr.151670.112.
Publisher:
Cold Spring Harbor Laboratory Press
Journal:
Genome Research
Issue Date:
8-Apr-2013
DOI:
10.1101/gr.151670.112
PubMed ID:
23568837
PubMed Central ID:
PMC3698503
Type:
Article
ISSN:
1088-9051
Sponsors:
This work was supported by the Sequencing Initiative of the Stanford Department of Pathology, grants from the California Breast Cancer Research Program and NIH/NCI to R.B.W. and a grant from KAUST to S.B. D.K.H. was supported by a STMicroelectronics Stanford Graduate Fellowship, and D.E.N. by a training grant from NIH/NLM and a Bio-X Stanford Interdisciplinary Graduate Fellowship. This study is the result of an equal collaboration among the Batzoglou, Sidow, and West groups. Listed order of corresponding authors was determined by a series of coin flips.
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Full metadata record

DC FieldValue Language
dc.contributor.authorNewburger, D. E.en
dc.contributor.authorKashef-Haghighi, D.en
dc.contributor.authorWeng, Z.en
dc.contributor.authorSalari, R.en
dc.contributor.authorSweeney, R. T.en
dc.contributor.authorBrunner, A. L.en
dc.contributor.authorZhu, S. X.en
dc.contributor.authorGuo, X.en
dc.contributor.authorVarma, S.en
dc.contributor.authorTroxell, M. L.en
dc.contributor.authorWest, R. B.en
dc.contributor.authorBatzoglou, S.en
dc.contributor.authorSidow, A.en
dc.date.accessioned2016-02-25T13:20:09Zen
dc.date.available2016-02-25T13:20:09Zen
dc.date.issued2013-04-08en
dc.identifier.citationNewburger DE, Kashef-Haghighi D, Weng Z, Salari R, Sweeney RT, et al. (2013) Genome evolution during progression to breast cancer. Genome Research 23: 1097–1108. Available: http://dx.doi.org/10.1101/gr.151670.112.en
dc.identifier.issn1088-9051en
dc.identifier.pmid23568837en
dc.identifier.doi10.1101/gr.151670.112en
dc.identifier.urihttp://hdl.handle.net/10754/598405en
dc.description.abstractCancer evolution involves cycles of genomic damage, epigenetic deregulation, and increased cellular proliferation that eventually culminate in the carcinoma phenotype. Early neoplasias, which are often found concurrently with carcinomas and are histologically distinguishable from normal breast tissue, are less advanced in phenotype than carcinomas and are thought to represent precursor stages. To elucidate their role in cancer evolution we performed comparative whole-genome sequencing of early neoplasias, matched normal tissue, and carcinomas from six patients, for a total of 31 samples. By using somatic mutations as lineage markers we built trees that relate the tissue samples within each patient. On the basis of these lineage trees we inferred the order, timing, and rates of genomic events. In four out of six cases, an early neoplasia and the carcinoma share a mutated common ancestor with recurring aneuploidies, and in all six cases evolution accelerated in the carcinoma lineage. Transition spectra of somatic mutations are stable and consistent across cases, suggesting that accumulation of somatic mutations is a result of increased ancestral cell division rather than specific mutational mechanisms. In contrast to highly advanced tumors that are the focus of much of the current cancer genome sequencing, neither the early neoplasia genomes nor the carcinomas are enriched with potentially functional somatic point mutations. Aneuploidies that occur in common ancestors of neoplastic and tumor cells are the earliest events that affect a large number of genes and may predispose breast tissue to eventual development of invasive carcinoma.en
dc.description.sponsorshipThis work was supported by the Sequencing Initiative of the Stanford Department of Pathology, grants from the California Breast Cancer Research Program and NIH/NCI to R.B.W. and a grant from KAUST to S.B. D.K.H. was supported by a STMicroelectronics Stanford Graduate Fellowship, and D.E.N. by a training grant from NIH/NLM and a Bio-X Stanford Interdisciplinary Graduate Fellowship. This study is the result of an equal collaboration among the Batzoglou, Sidow, and West groups. Listed order of corresponding authors was determined by a series of coin flips.en
dc.publisherCold Spring Harbor Laboratory Pressen
dc.subject.meshMutationen
dc.subject.meshGenome, Humanen
dc.titleGenome evolution during progression to breast canceren
dc.typeArticleen
dc.identifier.journalGenome Researchen
dc.identifier.pmcidPMC3698503en
dc.contributor.institutionBiomedical Informatics Training Program, Stanford, California 94305, USA.en

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