Genome evolution during progression to breast cancer

Daniel E. Newburger, Dorna Kashef-Haghighi, Ziming Weng, Raheleh Salari, Robert T. Sweeney, Alayne L. Brunner, Shirley X. Zhu, Xiangqian Guo, Sushama Varma, Megan Troxell, Robert B. West, Serafim Batzoglou, Arend Sidow

Research output: Contribution to journalArticle

67 Citations (Scopus)

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 wholegenome 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.

Original languageEnglish (US)
Pages (from-to)1097-1108
Number of pages12
JournalGenome Research
Volume23
Issue number7
DOIs
StatePublished - Jul 2013

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Genome
Breast Neoplasms
Carcinoma
Neoplasms
Aneuploidy
Breast
Phenotype
Mutation
Point Mutation
Epigenomics
Cell Division
Cell Proliferation
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Newburger, D. E., Kashef-Haghighi, D., Weng, Z., Salari, R., Sweeney, R. T., Brunner, A. L., ... Sidow, A. (2013). Genome evolution during progression to breast cancer. Genome Research, 23(7), 1097-1108. https://doi.org/10.1101/gr.151670.112

Genome evolution during progression to breast cancer. / Newburger, Daniel E.; Kashef-Haghighi, Dorna; Weng, Ziming; Salari, Raheleh; Sweeney, Robert T.; Brunner, Alayne L.; Zhu, Shirley X.; Guo, Xiangqian; Varma, Sushama; Troxell, Megan; West, Robert B.; Batzoglou, Serafim; Sidow, Arend.

In: Genome Research, Vol. 23, No. 7, 07.2013, p. 1097-1108.

Research output: Contribution to journalArticle

Newburger, DE, Kashef-Haghighi, D, Weng, Z, Salari, R, Sweeney, RT, Brunner, AL, Zhu, SX, Guo, X, Varma, S, Troxell, M, West, RB, Batzoglou, S & Sidow, A 2013, 'Genome evolution during progression to breast cancer', Genome Research, vol. 23, no. 7, pp. 1097-1108. https://doi.org/10.1101/gr.151670.112
Newburger DE, Kashef-Haghighi D, Weng Z, Salari R, Sweeney RT, Brunner AL et al. Genome evolution during progression to breast cancer. Genome Research. 2013 Jul;23(7):1097-1108. https://doi.org/10.1101/gr.151670.112
Newburger, Daniel E. ; Kashef-Haghighi, Dorna ; Weng, Ziming ; Salari, Raheleh ; Sweeney, Robert T. ; Brunner, Alayne L. ; Zhu, Shirley X. ; Guo, Xiangqian ; Varma, Sushama ; Troxell, Megan ; West, Robert B. ; Batzoglou, Serafim ; Sidow, Arend. / Genome evolution during progression to breast cancer. In: Genome Research. 2013 ; Vol. 23, No. 7. pp. 1097-1108.
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