AuthorsNewburger, D. E.
Sweeney, R. T.
Brunner, A. L.
Zhu, S. X.
Troxell, M. L.
West, R. B.
MetadataShow full item record
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.
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.
SponsorsThis 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.
PublisherCold Spring Harbor Laboratory Press
PubMed Central IDPMC3698503
CollectionsPublications Acknowledging KAUST Support
- Genomic patterns of allelic imbalance in disease free tissue adjacent to primary breast carcinomas.
- Authors: Ellsworth DL, Ellsworth RE, Love B, Deyarmin B, Lubert SM, Mittal V, Shriver CD
- Issue date: 2004 Nov
- PIK3CA mutations are common in lobular carcinoma in situ, but are not a biomarker of progression.
- Authors: Shah V, Nowinski S, Levi D, Shinomiya I, Kebaier Ep Chaabouni N, Gillett C, Grigoriadis A, Graham TA, Roylance R, Simpson MA, Pinder SE, Sawyer EJ
- Issue date: 2017 Jan 17
- p53 mutations in mammary ductal carcinoma in situ but not in epithelial hyperplasias.
- Authors: Done SJ, Arneson NC, Ozçelik H, Redston M, Andrulis IL
- Issue date: 1998 Feb 15
- Total-genome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation.
- Authors: Weber F, Shen L, Fukino K, Patocs A, Mutter GL, Caldes T, Eng C
- Issue date: 2006 Jun
- Three-dimensional modelling identifies novel genetic dependencies associated with breast cancer progression in the isogenic MCF10 model.
- Authors: Maguire SL, Peck B, Wai PT, Campbell J, Barker H, Gulati A, Daley F, Vyse S, Huang P, Lord CJ, Farnie G, Brennan K, Natrajan R
- Issue date: 2016 Nov