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PMID: 16461635 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Decoding the fine-scale structure of a breast cancer genome and transcriptome.

Genome research ·Vol. 16 ·No. 3 ·2006-03-00 ·Pages 394-404

Volik S, Raphael BJ, Huang G, Stratton MR, Bignel G, Murnane J, Brebner JH, Bajsarowicz K, Paris PL, Tao Q, Kowbel D, Lapuk A, Shagin DA, Shagina IA, Gray JW, Cheng JF, de Jong PJ, Pevzner P, Collins C

Abstract

A comprehensive understanding of cancer is predicated upon knowledge of the structure of malignant genomes underlying its many variant forms and the molecular mechanisms giving rise to them. It is well established that solid tumor genomes accumulate a large number of genome rearrangements during tumorigenesis. End Sequence Profiling (ESP) maps and clones genome breakpoints associated with all types of genome rearrangements elucidating the structural organization of tumor genomes. Here we extend the ESP methodology in several directions using the breast cancer cell line MCF-7. First, targeted ESP is applied to multiple amplified loci, revealing a complex process of rearrangement and co-amplification in these regions reminiscent of breakage/fusion/bridge cycles. Second, genome breakpoints identified by ESP are confirmed using a combination of DNA sequencing and PCR. Third, in vitro functional studies assign biological function to a rearranged tumor BAC clone, demonstrating that it encodes anti-apoptotic activity. Finally, ESP is extended to the transcriptome identifying four novel fusion transcripts and providing evidence that expression of fusion genes may be common in tumors. These results demonstrate the distinct advantages of ESP including: (1) the ability to detect all types of rearrangements and copy number changes; (2) straightforward integration of ESP data with the annotated genome sequence; (3) immortalization of the genome; (4) ability to generate tumor-specific reagents for in vitro and in vivo functional studies. Given these properties, ESP could play an important role in a tumor genome project.

MeSH Terms
Breast Neoplasms/genetics Cell Line, Tumor Chromosomes, Artificial, Bacterial/metabolism Chromosomes, Human Female Gene Expression Profiling/methods Genome, Human Humans In Situ Hybridization, Fluorescence Molecular Sequence Data Polymerase Chain Reaction Reproducibility of Results Sequence Analysis, DNA/methods Transcription, Genetic
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Volik Stanislav
Department of Urology, and Cancer Research Institute, University of California San Francisco Comprehensive Cancer Center, San Francisco, California 94115, USA.
Raphael Benjamin J
Huang Guiqing
Stratton Michael R
Bignel Graham
Murnane John
Brebner John H
Bajsarowicz Krystyna
Paris Pamela L
Tao Quanzhou
Kowbel David
Lapuk Anna
Shagin Dmitri A
Shagina Irina A
Gray Joe W
Cheng Jan-Fang
de Jong Pieter J
Pevzner Pavel
Collins Colin
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Article Info
Journal
Genome research
Abbr.
Genome Res
ISSN
1088-9051
DOI
10.1101/gr.4247306
Published
2006-03-00
Epub
2006-00-03
Pages
394-404
Language
English
Region
United States
NLM ID
9518021
PMCID
PMC1415204
Subset
IM
Grants
NHLBI NIH HHS · U01 HL66728 · United States
NCI NIH HHS · R33 CA103068 · United States
NCI NIH HHS · R01 CA69044 · United States
NIEHS NIH HHS · R01 ES008427 · United States
NCI NIH HHS · R01 CA069044 · United States
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PubMed source DOI: 10.1101/gr.4247306 PMC Full Text View journal details
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