A sequence-based survey of the complex structural organization of tumor genomes

Benjamin J Raphael^*¹ , Stanislav Volik^*² , Peng Yu³ , Chunxiao Wu⁴ , Guiqing Huang² , Elena V Linardopoulou⁵ , Barbara J Trask⁵ , Frederic Waldman² , Joseph Costello² , Kenneth J Pienta⁶ , Gordon B Mills⁷ , Krystyna Bajsarowicz² , Yasuko Kobayashi² , Shivaranjani Sridharan² , Pamela L Paris² , Quanzhou Tao⁸ , Sarah J Aerni⁹ , Raymond P Brown¹⁰ , Ali Bashir¹⁰ , Joe W Gray¹¹ , Jan-Fang Cheng¹² , Pieter de Jong¹³ , Mikhail Nefedov¹³ , Thomas Ried¹⁴ , Hesed M Padilla-Nash¹⁴ and Colin C Collins²

¹Department of Computer Science & Center for Computational Molecular Biology, Brown University, Waterman Street, Providence, RI 02912-1910, USA

²Cancer Research Institute, UCSF Comprehensive Cancer Center, Sutter Street, San Francisco, CA 94115, USA

³Chinese National Human Genome Center, North Yongchang Road, BDA, Beijing, P.R.C. 100016

⁴Shandong Provincial Hospital, JingWuWeiQi Road, Jinan, P.R.C. 250021

⁵Division of Human Biology, Fred Hutchinson Cancer Research Center, Fairview Avenue N, Seattle, WA 98109, USA

⁶The University of Michigan, Departments of Internal Medicine and Urology, E Medical Center Drive, Ann Arbor, MI 48109-0330, USA

⁷MD Anderson Cancer Center, University of Texas, Holcombe Blvd, Houston, TX 77030, USA

⁸Amplicon Express, NE Eastgate Blvd, Pullman, WA 99163, USA

⁹BioMedical Informatics Program, Stanford University, Stanford, CA 94305, USA

¹⁰Bioinformatics Program, University of California, San Diego, Gilman Drive, La Jolla, CA 92093, USA

¹¹Lawrence Berkeley National Laboratory, Life Sciences Division, Cyclotron Road, Berkeley, CA 94720-8268, USA

¹²Lawrence Berkeley National Laboratory, Genomics Division and Joint Genome Institute, Cyclotron Road, Berkeley, CA 94720, USA

¹³BACPAC Resources Children's Hospital Oakland, 52nd Street, Oakland, CA 94609, USA

¹⁴Section of Cancer Genomics, Genetics Branch, Center for Cancer Research, South Drive, Bldg. 50, MSC-8010, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

author email corresponding author email* Contributed equally

Genome Biology 2008, 9:R59doi:10.1186/gb-2008-9-3-r59


Published:	25 March 2008

Subject areas: Bioinformatics, Cancer, Genetics

Abstract

Background

The genomes of many epithelial tumors exhibit extensive chromosomal rearrangements. All classes of genome rearrangements can be identified using end sequencing profiling, which relies on paired-end sequencing of cloned tumor genomes.

Results

In the present study brain, breast, ovary, and prostate tumors, along with three breast cancer cell lines, were surveyed using end sequencing profiling, yielding the largest available collection of sequence-ready tumor genome breakpoints and providing evidence that some rearrangements may be recurrent. Sequencing and fluorescence in situ hybridization confirmed translocations and complex tumor genome structures that include co-amplification and packaging of disparate genomic loci with associated molecular heterogeneity. Comparison of the tumor genomes suggests recurrent rearrangements. Some are likely to be novel structural polymorphisms, whereas others may be bona fide somatic rearrangements. A recurrent fusion transcript in breast tumors and a constitutional fusion transcript resulting from a segmental duplication were identified. Analysis of end sequences for single nucleotide polymorphisms revealed candidate somatic mutations and an elevated rate of novel single nucleotide polymorphisms in an ovarian tumor.

Conclusion

These results suggest that the genomes of many epithelial tumors may be far more dynamic and complex than was previously appreciated and that genomic fusions, including fusion transcripts and proteins, may be common, possibly yielding tumor-specific biomarkers and therapeutic targets.