Chromosomal breakpoints in primary colon cancer cluster at sites of structural variants in the genome

Jordi Camps, Marian Grade, Quang Tri Nguyen, Patrick Hörmann, Sandra Becker, Amanda B. Hummon, Virginia Rodriguez, Settara Chandrasekharappa, Yidong Chen, Michael J. Difilippantonio, Heinz Becker, B. Michael Ghadimi, Thomas Ried

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Genomic aberrations on chromosome 8 are common in colon cancer, and are associated with lymph node and distant metastases as well as with disease susceptibility. This prompted us to generate a high-resolution map of genomic imbalances of chromosome 8 in 51 primary colon carcinomas using a custom-designed genomic array consisting of a tiling path of BAC clones. This analysis confirmed the dominant role of this chromosome. Unexpectedly, the position of the breakpoints suggested colocalization with structural variants in the human genome. In order to map these sites with increased resolution and to extend the analysis to the entire genome, we analyzed a subset of these tumors (n = 32) by comparative genomic hybridization on a 185K oligonucleotide array platform. Our comprehensive map of the colon cancer genome confirmed recurrent and specific low-level copy number changes of chromosomes 7, 8, 13, 18, and 20, and unveiled additional, novel sites of genomic imbalances including amplification of a histone gene cluster on chromosome 6p21.1-21.33 and deletions on chromosome 4q34-35. The systematic comparison of segments of copy number change with gene expression profiles showed that genomic imbalances directly affect average expression levels. Strikingly, we observed a significant association of chromosomal breakpoints with structural variants in the human genome: 41% of all copy number changes occurred at sites of such copy number variants (P < 2.2e-16). Such an association has not been previously described and reveals a yet underappreciated plasticity of the colon cancer genome; it also points to potential mechanisms for the induction of chromosomal breakage in cancer cells.

Original languageEnglish (US)
Pages (from-to)1284-1295
Number of pages12
JournalCancer Research
Volume68
Issue number5
DOIs
StatePublished - Mar 1 2008
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Camps, J., Grade, M., Nguyen, Q. T., Hörmann, P., Becker, S., Hummon, A. B., Rodriguez, V., Chandrasekharappa, S., Chen, Y., Difilippantonio, M. J., Becker, H., Ghadimi, B. M., & Ried, T. (2008). Chromosomal breakpoints in primary colon cancer cluster at sites of structural variants in the genome. Cancer Research, 68(5), 1284-1295. https://doi.org/10.1158/0008-5472.CAN-07-2864