Two Distinct Categories of Focal Deletions in Cancer Genomes

Rajaram, M., Zhang, J., Wang, T., Li, J., Kuscu, C., Qi, H., Kato, M., Grubor, V., Weil, R. J., Helland, A., Borrenson-Dale, A. L., Cho, K. R., Levine, D. A., Houghton, A. N., Wolchok, J. D., Myeroff, L., Markowitz, S. D., Lowe, S. W., Zhang, M., Krasnitz, A., Lucito, R., Mu, D., Powers, R. S. (June 2013) Two Distinct Categories of Focal Deletions in Cancer Genomes. PLoS ONE, 8 (6). e66264. ISSN 1932-6203 (Electronic)1932-6203 (Linking)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/23805207
DOI: 10.1371/journal.pone.0066264

Abstract

One of the key questions about genomic alterations in cancer is whether they are functional in the sense of contributing to the selective advantage of tumor cells. The frequency with which an alteration occurs might reflect its ability to increase cancer cell growth, or alternatively, enhanced instability of a locus may increase the frequency with which it is found to be aberrant in tumors, regardless of oncogenic impact. Here we've addressed this on a genome-wide scale for cancer-associated focal deletions, which are known to pinpoint both tumor suppressor genes (tumor suppressors) and unstable loci. Based on DNA copy number analysis of over one-thousand human cancers representing ten different tumor types, we observed five loci with focal deletion frequencies above 5%, including the A2BP1 gene at 16p13.3 and the MACROD2 gene at 20p12.1. However, neither RNA expression nor functional studies support a tumor suppressor role for either gene. Further analyses suggest instead that these are sites of increased genomic instability and that they resemble common fragile sites (CFS). Genome-wide analysis revealed properties of CFS-like recurrent deletions that distinguish them from deletions affecting tumor suppressor genes, including their isolation at specific loci away from other genomic deletion sites, a considerably smaller deletion size, and dispersal throughout the affected locus rather than assembly at a common site of overlap. Additionally, CFS-like deletions have less impact on gene expression and are enriched in cell lines compared to primary tumors. We show that loci affected by CFS-like deletions are often distinct from known common fragile sites. Indeed, we find that each tumor tissue type has its own spectrum of CFS-like deletions, and that colon cancers have many more CFS-like deletions than other tumor types. We present simple rules that can pinpoint focal deletions that are not CFS-like and more likely to affect functional tumor suppressors.

Item Type: Paper
Subjects: bioinformatics
diseases & disorders > cancer
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes
CSHL Authors:
Communities: CSHL labs > Krasnitz lab
CSHL labs > Lowe lab
CSHL labs > Lucito lab
CSHL labs > Powers lab
CSHL labs > Zhang lab
CSHL Cancer Center Program > Cancer Genetics
Depositing User: Matt Covey
Date: 21 June 2013
Date Deposited: 19 Jul 2013 15:50
Last Modified: 14 Oct 2015 20:16
PMCID: PMC3689739
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28447

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