A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions.

Proc Natl Acad Sci U S A 2012 May 7;109(21):8212-7. Epub 2012 May 7.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

The large chromosomal deletions frequently observed in cancer genomes are often thought to arise as a "two-hit" mechanism in the process of tumor-suppressor gene (TSG) inactivation. Using a murine model system of hepatocellular carcinoma (HCC) and in vivo RNAi, we test an alternative hypothesis, that such deletions can arise from selective pressure to attenuate the activity of multiple genes. By targeting the mouse orthologs of genes frequently deleted on human 8p22 and adjacent regions, which are lost in approximately half of several other major epithelial cancers, we provide evidence suggesting that multiple genes on chromosome 8p can cooperatively inhibit tumorigenesis in mice, and that their cosuppression can synergistically promote tumor growth. In addition, in human HCC patients, the combined down-regulation of functionally validated 8p TSGs is associated with poor survival, in contrast to the down-regulation of any individual gene. Our data imply that large cancer-associated deletions can produce phenotypes distinct from those arising through loss of a single TSG, and as such should be considered and studied as distinct mutational events.

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1206062109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361457PMC
May 2012
24 Reads

Publication Analysis

Top Keywords

chromosomal deletions
8
multiple genes
8
tumor-suppressor gene
8
8p22 adjacent
4
gene data
4
frequently deleted
4
deleted human
4
human 8p22
4
adjacent regions
4
individual gene
4
half major
4
contrast down-regulation
4
lost half
4
down-regulation individual
4
regions lost
4
data imply
4
mouse orthologs
4
patients combined
4
attenuate activity
4
pressure attenuate
4

References

(Supplied by CrossRef)

Baker et al.
Science 1989

Birnbaum et al.
The lancet oncology 2003

Xue et al.
Genes & Development 2008

Clinical Cancer Research 2010

Cooke et al.
BMC cancer [electronic resource] 2008

Williams et al.
Genes, chromosomes & cancer 2010

Berger et al.
Nature genetics 2010

Gorringe et al.
Genes, chromosomes & cancer 2009

Beroukhim et al.
Nature; Physical Science (London) 2010

Chiang et al.
Cancer Research 2008

Zender et al.
Cell 2008

Similar Publications