Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion-positive prostate cancers

Abstract

Deletion of 3p13 has been reported from about 20% of prostate cancers. The clinical significance of this alteration and the tumour suppressor gene(s) driving the deletion remain to be identified. We have mapped the 3p13 deletion locus using SNP array analysis and performed fluorescence in situ hybridization (FISH) analysis to search for associations between 3p13 deletion, prostate cancer phenotype and patient prognosis in a tissue microarray containing more than 3200 prostate cancers. SNP array analysis of 72 prostate cancers revealed a small deletion at 3p13 in 14 (19%) of the tumours, including the putative tumour suppressors FOXP1, RYBP and SHQ1. FISH analysis using FOXP1-specific probes revealed deletions in 16.5% and translocations in 1.2% of 1828 interpretable cancers. 3p13 deletions were linked to adverse features of prostate cancer, including advanced stage (p < 0.0001), high Gleason grade (p = 0.0125), and early PSA recurrence (p = 0.0015). In addition, 3p13 deletions were linked to ERG(+) cancers and to PTEN deletions (p < 0.0001 each). A subset analysis of ERG(+) tumours revealed that 3p13 deletions occurred independently from PTEN deletions (p = 0.3126), identifying tumours with 3p13 deletion as a distinct molecular subset of ERG(+) cancers. mRNA expression analysis confirmed that all 3p13 genes were down regulated by the deletion. Ectopic over-expression of FOXP1, RYBP and SHQ1 resulted in decreased colony-formation capabilities, corroborating a tumour suppressor function for all three genes. In summary, our data show that deletion of 3p13 defines a distinct and aggressive molecular subset of ERG(+) prostate cancers, which is possibly driven by inactivation of multiple tumour suppressors.

Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer

“…16 The molecular database attached to this TMA contained results on ERG expression in 9,628, ERG break apart FISH analysis in 6 21 and 3p13 deletions and breakage (FOXP1) in 1,814 tumors. 22 …”

Genomic Predictors of Outcome in Prostate Cancer

“…ETS fusion-type cancers are believed to represent a genetically distinct subset of PCa characterized by deletions of the phosphatase and tensin homolog (PTEN) gene and of chromosome 3p, whereas deletions of 5q and 6q prevail in fusion-negative cancers [14][15][16][17]. Although gene fusions in general, and specifically ETS fusions, have been associated with the early onset of PCa [18,19], the clinical utility of the gene fusion as a prognostic or predictive tool is still unclear.…”

Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer

“…Others and us had previously described a strong link between PTEN and 3p13 deletions and ERG positivity, as well as between 5q21 and 6q15 deletions and ERG negativity (21)(22)(23). To study whether p62 expression might be particularly linked to one of these genomic deletions, p62 data were compared with preexisting findings on PTEN (10q23), FOXP1 (3p13), MAP3K7 (6q15), and CHD1 (5q21) deletions.…”