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


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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 fluorescencein situhybridization (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 suppressorsFOXP1,RYBPandSHQ1. FISH analysis usingFOXP1-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 toERG+ 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 ofFOXP1,RYBPandSHQ1resulted 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. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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