Recurrent deletion of 3p13 targets multiple tumor suppressor genes and defines a distinct subgroup of aggressive ERG fusion positive prostate cancers
Krohn A, Seidel A, Burkhardt L, Bachmann F, Mader M, Grupp K, Eichenauer T, Becker A, Adam M, Graefen M, Huland H, Kurtz S, Steurer S, Tsourlakis MC, Minner S, Michl U, Schlomm T, Sauter G, Simon R, Sirma H. J Pathol. 2013 Jun 22. doi: 10.1002/path.4223. [Epub ahead of print]

Source

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Abstract

Deletion of 3p13 has been reported from about 20% of prostate cancers. The clinical significance of this alteration and the tumor 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 3,200 prostate cancers. SNP array analysis of 72 prostate cancers revealed a small deletion at 3p13 in 14 (19%) of the tumors, including the putative tumor suppressors FOXP1, RYBP, and SHQ1. FISH analysis using FOXP1-specific probes revealed deletions in 16.5% and translocations in 1.2% of 1,828 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+ tumors revealed that 3p13 deletions occurred independently from PTEN deletions (p=0.3126), identifying tumors with 3p13 deletion as distinct molecular subset of ERG+ cancers. MRNA expression analysis confirmed that all 3p13 genes were down regulated by the deletion. Ectopic overexpression of FOXP1, RYBP, and SHQ1 resulted in decreased colony formation capabilities, corroborating a tumor 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 tumor suppressors.