Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion-positive prostate cancers
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Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion-positive prostate cancers. / Krohn, Antje; Seidel, Annemarie; Burkhardt, Lia; Bachmann, Frederik; Mader, Malte; Grupp, Katharina; Eichenauer, Till; Becker, Andreas; Adam, Meike; Graefen, Markus; Huland, Hartwig; Kurtz, Stefan; Steurer, Stefan; Tsourlakis, Maria C; Minner, Sarah; Michl, Uwe; Schlomm, Thorsten; Sauter, Guido; Simon, Ronald; Sirma, Hüseyin.
In: AM J PATHOL, Vol. 231, No. 1, 01.09.2013, p. 130-41.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion-positive prostate cancers
AU - Krohn, Antje
AU - Seidel, Annemarie
AU - Burkhardt, Lia
AU - Bachmann, Frederik
AU - Mader, Malte
AU - Grupp, Katharina
AU - Eichenauer, Till
AU - Becker, Andreas
AU - Adam, Meike
AU - Graefen, Markus
AU - Huland, Hartwig
AU - Kurtz, Stefan
AU - Steurer, Stefan
AU - Tsourlakis, Maria C
AU - Minner, Sarah
AU - Michl, Uwe
AU - Schlomm, Thorsten
AU - Sauter, Guido
AU - Simon, Ronald
AU - Sirma, Hüseyin
N1 - Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PY - 2013/9/1
Y1 - 2013/9/1
N2 - 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.
AB - 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.
KW - Adenocarcinoma
KW - Cell Line, Tumor
KW - Chromosome Deletion
KW - Chromosomes, Human, Pair 3
KW - Forkhead Transcription Factors
KW - Gene Expression Profiling
KW - Gene Knockdown Techniques
KW - Genes, Tumor Suppressor
KW - Germany
KW - Humans
KW - Kaplan-Meier Estimate
KW - Male
KW - Neoplasm Recurrence, Local
KW - Oligonucleotide Array Sequence Analysis
KW - Oncogene Proteins, Fusion
KW - Polymorphism, Single Nucleotide
KW - Prostate
KW - Prostatectomy
KW - Prostatic Neoplasms
KW - Repressor Proteins
KW - Tissue Array Analysis
U2 - 10.1002/path.4223
DO - 10.1002/path.4223
M3 - SCORING: Journal article
C2 - 23794398
VL - 231
SP - 130
EP - 141
JO - AM J PATHOL
JF - AM J PATHOL
SN - 0002-9440
IS - 1
ER -