The prognostic impact of high Nijmegen breakage syndrome (NBS1) gene expression in ERG-negative prostate cancers lacking PTEN deletion is driven by KPNA2 expression.

Abstract

The Nijmegen breakage syndrome (NBS1) gene was suggested as a prostate cancer susceptibility gene. This study was undertaken to determine, whether NBS1 expression is linked to clinically or molecularly relevant subgroups of prostate cancer. NBS1 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancer specimens. NBS1 expression was absent or only weakly detectable in benign prostate. In prostate cancers, NBS1 expression was found in 81.3% of interpretable tumors and was considered strong in 41.3% of cases. NBS1 upregulation was tightly linked to ERG-positive cancers (p<0.0001). Within ERG-negative cancers, strong NBS1 immunostaining was linked to advanced pathological tumor stage, high Gleason grade, and positive nodal status (p<0.0001 each), while high NBS1 immunostaining was only weakly associated with advanced pathological tumor stage in ERG-positive cancers (p=0.0099). A comparison with chromosomal deletions revealed a strong NBS1 upregulation in PTEN-deleted cancers, while deletions of 3p13, 5q21 and 6q15 did not affect NBS1 expression. High NBS1 expression was linked to biochemical recurrence in ERG-negative and PTEN non-deleted cancers (p<0.0001), which was largely driven by high KPNA2 karyopherin alpha 2 expression. In conclusion, our study identifies an association of NBS1 expression with surrogates of genomic instability in prostate cancer including TMPRSS2-ERG rearrangements and PTEN deletion. The prognostic impact of NBS1 expression in ERG-negative, PTEN non-deleted cancers was dependent of the expression status of its interaction partner KPNA2.

• Authors: Katharina Grupp, Rebecca Boumesli, Maria Christina Tsourlakis, Christina Koop, Waldemar Wilczak, Meike Adam, Guido Sauter, Ronald Simon, Jakob Robert Izbicki, Markus Graefen, Hartwig Huland, Stefan Steurer, Thorsten Schlomm, Sarah Minner, Alexander Quaas
• Journal: International journal of cancer (Int J Cancer) Vol. 135 Issue 6 Pg. 1399-407 (Sep 15 2014) ISSN: 1097-0215 [Electronic] United States
• PMID: 24510842 (Publication Type: Journal Article)
• Copyright: © 2014 UICC.

Chemical References

• Cell Cycle Proteins
• ERG protein, human
• KPNA2 protein, human
• NBN protein, human
• Nuclear Proteins
• Oncogene Proteins, Fusion
• TMPRSS2-ERG fusion protein, human
• Trans-Activators
• Transcriptional Regulator ERG
• alpha Karyopherins
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Aged
• Cell Cycle Proteins (biosynthesis, genetics)
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Neoplasm Grading
• Neoplasm Staging
• Nuclear Proteins (biosynthesis, genetics)
• Oncogene Proteins, Fusion (biosynthesis, genetics)
• PTEN Phosphohydrolase (deficiency, genetics, metabolism)
• Prognosis
• Prostatic Neoplasms (genetics, metabolism, pathology, surgery)
• Trans-Activators (deficiency, genetics, metabolism)
• Transcriptional Regulator ERG
• alpha Karyopherins (biosynthesis, genetics)