The prognostic impact of high Nijmegen breakage syndrome (NBS1) gene expression in ERG-negative prostate cancers lacking PTEN deletion is driven by KPNA2 expression
The prognostic impact of high Nijmegen breakage syndrome (NBS1) gene expression in ERG-negative prostate cancers lacking PTEN deletion is driven by KPNA2 expression
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DOI：
10.1002/ijc.28778
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发表时间：
2014-09-15
影响因子：
6.4
通讯作者：
Quaas, Alexander
中科院分区：
文献类型：
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作者：
Grupp, Katharina;Boumesli, Rebecca;Quaas, Alexander
奈梅根断裂综合征(NBS1)基因被认为是前列腺癌的易感基因。这项研究是为了确定NBS1的表达是否与前列腺癌的临床或分子相关亚群有关。在包含11,152例前列腺癌标本的组织芯片上用免疫组织化学方法分析NBS1的表达。NBS1在良性前列腺组织中无表达或仅有微弱表达。在前列腺癌中，NBS1在81.3%的可解释肿瘤中表达，在41.3%的病例中被认为是强表达。Nbs1基因上调与ERG阳性癌症密切相关(p<；0.0001)。在ERG阴性的肿瘤中，NBS1的高表达与晚期病理肿瘤分期、高Gleason分级和阳性结节状态有关(p<；各0.0001)，而在ERG阳性的肿瘤中，NBS1的高表达仅与晚期的病理肿瘤分期密切相关(p=0.0099)。与染色体缺失的比较显示，在PTEN缺失的癌症中，NBS1表达上调，而3p13、5q21和6q15的缺失不影响NBS1的表达。Nbs1的高表达与ERG阴性和pten非缺失型癌症的生化复发有关(p<；0.0001)，这在很大程度上是由KPNA2核粘附素α2的高表达驱动的。总之，我们的研究确定了NBS1的表达与前列腺癌基因组不稳定的替代指标之间的关系，包括TMPRSS2-ERG重排和PTEN缺失。在ERG阴性、PTEN未缺失的癌症中，NBS1的表达对预后的影响取决于其相互作用伙伴KPNA2的表达状态。
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 nondeleted cancers was dependent of the expression status of its interaction partner KPNA2.