High nuclear karyopherin α 2 expression is a strong and independent predictor of biochemical recurrence in prostate cancer patients treated by radical prostatectomy

Purpose: Sequestosome 1 (p62) is a multifunctional adapter protein accumulating in autophagy-defective cells.Experimental Design: To evaluate the clinical impact and relationship with key genomic alterations in prostate cancer, p62 protein levels were analyzed by immunohistochemistry on a tissue microarray containing 12,427 prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21, and 6q15 were available from earlier studies.Results: p62 immunostaining was absent in benign prostatic glands but present in 73% of 7,822 interpretable prostate cancers. Strong cytoplasmic p62 staining was tightly linked to high Gleason grade, advanced pathologic tumor (pT) stage, positive nodal status, positive resection margin, and early PSA recurrence (P < 0.0001 each). Increased levels of p62 were significantly linked to TMPRSS2-ERG fusions, both by FISH and immunohistochemical analysis (P < 0.0001 each). For example, moderate or strong p62 immunostaining was seen in 28.5% of cancers with TMPRSS2-ERG fusion detected by FISH and in 23.1% of cancers without such rearrangements (P < 0.0001). Strong p62 staining was significantly linked to the presence of all tested deletions, including PTEN (P < 0.0001), 6q15 (P < 0.0001), 5q21 (P ¼ 0.0002), 3p13 (P ¼ 0.0088), and 6q15 (P < 0.0001), suggesting a link between p62 accumulation and loss of genomic stability. The prognostic role of p62 protein accumulation was striking and independent of Gleason grade, pT stage, pN stage, surgical margin status, and preoperative PSA, regardless of whether preoperative or postoperative parameters were used for modeling.Conclusions: Our study identifies cytoplasmic accumulation of p62 as a strong predictor of an adverse prognostic behavior of prostate cancer independently from established clinicopathologic findings.

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“…alterations (16,22,26,27). The high relevance of p62 protein is further emphasized by strong data from our multivariate analysis.…”

Section: Discussionmentioning

confidence: 76%

Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer

Burdelski

Reiswich

Hube‐Magg

et al. 2015

Clinical Cancer Research

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“…Next, we were interested whether the prognostic impact of NBS1 expression was independent of KPNA2 IHC, which has been earlier demonstrated as independent prognostic factor in prostate cancers. 23 The results demonstrate that the prognostic impact of NBS1 was mainly driven by high KPNA2 expression (Supporting Information Fig. 4).…”

Section: Relationship Of Nbs1 With Kpna2 Datamentioning

confidence: 84%

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

Grupp

Boumesli

Koop

et al. 2014

Intl Journal of Cancer

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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 5 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 nondeleted 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.Prostate cancer is the most frequent cancer in men in developed countries and a leading cause of cancer-related death. It is estimated that about 5 to 10% of prostate cancers are hereditary in nature.1 Several genes have recently been identified or suggested as hereditary prostate cancer genes but the relevant genes are still unknown for most hereditary cancers. The high prevalence of sporadic prostate cancer is one of the causes rendering the search for hereditary prostate cancer genes complicated, especially in societies where large families are often small. More than 60% of men older than 60 carry prostate cancer but most of these patients will never face clinical consequences of their disease. The established pre-treatment prognostic parameters Gleason grade, tumor extent on biopsies, preoperative PSA and clinical parameters are statistically powerfull but still insufficent for optimal individual treatment decisions. The identification of these prostate cancers requiring therapy is thus another major need in prostate cancer research.Cancer development and progression is often caused by situations increasing a cell's risk to develop genomic alterations or its ability to repair such DNA alterations. Genes involved in DNA repair mechanisms are thus optimal candidates for affecting cancer progression and have also been identified as the cause for hereditary cancer syndromes such as in hereditary non-polypos...

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“…KPNA2 may play critical roles in carcinogenesis, cell differentiation, transcription regulation and immune response. Recently studies have demonstracted that high expression of KPNA2 is associated with poor prognosis of esophageal squamous cell carcinoma12, epithelial ovarian carcinamos13, gastric cancer14, prostate cancer15, upper tract urothelial carcinoma16 and breast cancer17. Teng et al .…”

Section: Discussionmentioning

confidence: 99%

Analysis of Microarray Data on Gene Expression and Methylation to Identify Long Non-coding RNAs in Non-small Cell Lung Cancer

Feng

Ching

Wang

et al. 2016

Sci Rep

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To identify what long non-coding RNAs (lncRNAs) are involved in non-small cell lung cancer (NSCLC), we analyzed microarray data on gene expression and methylation. Gene expression chip and HumanMethylation450BeadChip were used to interrogate genome-wide expression and methylation in tumor samples. Differential expression and methylation were analyzed through comparing tumors with adjacent non-tumor tissues. LncRNAs expressed differentially and correlated with coding genes and DNA methylation were validated in additional tumor samples using RT-qPCR and pyrosequencing. In vitro experiments were performed to evaluate lncRNA’s effects on tumor cells. We identified 8,500 lncRNAs expressed differentially between tumor and non-tumor tissues, of which 1,504 were correlated with mRNA expression. Two of the lncRNAs, LOC146880 and ENST00000439577, were positively correlated with expression of two cancer-related genes, KPNA2 and RCC2, respectively. High expression of LOC146880 and ENST00000439577 were also associated with poor survival. Analysis of lncRNA expression in relation to DNA methylation showed that LOC146880 expression was down-regulated by DNA methylation in its promoter. Lowering the expression of LOC146880 or ENST00000439577 in tumor cells could inhibit cell proliferation, invasion and migration. Analysis of microarray data on gene expression and methylation allows us to identify two lncRNAs, LOC146880 and ENST00000439577, which may promote the progression of NSCLC.

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High nuclear karyopherin α 2 expression is a strong and independent predictor of biochemical recurrence in prostate cancer patients treated by radical prostatectomy

Cited by 27 publications

References 50 publications

Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer

Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer

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

Analysis of Microarray Data on Gene Expression and Methylation to Identify Long Non-coding RNAs in Non-small Cell Lung Cancer

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