Association of p27Kipl Levels With Recurrence and Survival in Patients With Stage C Prostate Carcinoma

Côté, Richard J.; Shi, Yan; Groshen, Susan; Feng, An‐Chen; Skinner, Donald G.; Lieskovosky, Gary; Cordon‐Cardo, Carlos

doi:10.1093/jnci/90.12.916

Cited by 175 publications

(106 citation statements)

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“…This difference proved to be statistically significant (P = 0.02). Whereas in univariate statistical analysis tumour stage in combination with altered p27 Kip1 protein expression was identified as predictor of an early tumour recurrence following radical prostatectomy, during multivariate analysis loss of p27 Kip1 protein expression was identified as the only independent prognostic predictor of recurrencefree survival.However, in contrast to the results reported by Cote et al (1998) and in accordance with the observation by Yang et al (1998), in our study decreased expression of the p27 Kip1 protein was not correlated to the long-term survival of the patients. This observation might be explained with the high frequency of low-stage tumours (≤ T2) (52%) included in our study, whereas the investigation by Cote et al (1998) exclusively evaluated the prognostic importance of p27 Kip1 in locally advanced (Stage C) prostate cancer specimens.…”

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confidence: 74%

“…Recently, it has been suggested that the lower or even undetectable protein level in tumorous tissue specimens when compared with normal somatic cells more likely results from an increased degradation of the p27 Kip1 protein than from an altered p27 Kip1 gene transcription or p27 Kip1 mRNA stability (Ponce-Castaneda, 1995). Therefore, the investigation of cancerous tissue specimens for p27 Kip1 alterations on the protein level by immunohistochemistry, for example, appears as the most suitable analytical approach to clarify the possible involvement of p27 Kip1 in the development and progression of human malignancies and to further evaluate the role as a biological variable of possible prognostic importance (Cote et al, 1998).Whereas for non-small-cell lung cancer, colorectal and breast cancers (Esposito et al, 1997;Porter et al, 1997), decreased p27 Kip1 protein expression was correlated with a shorter overall survival of the patients, Fredersdorf et al (1997) also reported contradictory findings for a subset of highly proliferative breast cancer cell lines exhibiting high level p27 Kip1 expression. An initial study in bladder cancer, investigating the expression of p27 Kip1 mRNA in 14 superficial and 14 muscle invasive tumour specimens, reported a decreased level of the p27 Kip1 transcript in invasive compared with superficial lesions (McGarvey et al, 1997).…”

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Predictive value of decreased p27Kip1 protein expression for the recurrence-free and long-term survival of prostate cancer patients

et al. 1999

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SummaryThe p27 Kip1 gene has been identified as inductor of cell cycle arrest at the G1 checkpoint to prevent entry of somatic cells into the S phase of the cell cycle when substantial DNA damage has occurred. It has been suggested that decreased expression of the p27 Kip1 protein may contribute to the development of human malignancies due to loss of critical antiproliferative mechanisms. In the present study, 95 specimens (T1-T4) from 95 randomly selected patients undergoing radical prostatectomy at the Urological Department of Hannover University (82 patients) as well as in the Josef Hospital Regensburg (13 patients) between 1981 and 1992 for whom tissue blocks for immunohistochemical investigation were available, were investigated for different biological and clinical characteristics as possible predictors for recurrence-free and long-term survival: age, depth of tumour infiltration, histological grade, lymph node status, as well as decreased expression of the p27 Kip1 protein. After a median follow-up up of 56 months (24-151 months), seven of 21 (33%) patients (Group 1) with loss of p27 Kip1 protein expression or a relative amount of <10% of positively stained tumour cells developed recurrent disease in contrast to 17 of 74 (23%) patients (Group 2) with retained p27 Kip1 protein expression (≥10% of positively stained tumour cells). The median recurrence-free survival was 14 months (5-40 months) for patients from Group 1 and 31 months (7-133 months) for Group 2 patients (P = 0.02). In multivariate analysis, loss of p27 Kip1 protein expression was identified as the only independent prognostic parameter for recurrence-free survival. In contrast, neither the univariate nor the multivariate analysis showed a correlation between loss of p27 Kip1 protein expression and the long-term survival of the patients. Prospective studies are urgently needed to confirm the independent prognostic value of decreased p27 Kip1 protein expression together with overexpression of the p53 tumour suppressor protein in patients with localized prostate cancer. The availability of more refined prognostically important biological variables in addition to established prognostic factors like tumour stage or Gleason score might help decision making in patients at high risk for the development of local recurrence or systemic tumour progression. © 1999 Cancer Research Campaign Keywords: prostate cancer; prognosis; p27 Kip1 gene 1052British Journal of Cancer (1999) 81(6), 1052-1058 © 1999 Cancer Research Campaign Article no. bjoc.1999 Received 10 cell cycle arrest at the G1 checkpoint by a negative regulatory influence on cyclins and cdks . Recently, a heat stable 27 kDa protein, the transcript of the p27 Kip1 gene that has been mapped on chromosome 12p12.3 (Martin et al, 1995), has been suggested to substantially participate in cell cycle control by preventing entry of somatic cells into the S phase of the cell cycle (Craig et al, 1997). p27 Kip1 , first identified in extracts of tumour growth factor β (TGF-β)-treated cells as an inhibitor ...

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Predictive value of decreased p27Kip1 protein expression for the recurrence-free and long-term survival of prostate cancer patients

et al. 1999

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“…[35][36][37][38][39] p27 Kip1 plays a key role in cell cycle progression, and it is, therefore, not surprising that dysfunction of p27 Kip1 is involved in human carcinogenesis. [6][7][8][9][10][11][12][13][14][15][16][17]40,41 Some studies have suggested that p27 Kip1 may act as a tumor suppressor. Mutations in p27 Kip1 are rare, [42][43][44] and dysfunction of p27 Kip1 appears to occur through degradation by the ubiquitin-proteasome pathway 6,7,9 in human cancers.…”

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confidence: 99%

“…p27 Kip , a member of the universal cyclin-dependent kinase (CDK) inhibitor family, has recently been shown to be a prognostic factor for various human cancers including breast, [6][7][8] colon, 8,9 prostate, 10,11 gastric, 12 pancreatic, 13 esophageal, 14,15 and lung 16,17 cancers. These results suggest that the p27 Kip1 cell cycle inhibition pathway plays a significant role in human carcinogenesis and cancer progression.…”

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Decreased p27Kip1 expression and cyclin D1 overexpression, alone and in combination, influence recurrence and survival of patients with resectable extrahepatic bile duct carcinoma

et al. 1999

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This study was undertaken to identify potential abnormalities of p27 Kip1 and cyclin D1 expression in extrahepatic bile duct carcinomas and to assess the prognostic significance of p27 Kip1 and cyclin D1 levels for patients with this disease. Decreased p27 Kip1 expression (F50% nuclei staining) and cyclin D1 overexpression (G5% nuclei staining) was observed immunohistochemically in 19 (56%) and 23 (68%) of the 34 tumors examined, respectively. Both decreased p27 Kip1 and cyclin D1 overexpression were associated with relapse (P ‫؍‬ .0005 for p27 Kip1 and P ‫؍‬ .0004 for cyclin D1). Kaplan-Meier curves showed that both decreased p27 Kip1 and cyclin D1 overexpression correlate significantly with shortened survival rates (for p27 Kip1 , P ‫؍‬ .0419 and P ‫؍‬ .002 for overall and disease-free survival; for cyclin D1, P ‫؍‬ .0392 and P ‫؍‬ .0021 for overall and disease-free survival). Cox regression model analyses identified decreased p27 Kip1 and cyclin D1 overexpression as independent markers predicting death from relapse (P ‫؍‬ .0371, risk ratio: 3.891 for p27 Kip1 ; P ‫؍‬ .0429, risk ratio: 8.31 for cyclin D1). Carcinoma of the extrahepatic bile duct (EBDC) is notoriously difficult to cure. Surgical resection is the first choice of treatment, however, postoperative survival remains unsatisfactory. The effects of adjuvant therapy remain poorly understood. Understanding the molecular underpinnings of EBDC is important because it may provide new biotherapy for this disease. Identification of biomarkers related to the outcome of patients with EBDC after surgery is another avenue to improve the prognosis, which may assist in the selection of patients who might benefit from adjuvant therapy. Multiple specific gene alterations contribute to human carcinogenesis and cancer progression. For hepatobiliary malignancies in hepatocellular carcinoma, several genetic and epigenetic alterations have been identified and some have been linked with prognosis, 1 but the molecular basis of EBDC remains poorly understood. p53 overexpression has been observed in EBDC immunohistochemically, however, the impact of this alteration on prognosis remains controversial. [2][3][4] Recently, although frequent p16 INK4 mutations have been found in hilar bile duct and common bile duct cancers, their significance was not evaluated because the sample size was too small (total 10 tumors). 5 To date, there is no good biomarker for predicting the outcome in EBDC.p27 Kip , a member of the universal cyclin-dependent kinase (CDK) inhibitor family, has recently been shown to be a prognostic factor for various human cancers including breast, 6-8 colon, 8,9 prostate, 10,11 gastric, 12 pancreatic, 13 esophageal, 14,15 and lung 16,17 cancers. These results suggest that the p27 Kip1 cell cycle inhibition pathway plays a significant role in human carcinogenesis and cancer progression. p27 Kip1 exerts its cell-cycle inhibition effects through interaction with several molecules including cyclin D, cyclin E, CDK2, CDK4, and CDK6. Therefore, we hypothesized that th...

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“…14 Both were attractive candidates since they had been previously implicated in malignancy in general and CDKN1B in prostate cancer specifically. [15][16][17][18] Subsequent analysis of both candidates in metastatic prostate cancer samples failed to demonstrate evidence of genomic inactivation by either hypermethylation or mutation. 19,20 An alternative approach to identifying the prostate cancer tumor-suppressor gene at this locus is to use expression analysis to prioritize the genes lying within the region of interest; the prostate tumor-suppressor gene will demonstrate decreased expression in tumors compared to normals.…”

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Expression mapping at 12p12‐13 in advanced prostate carcinoma

Kibel

Huagen

Guo

et al. 2004

Intl Journal of Cancer

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We have previously mapped a putative prostate cancer tumor-suppressor gene to a 1-2 Mb region of 12p12-13. Initial work to identify the tumor suppressor at this locus focused on candidates previously implicated in malignancy; however, mutational and methylation analyses failed to identify significant genomic events. An alternative approach is to use expression analysis to prioritize the genes within the region of interest. This experimental design is based on the hypothesis that tumor-suppressor genes demonstrate decreased expression in tumors compared to normals. Herein, we narrow the region of interest using deletion mapping data and employ expression analysis to prioritize the genes in the minimal deleted region. Highly informative polymorphic markers spanning our region were used to assess for loss of heterozygosity in 99 tumor and normal DNA pairs. The minimal region of deletion was determined to be approximately 500 kb bounded by D12S391 and A002Q26. Publically available databases place 7 genes within this minimal deletion region. An additional 3 genes lie just outside this minimal deletion region and could possibly be inactivated by deletion of promoter, 3 -untranslated region sequences or alternative splice variants. Relative levels of expression of these 10 candidate genes were determined in 6 normal prostates, 5 local prostate tumors, 9 prostate lymph node metastases, 6 prostate cancer cell lines and 12 prostate cancer xenografts using quantitative RT-PCR. DUSP16, FLJ10298 and BCLG were significantly downregulated in both clinical tumors and cultured prostate cancer tissue, indicating that one or all may be critical to initiation or progression of prostate carcinoma.

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Association of p27Kipl Levels With Recurrence and Survival in Patients With Stage C Prostate Carcinoma

Abstract: Levels of nuclear p27 immunoreactivity in the primary tumor can be used to predict recurrence and survival among patients with localized prostate cancer.

Cited by 175 publications

References 19 publications

Predictive value of decreased p27Kip1 protein expression for the recurrence-free and long-term survival of prostate cancer patients

Predictive value of decreased p27Kip1 protein expression for the recurrence-free and long-term survival of prostate cancer patients

Decreased p27Kip1 expression and cyclin D1 overexpression, alone and in combination, influence recurrence and survival of patients with resectable extrahepatic bile duct carcinoma

Expression mapping at 12p12‐13 in advanced prostate carcinoma

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