Increased expression of cyclin-dependent kinase inhibitor 2 (CDKN2A) gene product P16INK4A in ovarian cancer is associated with progression and unfavourable prognosis

Dong, Ying; Walsh, Michael D.; McGuckin, Michael A.; Gabrielli, Brian; Cummings, Margaret C.; Wright, Robert F.; Hurst, Terry; Khoo, S. K.; Parsons, Peter G.

doi:10.1002/(sici)1097-0215(19970220)74:1<57::aid-ijc10>3.0.co;2-f

Cited by 79 publications

(73 citation statements)

References 20 publications

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“…Furthermore, seven of the 11 Rb-positive tumors overexpressed p16 protein, relative to normal ovarian tissue controls. These data support the high frequency of p16 expression in ovarian tumors observed by Dong et al (1997), Milde-Langosch et al (1998) and Marchini et al (1997). The expression of both Rb and p16 proteins in four of the six ovarian cancer cell lines further indicated that the transformation of ovarian cancer cells frequently occurs in the absence of the loss of either one of these two negative regulators of the G1 checkpoint.…”

Section: Discussionsupporting

confidence: 76%

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Ovarian cancer cells that coexpress endogenous Rb and p16 are insensitive to overexpression of functional p16 protein

2000

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Defects of the`Rb/cyclin D1/p16 pathway' have been shown to play a critical role in the development of virtually all human malignancies assessed. To determine the contribution of G1 phase cell cycle defects to ovarian tumorigenesis, we have examined a panel of normal and tumor ovarian tissues and ovarian cancer cell lines for the expression of Rb, p16 and cyclin D1 proteins. Unlike most types of human cancer whose development involves the loss of either Rb or p16 expression, we observed the coexpression of Rb, p16 and cyclin D1 in 82% of ovarian cancer tissues and cell lines. Furthermore, the growth and cell cycle distribution pro®les of three ovarian cancer cell lines (ES-2, PA-1 and NIH OVCAR-3) that coexpressed Rb and p16, were found to be una ected by adenoviral-mediated overexpression of functional p16 protein, indicating the existence of a defect(s) downstream from p16 in these cells. By contrast overexpression of ectopic p16 in the one ovarian cancer cell line (SK-OV-3) that expressed Rb but lacked p16 protein, resulted in a G1 growth arrest. These data suggest that defects of the`Rb/cyclin D1/p16 pathway', other than the loss of Rb or p16, may play a major role in the development of ovarian cancer. Oncogene (2000) 19, 258 ± 264.

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Section: Discussionsupporting

confidence: 76%

“…Immunohistochemical studies by Dong et al (1997) and Milde-Langosch et al (1998) detected the expression of p16 protein in 89 and 80% of ovarian tumors, respectively. Furthermore, Marchini et al (1997) detected p16 protein expression in 74% of ovarian tumors by Western blot analysis.…”

Section: Introductionmentioning

confidence: 99%

Ovarian cancer cells that coexpress endogenous Rb and p16 are insensitive to overexpression of functional p16 protein

2000

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“…While no prognostic significance of p16 INK4a immunoreactivity was described by Milde-Langosch et al (2003), Sui et al (2000), as well as by Kusume et al (1999), other reports suggested that high levels of p16 INK4a expression predict poor prognosis (Dong et al, 1997a). These contrary findings may be due to inherent limitations of some of the previously published studies.…”

Section: Discussionmentioning

confidence: 91%

“…While the present collective contains only advanced-stage patients receiving standardized chemotherapy (du Bois et al, 2003), series comprising both early and advanced FIGO stages were analysed by others (Dong et al, 1997a, b;Niemann et al, 1998;Kusume et al, 1999;Sui et al, 2000;Milde-Langosch et al, 2003;Hashiguchi et al, 2004). Postoperative therapy was either variable (Dong et al, 1997b;Kusume et al, 1999;Milde-Langosch et al, 2003;Hashiguchi et al, 2004) or not mentioned (Dong et al, 1997a;Sui et al, 2000). Furthermore, case numbers were limited in many of the previous reports (some authors reporting o50 cases (Raspollini et al, 2004;Niemann et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Independent prognostic significance of cell cycle regulator proteins p16INK4a and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group

et al. 2007

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The purpose of the study is to test the hypothesis that expression of cell cycle regulatory proteins p16 INK4a and pRb is significantly associated with prognosis in ovarian carcinomas. We performed immunohistochemical analysis of p16 INK4a and pRb expression and correlated with survival in a series of 300 patients with FIGO stage IIb-IV ovarian carcinoma which were enrolled in a randomized prospective trial evaluating two different platinum and paxlitaxel chemotherapy combinations after radical surgery. p16 INK4a negative tumours (17/300; 6%) had a significantly worse prognosis (univariate analysis, Po0.001; multivariate analysis: odds ratio 2.41, P ¼ 0.009). Among p16 INK4a -positive tumours (283 out of 300; 94%), survival was better for patients with intermediate expression as compared to low or high expression levels (P ¼ 0.001). High expression levels of pRb were associated with an incremental deterioration of prognosis (univariate analysis, P ¼ 0.004; multivariate analysis: odds ratio 2.98, P ¼ 0.002). This observation held also true in the subgroup of optimally debulked patients (n ¼ 82), in whom the most important established prognostic factor, postoperative residual tumour cannot be applied. In conclusion p16 INK4a and pRb are independent prognostic factors in advancedstage ovarian carcinomas after radical surgery and postoperative chemotherapy. High pRb expression is a significant prognosticator in optimally debulked patients and may hold potential for subgroup stratification in postoperative treatment.

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“…Older studies combining all histotypes showed that either overexpression or complete absence of p16 were associated with unfavorable outcomes 13, 14, 15. Recently, histotype‐specific studies also reported that normal heterogeneous p16 expression was significantly associated with longer progression‐free and overall survival (OS) in two series of 334 and 115 women with HGSC 16, 17.…”

Section: Introductionmentioning

confidence: 99%

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

Rambau

Vierkant

Intermaggio

et al. 2018

The Journal of Pathology CR

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We aimed to validate the prognostic association of p16 expression in ovarian high‐grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical‐grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis‐associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47–2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30–2.75, p = 0.004), while absence was associated with shorter OS in low‐grade serous carcinomas (HR: 2.95, 95% CI 1.61–5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype‐specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low‐grade serous carcinoma justifies CDK4 inhibition.

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Increased expression of cyclin-dependent kinase inhibitor 2 (CDKN2A) gene product P16INK4A in ovarian cancer is associated with progression and unfavourable prognosis

Cited by 79 publications

References 20 publications

Ovarian cancer cells that coexpress endogenous Rb and p16 are insensitive to overexpression of functional p16 protein

Ovarian cancer cells that coexpress endogenous Rb and p16 are insensitive to overexpression of functional p16 protein

Independent prognostic significance of cell cycle regulator proteins p16INK4a and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study

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