Low levels of cathepsin D are associated with a poor prognosis in endometrial cancer

Falcón, Orlando; Chirino, Ricardo; León, Laureano; López-Bonilla, Argelia; Torres, Santiago Hernández; Fernández, Leandro; García-Hernández, José Ángel; Valerón, Pilar F.; Díaz-Chico, J. C.

doi:10.1038/sj.bjc.6690090

Cited by 16 publications

(11 citation statements)

References 41 publications

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“…The 1988 FIGO surgical staging that was used for risk stratification for more than two decades as well as complex clinicopathologic algorithms developed for therapeutic triage, lack the desired prognostic precision 4, 5, 7, 19. The need for an accurate risk stratification system for patients with endometrial cancer has motivated multiple efforts aimed at identifying prognostic biomarkers 20-27. Molecular biomarkers may potentially identify women at high risk for recurrence and death, predict response to currently available treatments and direct the development of novel targeted therapies.…”

Section: Discussionmentioning

confidence: 99%

DICER1 expression and outcomes in endometrioid endometrial adenocarcinoma

Zighelboim

Reinhart

Gao

et al. 2010

Cancer

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BACKGROUND: The objective of this study was to determine whether lower expression levels of DICER1 are associated with disease recurrence in patients with endometrioid endometrial cancer. The authors also explored DNA methylation and haploinsufficiency as potential mechanisms related to altered DICER1 expression in these tumors. METHODS: DICER1 expression was assessed by quantitative polymerase chain reaction in a selected cohort of endometrioid endometrial tumors (N = 169). Loss of heterozygosity analyses were conducted using 2 single nucleotide polymorphisms, and combined bisulfate restriction analysis was used to assess methylation in the 5′‐untranslated region of DICER1 in representative tumors. The correlations between DICER1 expression and clinicopathologic variables, including overall survival (OS) and disease‐free survival (DFS), were assessed using nonparametric rank‐sum tests and Cox proportional hazard models as appropriate. Survival distributions were described using the Kaplan‐Meier method. A nested case‐control analysis was conducted to confirm the association between transcript levels and disease recurrence. RESULTS: Lower DICER1 expression (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.05‐1.75; P = .02) and advanced disease stage (HR, 2.79; 95%CI, 1.59‐4.90; P < .001) were associated with worse DFS. Three variables were associated significantly with reduced OS: age (HR, 1.04; 95%CI, 1.02‐1.06; P < .0001), advanced disease stage (HR, 6.41; 95%CI, 3.57‐11.52; P < .0001), and high tumor grade (HR, 2.96; 95%CI, 1.46‐5.99; P = .003). Nested case‐control analyses confirmed that there were lower DICER1 transcript levels in patients who had recurrent disease (P = .01). Deletion of DICER1 sequences was an infrequent event (5% of analyzed patients), and no methylation was observed in the 5′ DICER1 regulatory region. CONCLUSIONS: Lower DICER1 transcript levels were correlated with disease recurrence and worse DFS survival in patients with endometrioid endometrial cancer. The factors that influence DICER1 transcript levels in primary endometrial cancers remain unknown. Cancer 2011. © 2010 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

DICER1 expression and outcomes in endometrioid endometrial adenocarcinoma

Zighelboim

Reinhart

Gao

et al. 2010

Cancer

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“…The cytosolic assay is a well-standardized method for the quantification of the expression of enzymes. Falcón et al [10]reported that in stage I–III primary endometrial adenocarcinoma, patients with low cytosolic cathepsin D levels estimated by an immunoradiometric assay showed poorer survival than patients with high cathepsin D levels. On the other hand, Lösch et al [11]reported quite opposite results detected by immunohistochemical analysis in patients with stage I–III endometrial adenocarcinoma.…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological Significance of Cathepsin D Expression in Gastric Adenocarcinoma

Ikeguchi¹,

Fukuda²,

Oka³

et al. 2001

Oncology

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Objective: An estrogen-regulated lysosomal protease, cathepsin D, has been detected in a variety of tissues. This proteinase has been described as closely associated with tumor progression and metastasis in malignant tumors. The purpose of this study was to determine the clinicopathological and prognostic significance of cathepsin D expression in gastric adenocarcinoma. Methods: In a consecutive series of 478 patients with gastric carcinoma (median follow-up period: 93 months, range: 1–285 months), cathepsin D expression in tumors was quantitatively analyzed with immunohistochemistry using a monoclonal antibody against cathepsin D (clone: 1C11). The percentage of cathepsin-D-positive cancer cells (the CD index) was calculated. In addition, the amount of cathepsin-D-positive stromal cells was evaluated; three grades (high, intermediate, and low) were used for the classification. Results: The mean CD index of 478 tumors was 12.8% (range: 0–100%, median: 8%). The mean CD index of diffuse-type gastric carcinomas (14.9%) was significantly higher than that of intestinal-type carcinomas (10.1%, p < 0.0001). Cathepsin D expression of cancer cells was significantly associated with the depth of tumor invasion in both types. The percentage of tumors with high cathepsin D expression in stromal cells was significantly higher in well-differentiated tumors (25.5%) than in moderately differentiated (12.8%) or in poorly differentiated tumors (19.1%). Cathepsin D expression of stromal cells was significantly associated with the depth of tumor invasion in the intestinal type, in contrast to the diffuse type. Highly expressed cathepsin D in cancer cells was associated with a poor prognosis in both types of carcinoma, but in stromal cells highly expressed cathepsin D was associated to a poor prognosis in the intestinal type only. Conclusion: These results indicate that cathepsin D expression in cancer cells may play an important role in tumor progression in diffuse-type gastric carcinoma, whereas in the intestinal type of carcinoma, cathepsin D expression in stromal cells may play an important role in tumor progression.

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“…The tissue was mechanically disrupted and the sub-cellular fractions (cytosolic and nuclear) were obtained as previously described [50]. DNA was extracted by a standard procedure.…”

Section: Methodsmentioning

confidence: 99%

“…Ploidy status and S-phase fraction were estimated by flow cytometry as previously reported [50]. Tumors with a DNA index > 0.9 and < 1.1 were classified as “(quasi)diploid” and others as aneuploid.…”

Section: Methodsmentioning

confidence: 99%

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Microsatellite instability and ploidy status define three categories with distinctive prognostic impact in endometrioid endometrial cancer

et al. 2014

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Microsatellite instability (MSI) and aneuploidy are inversely related phenomena. We tested whether ploidy status influences the clinical impact of MSI in endometrioid endometrial cancer (EEC). We analyzed 167 EECs for MSI and ploidy. Tumors were classified in three categories according to MSI and ploidy status. Associations with clinicopathological and molecular variables, survival, and treatment response were assessed.All MSI tumors (23%) were scored as diploid, and 14% of microsatellite stable (MSS) tumors presented aneuploidy. MSI tumors associated with older age at diagnosis, non-obesity, high histological grade, and advanced surgical stage. MSS-aneuploid tumors also associated with higher grade and advanced stage. In multivariate survival analysis MSI did not influence disease-free survival (DFS) or cancer-specific survival (CSS). However, when just diploid tumors were considered for the analysis, MSI significantly contributed to worse DFS and CSS, and the same was observed for aneuploidy when MSS tumors were analyzed alone. In diploid tumors, a differential response to postoperative radiotherapy (RT) was observed according to MSI, since it predicted poor DFS and CSS in the multivariate analysis.We conclude that ploidy status influences the clinical impact of MSI in EEC. Among diploid tumors those with MSI have poor clinical outcome and respond worse to RT.

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Low levels of cathepsin D are associated with a poor prognosis in endometrial cancer

Cited by 16 publications

References 41 publications

DICER1 expression and outcomes in endometrioid endometrial adenocarcinoma

DICER1 expression and outcomes in endometrioid endometrial adenocarcinoma

Clinicopathological Significance of Cathepsin D Expression in Gastric Adenocarcinoma

Microsatellite instability and ploidy status define three categories with distinctive prognostic impact in endometrioid endometrial cancer

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