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Prognostic impact of the expression of Hedgehog proteins in cervical carcinoma FIGO stages I-IV treated with radiotherapy or chemoradiotherapy
Orebro University Hospital. Department of Oncology.
Department of Oncology, Örebro University Hospital, Örebro, Sweden.
Orebro University Hospital. Department of Oncology.ORCID iD: 0000-0002-5063-631X
2014 (English)In: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 135, no 2, 305-311 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Hedgehog signaling proteins were assessed in patients with cervical carcinoma receiving chemoradiation. Associations between five Hedgehog proteins and prognosis were studied.

Methods: In all, 131 cases of cervical carcinomas (FIGO stages I-IV) were immunohistochemically (IHC) analyzed for Patched (PTCH), Smoothened (SMO), and GLI1, GLI2 and GLI3 protein expression. Associations between Hedgehog protein expressions, clinicopathological factors, and clinical outcome data were examined.

Results: Positive IHC staining for the five Hedgehog proteins was recorded in 8% to 37% of the tumor cells. The highest frequency was noted for SMO and the lowest for all. There was a significant association between low SMO- and GLI2-expression and KRAS-mutation. Tumors with overexpressed SMO had a higher frequency of residual tumor or local recurrences than tumors with low SMO expression. Patients with tumors expressing PTCH in more than 75% of the cells had significantly (P = 0.023) better recurrence-free survival than patients with tumors with low expression. The opposite situation was true for SMO. For GLI2, there was a statistically significant difference with regard to overall (P = 0.004) and distant (P = 0.015) relapse rate for groups with expression of GLI2 in the range of 5-25% compared to higher rates.

Conclusions: A predictive and prognostic value was found for PTCH, SMO, and GLI2 with regard to residual carcinoma, local recurrences, and for GLI2 distant relapses. The Hedgehog signaling pathway also seems to play an important role in cervical carcinogenesis together with HPV16-infection and KRAS-mutation.

Place, publisher, year, edition, pages
Academic Press, 2014. Vol. 135, no 2, 305-311 p.
Keyword [en]
Cervical carcinoma, Hedgehog proteins, Prognosis
National Category
Cancer and Oncology Obstetrics, Gynecology and Reproductive Medicine
Identifiers
URN: urn:nbn:se:oru:diva-56331DOI: 10.1016/j.ygyno.2014.08.026ISI: 000345605200023PubMedID: 25158038Scopus ID: 2-s2.0-84914169236OAI: oai:DiVA.org:oru-56331DiVA: diva2:1081655
Note

Funding Agencies:

Research Foundation at the Department of Oncology

Research Funds of the University Hospital, Örebro

Foundation for Research in Gynecological Cancer, Örebro, Sweden 

Available from: 2017-03-14 Created: 2017-03-14 Last updated: 2017-03-29Bibliographically approved
In thesis
1. Predictive and prognostic factors in cervical carcinomas treated with (chemo-) radiotherapy
Open this publication in new window or tab >>Predictive and prognostic factors in cervical carcinomas treated with (chemo-) radiotherapy
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A series of 131 women with cervical carcinoma FIGO stage I-IV were treated with external radiotherapy and intracavitary brachytherapy. In 47 patients (36%) concomitant chemotherapy was given. One hundred and twenty-one tumors (92%) achieved complete remission. Addition of chemotherapy increased primary cure rate to 98%. Tumor stage, tumor size, and histology were significant predictive factors for primary cure. Treatment related factors were: brachytherapy dose and interruption of irradiation.

Thirty-nine recurrences (30%) were recorded. Tumor stage, histology, and concomitant chemotherapy were significant predictive factors.

The 5-year cancer-specific survival rate of the complete series was 65%. Tumor size was a strong prognostic factor in multivariate analysis.

Serum samples from 44 patients were analyzed. Ten candidate biomarker proteins with regard to tumor recurrences were identified.

Five Hedgehog proteins were analyzed with immunohistochemistry. Residual tumor, local and distant recurrences and survival rate were associated with PTCH, SMO and GLI2. In the Wnt-β-catenin study intense staining of the membranes and nuclear staining > 5% were of significant predictive and prognostic value. Intense nuclear APC staining was associated with recurrences and cancer-specific survival rate.

Conclusion: Histology, tumor size and brachytherapy dose were important clinical predictive and prognostic factors. Multiprotein analysis identified ten biomarker proteins associated with tumor recurrences. Three proteins (PTCH, SMO, and GLI2) in the Hedgehog pathway were of predictive and prognostic value. In the Wnt-β-catenin pathway intensity of β-catenin membrane staining and accumulation in the nuclei as well as nuclear APC-expression were of predictive and prognostic value.

Place, publisher, year, edition, pages
Örebro: Örebro University, 2017. 61 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 159
Keyword
cervical carcinoma, radio-chemotherapy, biomarkers, predictive factors, prognostic factors, multiprotein analysis, Hedgehog pathway, Wnt/β-catenin pathway
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:oru:diva-56127 (URN)978-91-7529-185-7 (ISBN)
Public defence
2017-04-21, Örebro universitet, Campus USÖ, hörsal C1, Södra Grev Rosengatan 32, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2017-03-06 Created: 2017-03-06 Last updated: 2017-04-19Bibliographically approved

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