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Wingren, Sten
Publications (10 of 20) Show all publications
Göthlin Eremo, A., Tina, E., Wegman, P., Stål, O., Fransén, K., Fornander, T. & Wingren, S. (2015). HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen. International Journal of Oncology, 47(4), 1311-1320
Open this publication in new window or tab >>HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen
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2015 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 47, no 4, p. 1311-1320Article in journal (Refereed) Published
Abstract [en]

The human epidermal growth factor receptor (HER) 4 is a relative of HER2 and has been associated to endocrine breast cancer and prediction of tamoxifen response. In addition to PI3K/Akt and MAPK pathway activation, ligand binding to HER4 triggers proteolytic cleavage and release of an intracellular receptor domain (4ICD) with signaling properties. The aim of the present study was to analyze HER4 protein expression and intracellular localization in breast cancer tissue from patients randomized to treatment with or without adjuvant tamoxifen. To investigate HER4 expression and localization in response to estradiol (E2) and 4-hydroxytamoxifen (4-OHT) exposure, we also performed in vitro studies. Cytoplasmic, nuclear and membrane expression of HER4 protein was evaluated by immunohistochemical staining in tumor tissue from 912 breast cancer patients. Three different breast epithelia cancer cell lines were exposed to E2 and 4-OHT and mRNA expression was analyzed using qPCR. Further, nuclear and cytoplasmic proteins were separated and analyzed with western blotting. We found an association between nuclear HER4 protein expression and ER-positivity (P=0.004). Furthermore, significant association was found between cytoplasmic HER4 and ER-negativity (P<0.0005), PgR-negativity (P<0.0005), tumor size >20 mm (P=0.001) and HER2-negativity (P=0.008). However, no overall significance of HER4 on recurrence-free survival was found. After E2 exposure, HER4 mRNA and protein expression had decreased in two cell lines in vitro yet no changes in nuclear or cytoplasmic protein fractions were seen. In conclusion, nuclear HER4 seem to be co-located with ER, however, we did not find support for overall HER4 expression in independently predicting response of tamoxifen treatment. The possible influence of separate isoforms was not tested and future studies may further evaluate HER4 significance.

Place, publisher, year, edition, pages
Athens: Spandidos publications, 2015
Keywords
breast cancer, ErBb4, HER4, randomized patients, tamoxifen
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:oru:diva-45679 (URN)10.3892/ijo.2015.3108 (DOI)000362058300015 ()26238412 (PubMedID)2-s2.0-84941006155 (Scopus ID)
Note

Funding Agencies:

Nyckelfonden, Örebro University Hospital, Sweden

Lions Cancer Research Foundation, Region Uppsala - Örebro, Sweden

Stockholm Cancer Society, Sweden

Available from: 2015-08-31 Created: 2015-08-31 Last updated: 2018-07-01Bibliographically approved
Province, M. A., Goetz, M. P., Brauch, H., Flockhare, D. A., Hebert, J. M., Whaley, R., . . . Klein, T. E. (2014). CYP2D6 Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Populations. Clinical Pharmacology and Therapeutics, 95(2), 216-227
Open this publication in new window or tab >>CYP2D6 Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Populations
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2014 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 95, no 2, p. 216-227Article in journal (Refereed) Published
Abstract [en]

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1), CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

Place, publisher, year, edition, pages
New York, USA: Nature Publishing Group, 2014
National Category
Medical and Health Sciences Pharmacology and Toxicology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-33895 (URN)10.1038/clpt.2013.186 (DOI)000330151100026 ()24060820 (PubMedID)2-s2.0-84893732936 (Scopus ID)
Note

Funding Agencies:

National Institutes of Health (National Institute of General Medical Sciences)

National Institutes of Health (National Cancer Institute)

National Institutes of Health (National Institute of Child Health and Human Development)

Breast Cancer Research (Scotland)  

Tayside Tissue Bank  

California Breast Cancer Research Program 

Cancer Research UK  

Deutsches Krebsforschungszentrum, Heidelberg, Germany  

Robert Bosch Foundation, Stuttgart, Germany  

Marie Curie Initial Training Network "FightingDrugFailure" 

GrantStichting Emmanuel van der Schueren (scientific partner of the Vlaamse Liga tegen Kanker)  

National Project for Personalized Genomic Medicine, Ministry for Health & Welfare, Republic of Korea 

Deutsche Forschungsgemeinschaft, Germany 

Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2018-08-27Bibliographically approved
Lindqvist, B. M., Wingren, S., Motlagh, P. B. & Nilsson, T. K. (2014). Whole genome DNA methylation signature of HER2-positive breast cancer. Epigenetics, 9(8), 1149-1162
Open this publication in new window or tab >>Whole genome DNA methylation signature of HER2-positive breast cancer
2014 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 9, no 8, p. 1149-1162Article in journal (Refereed) Published
Abstract [en]

In order to obtain a comprehensive DNA methylation signature of HER2-positive breast cancer (HER2+ breast cancer), we performed a genome-wide methylation analysis on 17 HER2+ breast cancer and compared with ten normal breast tissue samples using the Illumina Infinium HumanMethylation450 BeadChip (450K). In HER2+ breast cancer, we found altered DNA methylation in genes involved in multicellular development, differentiation and transcription. Within these genes, we observed an overrepresentation of homeobox family genes, including several genes that have not been previously reported in relation to cancer (DBX1, NKX2-6, SIX6). Other affected genes included several belonging to the PI3K and Wnt signaling pathways. Notably, HER2, AKT3, HK1, and PFKP, genes for which altered methylation has not been previously reported, were also identified in this analysis. In total, we report 69 candidate biomarker genes with maximum differential methylation in HER2+ breast cancer. External validation of gene expression in a selected group of these genes (n = 13) revealed lowered mean gene expression in HER2+ breast cancer. We analyzed DNA methylation in six top candidate genes (AKR1B1, INA, FOXC2, NEUROD1, CDKL2, IRF4) using EpiTect Methyl II Custom PCR Array and confirmed the 450K array findings. Future clinical studies focusing on these genes, as well as on homeobox-containing genes and HER2, AKT3, HK1, and PFKP, are warranted which could provide further insights into the biology of HER2+ breast cancer.

Place, publisher, year, edition, pages
Austin, USA: Landes Bioscience, 2014
Keywords
DNA methylation, HER2-positive breast cancer, Illumina Infinium HumanMethylation450 BeadChip
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-37169 (URN)10.4161/epi.29632 (DOI)000341360600010 ()25089541 (PubMedID)2-s2.0-84905672549 (Scopus ID)
Note

Funding Agencies:

Swedish Cancer Society

Örebro County Council

Lions Cancer Foundation, Uppsala

Nyckelfonden, Örebro

Available from: 2014-09-25 Created: 2014-09-25 Last updated: 2017-12-05Bibliographically approved
Göthlin Eremo, A., Wegman, P., Stål, O., Nordenskjöld, B., Fornander, T. & Wingren, S. (2013). Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast cancer patients. Oncology Reports, 29(4), 1467-1474
Open this publication in new window or tab >>Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast cancer patients
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2013 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 29, no 4, p. 1467-1474Article in journal (Refereed) Published
Abstract [en]

Reduced or absent Wwox expression has recently been associated with tamoxifen resistance in breast cancer and has also been proposed as a candidate predictive marker for treatment. We aimed to investigate the correlation of Wwox expression with the outcome of tamoxifen treatment by examining tissues from 912 randomized breast cancer patients. Paraffin-embedded tissues from patient tumors were arranged on tissue microarray, and Wwox protein was stained using immunohistochemistry. After microscopic examination, the results were analyzed with Cox regression, Kaplan-Meier survival curves and the log-rank test. In the group of cases having a tumor absent for Wwox expression, there was no difference in recurrence-free survival between treated and untreated patients (P=0.81). For treated cases with a tumor expressing moderate or strong Wwox protein, recurrence-free survival was improved (P=0.001 and P=0.003, respectively). The test for interaction between Wwox and treatment response demonstrated a decreased risk of recurrence for treated patients with a moderate or strong Wwox expression (HR=0.31, 95% CI 0.10-0.98 and HR=0.28, 95% CI 0.08-0.97, respectively). Our results indicate that patients with high expression of Wwox may gain more benefit from treatment with tamoxifen.

Place, publisher, year, edition, pages
Athens, Greece: Spandidos Publications, 2013
Keywords
Wwox, breast cancer, tamoxifen, randomized patients
National Category
Cancer and Oncology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-41720 (URN)10.3892/or.2013.2261 (DOI)000316510600028 ()23381945 (PubMedID)2-s2.0-84874702740 (Scopus ID)
Available from: 2015-01-15 Created: 2015-01-15 Last updated: 2018-05-23Bibliographically approved
Lindqvist, B. M., Farkas, S. A., Wingren, S. & Nilsson, T. K. (2012). DNA methylation pattern of the SLC25A43 gene in breast cancer. Epigenetics, 7(3), 300-306
Open this publication in new window or tab >>DNA methylation pattern of the SLC25A43 gene in breast cancer
2012 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 7, no 3, p. 300-306Article in journal (Refereed) Published
Abstract [en]

Solute carrier family 25A member 43 (SLC25A43) gene is a putative tumor suppressor gene that undergoes loss of heterozygosity (LOH) in human epidermal growth factor receptor 2 (HER2) positive breast cancer. Also, knockdown of SLC25A43 in cell lines influences cell turnover and metabolism. Absence of mutations in this gene in breast cancers prompted us to study methylation as an alternate mechanism for gene inactivation of this X encoded gene. Quantification of CpG site methylation using pyrosequencing was performed upstream of the SLC25A43 gene and at its 5' end in a cohort of breast tumor tissues (n = 80, HER2 positive or negative) with different SLC25A43 gene deletion status. Compared with control tissue, cancer tissues had lower levels of methylation at the 5' and 3' shores of the gene. Cancer tissues with no deletion in the SLC25A43 gene (Del(-)) had higher methylation in the CpG island (CGI) of the gene than cancers carrying the deletion (Del(+)). Methylation in the CGI of the SLC25A43 gene was negatively correlated with age at diagnosis. In HER2 positive breast cancer, ER negativity and lymph node positivity was associated with higher methylation in the CGI and in the adjacent shores of this gene. Our results suggest that methylation in the CGI of the SLC25A43 gene could be an alternate mechanism of gene silencing in the absence of LOH. Also, associations between site-specific methylation and clinicopathological parameters suggest that epigenetic changes in SLC25A43 gene could be of importance in breast carcinogenesis.

Place, publisher, year, edition, pages
Austin, USA: Landes Bioscience, 2012
Keywords
Breast cancer, CpG island, CpG shore, gene inactivation, HER2 receptor, methylation, SLC25A43 gene
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-22553 (URN)10.4161/epi.7.3.19064 (DOI)000301428800011 ()22430806 (PubMedID)2-s2.0-84858205498 (Scopus ID)
Funder
Swedish Cancer Society
Note

Funding Agencies:

Nyckelfonden Örebro, Sweden 

Lions Cancer Foundation, Sweden 

Available from: 2012-04-16 Created: 2012-04-16 Last updated: 2017-12-07Bibliographically approved
Tina, E., Lindqvist, B. M., Gabrielson, M., Lubovac, Z., Wegman, P. & Wingren, S. (2012). The mitochondrial transporter SLC25A43 is frequently deleted and may influence cell proliferation in HER2-positive breast tumors. BMC Cancer, 12(1), Article ID 350.
Open this publication in new window or tab >>The mitochondrial transporter SLC25A43 is frequently deleted and may influence cell proliferation in HER2-positive breast tumors
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2012 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, no 1, article id 350Article in journal (Refereed) Published
Abstract [en]

Background: Overexpression of the human epidermal growth factor receptor (HER) 2 is associated with poor prognosis and shortened survival in breast cancer patients. HER2 is a potent activator of several signaling pathways that support cell survival, proliferation and metabolism. In HER2-positive breast cancer there are most likely unexplored proteins that act directly or indirectly downstream of well established pathways and take part in tumor development and treatment response.

Methods: In order to identify novel copy number variations (CNVs) in HER2-positive breast cancer whole-genome single nucleotide polymorphism (SNP) arrays were used. A PCR-based loss of heterozygosis (LOH) assay was conducted to verify presence of deletion in HER2-positive breast cancer cases but also in HER2 negative breast cancers, cervical cancers and lung cancers. Screening for mutations was performed using single-strand conformation polymorphism (SSCP) followed by PCR sequencing. Protein expression was evaluated with immunohistochemistry (IHC).

Results: A common deletion at chromosome Xq24 was found in 80% of the cases. This locus harbors the gene solute carrier (SLC) family 25A member 43 (SLC25A43) encoding for a mitochondrial transport protein. The LOH assay revealed presence of SLC25A43 deletion in HER2-positive (48%), HER2-negative (9%), cervical (42%) and lung (67%) cancers. HER2-positive tumors with negative or low SLC25A43 protein expression had significantly lower S-phase fraction compared to tumors with medium or high expression (P = 0.024).

Conclusions: We have found deletion in the SLC25A43 gene to be a common event in HER2-positive breast cancer as well as in other cancers. In addition, the SLC25A43 protein expression was shown to be related to S-phase fraction in HER2-positive breast cancer. Our results indicate a possible role of SLC25A43 in HER2-positive breast cancer and support the hypothesis of altered mitochondrial function in cancer.

Keywords
Breast cancer, HER2, SLC25A43, S-phase
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-27546 (URN)10.1186/1471-2407-12-350 (DOI)000309407100001 ()22883974 (PubMedID)2-s2.0-84864803696 (Scopus ID)
Available from: 2013-02-13 Created: 2013-02-13 Last updated: 2017-12-06Bibliographically approved
Gao, L., Tu, Y., Wegman [Palmebäck-Wegman], P., Wingren, S. & Eriksson, L. A. (2011). A mechanistic hypothesis for the cytochrome P450-catalyzed cis-trans isomerization of 4-hydroxytamoxifen: an unusual redox reaction. Journal of Chemical Information and Modeling, 51(9), 2293-2301
Open this publication in new window or tab >>A mechanistic hypothesis for the cytochrome P450-catalyzed cis-trans isomerization of 4-hydroxytamoxifen: an unusual redox reaction
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2011 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 51, no 9, p. 2293-2301Article in journal (Refereed) Published
Abstract [en]

We provide a detailed description of the cis-trans isomerization of 4-hydroxytamoxifen/endoxifen catalyzed by several isoforms from the cytochrome P450 (CYP) superfamily, including CYP1B1, CYP2B6, and CYP2C19. We show that the reactions mainly involve redox processes catalyzed by CYP, DFT calculation results strongly suggest that the isomerization occurs via a cationic intermediate. The cationic cis-isomer is more than 3 kcal/mol more stable than the trans form, resulting in an easier conversion from trans-to-cis than cis-to-trans. The cis-trans isomerization is a rarely reported CYP reaction and is ascribed to the lack of a second abstractable proton on the ethenyl group of the triarylvinyl class of substrates. The cationic intermediates thus formed instead of the stable dehydrogenation products allow for isomerization to occur. As a comparison, the reactions for the tamoxifen derivatives are compared to those of other substrates, 4-hydroxyacetanilide and raloxifene, for which the stable dehydrogenation products are formed.

National Category
Chemical Sciences Biomedical Laboratory Science/Technology
Research subject
Chemistry; Biomedicine
Identifiers
urn:nbn:se:oru:diva-20857 (URN)10.1021/ci2001082 (DOI)000295114700026 ()
Available from: 2012-01-11 Created: 2012-01-11 Last updated: 2018-02-14Bibliographically approved
Gao, L., Tu, Y., Wegman [Palmebäck-Wegman], P., Wingren, S. & Eriksson, L. A. (2011). Conformational enantiomerization and estrogen receptor alpha binding of anti-cancer drug tamoxifen and its derivatives. Journal of Chemical Information and Modeling, 51(2), 306-314
Open this publication in new window or tab >>Conformational enantiomerization and estrogen receptor alpha binding of anti-cancer drug tamoxifen and its derivatives
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2011 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 51, no 2, p. 306-314Article in journal (Refereed) Published
Abstract [en]

The anticancer drug tamoxifen (TAM) displays two chiral vinyl propeller structures, which interconvert so rapidly that the process is undetectable on the NMR time scale. In the present work, the enantiomerization processes were investigated with molecular modeling techniques. The threshold mechanisms probed at the different rings were shown to be identical, i.e., involving a synchronous three-ring flip, with a correlated rotation of the rings. In order to reveal the pharmacological profiles of the two chiral forms, we performed structural studies on the ligand binding domain of estrogen receptor alpha. (ER alpha LBD) and associated ligands. The enantiomers, with opposite torsional twist, were found to be discriminated by ER alpha. For TAM and its main metabolites, the effects of the stereoselectivity of ER alpha are overcome by the low energy cost for helical inversion between the two torsional enantiomers, estimated to be similar to 3 kcal/mol.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2011
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-17124 (URN)10.1021/ci100401t (DOI)000287685700012 ()21194224 (PubMedID)2-s2.0-79952139350 (Scopus ID)
Available from: 2011-09-05 Created: 2011-09-02 Last updated: 2017-12-08Bibliographically approved
Wegman, P., Göthlin Eremo, A., Lindlöf, A., Karlsson, M. G., Stål, O. & Wingren, S. (2011). Expression of the forkhead transcription factor FOXL2 correlates with good prognosis in breast cancer patients treated with tamoxifen. International Journal of Oncology, 38(4), 1145-1151
Open this publication in new window or tab >>Expression of the forkhead transcription factor FOXL2 correlates with good prognosis in breast cancer patients treated with tamoxifen
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2011 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 38, no 4, p. 1145-1151Article in journal (Refereed) Published
Abstract [en]

Aromatase is an important enzyme in the local synthesis of oestrogens and its expression has been shown to be increased in breast cancer through the activation of multiple promoters. However, the mechanisms behind this are not yet fully understood. A novel candidate in this context is the transcription factor forkhead box L2 (FOXL2), which has been recognised to be co-expressed with aromatase and transcriptionally active promoter 11 in developing goat and chicken ovaries. We propose that FOXL2 could be involved in the increased expression of aromatase in breast cancer. We examined FOXL2 and its relation to aromatase in 132 postmenopausal breast cancer patients by immunohistochemistry. Using in silico analysis, we further searched for FOXL2 binding-elements in the aromatase gene promoters. The results demonstrate that FOXL2 is expressed in breast cancer and influences clinical outcome with improved recurrence-free survival in cases with nuclear expression. In a multivariate Cox model, nuclear FOXL2 was a significant prognostic factor in ER-positive patients treated with tamoxifen (HR=0.18, 95% confidence interval (CI)=0.04-0.81, P=0.03). Tumours expressing nuclear FOXL2 were also more likely positive for stromal and/or cytoplasmic aromatase (P=0.03 and P=0.008, respectively). In silico analyses revealed binding elements of FOXL2 in promoters 1.3, 11 and 17 of the aromatase gene of which promoter 1.7 was most significant. In conclusion, this is the first study to report that FOXL2 is expressed in breast cancer and correlates with aromatase as well as with clinical outcome. The results further strengthen a possible binding of FOXL2 to aromatase promoter 1.7. Nevertheless, whether FOXL2 is a direct activator of aromatase requires further investigation.

Keywords
breast cancer, forkhead box L2, aromatase, tissue specific promoters, in silico
National Category
Cancer and Oncology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-16840 (URN)10.3892/ijo.2011.923 (DOI)000288581100027 ()21271216 (PubMedID)2-s2.0-79952329924 (Scopus ID)
Available from: 2011-09-02 Created: 2011-09-02 Last updated: 2018-05-03Bibliographically approved
Löf-Ohlin, Z. M., Sorbe, B., Wingren, S. & Nilsson, T. K. (2011). Hypermethylation of promoter regions of the APC1A and p16(INK4a) genes in relation to prognosis and tumor characteristics in cervical cancer patients. International Journal of Oncology, 39(3), 683-688
Open this publication in new window or tab >>Hypermethylation of promoter regions of the APC1A and p16(INK4a) genes in relation to prognosis and tumor characteristics in cervical cancer patients
2011 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 39, no 3, p. 683-688Article in journal (Refereed) Published
Abstract [en]

Hypermethylation of the O(6)-MGMT, p14(ARF), p16(INK4a), RASSFIA and APC1A genes are unfavourable prognostic markers in colorectal cancer (CRC). We hypothesized that they could be related to prognosis also in cervical cancer. Methylation was studied in DNA extracts from surgical specimens of cancer tissue by novel pyrosequencing methods. In 109 patients (90 squamous cell carcinomas, 19 adenocarcinomas), we found that hypermethylation of the APC1A gene promoter occurred in 8.3% of patients, and of p16(INK4a) in 1.8%. APC1A hypermethylation was significantly related to more advanced FIGO stage of the tumor (P=0.013), larger tumor diameter (P=0.049) and distant recurrence-free survival (P=0.0007), but not with locoregional recurrence rate, age, HPV status, DNA ploidy, tumor grade or malignancy grading score. We conclude that methylation of the APC1A promoter in cervical cancer, as diagnosed by pyrosequencing, is significantly related to major biological characteristics of the tumor, and may be a new predictor of poor prognosis in cervical cancer.

National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-18651 (URN)10.3892/ijo.2011.1078 (DOI)000293492900018 ()
Available from: 2011-09-30 Created: 2011-09-29 Last updated: 2017-12-08Bibliographically approved
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