Publications by authors named "Elisabeth Wik"

55 Publications

Tumor-associated lymphocytes and macrophages are related to stromal elastosis and vascular invasion in breast cancer.

J Pathol Clin Res 2021 Sep 2;7(5):517-527. Epub 2021 Jun 2.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

The tumor microenvironment plays a critical role in breast cancer progression. Here, we investigated tumor-infiltrating lymphocytes (TILs) and associations with macrophage numbers, tumor stromal elastosis, vascular invasion, and tumor detection mode. We performed a population-based retrospective study using data from The Norwegian Breast Cancer Screening Program in Vestfold County (2004-2009), including 200 screen-detected and 82 interval cancers. The number of TILs (CD45+, CD3+, CD4+, CD8+, and FOXP3+) and tumor-associated macrophages (CD163+) was counted using immunohistochemistry on tissue microarray slides. Lymphatic and blood vessel invasion (LVI and BVI) were recorded using D2-40 and CD31 staining, and the amount of elastosis (high/low) was determined on regular HE-stained slides. High numbers of all TIL subsets were associated with LVI (p ≤ 0.04 for all), and high counts of several TIL subgroups (CD8+, CD45+, and FOXP3+) were associated with BVI (p ≤ 0.04 for all). Increased levels of all TIL subsets, except CD4+, were associated with estrogen receptor-negative tumors (p < 0.001) and high tumor cell proliferation by Ki67 (p < 0.001). Furthermore, high levels of all TIL subsets were associated with high macrophage counts (p < 0.001) and low-grade stromal elastosis (p ≤ 0.02). High counts of CD3+, CD8+, and FOXP3+ TILs were associated with interval detected tumors (p ≤ 0.04 for all). Finally, in the luminal A subgroup, high levels of CD3+ and FOXP3+ TILs were associated with shorter recurrence-free survival, and high counts of FOXP3+ were linked to reduced breast cancer-specific survival. In conclusion, higher levels of different TIL subsets were associated with stromal features such as high macrophage counts (CD163+), presence of vascular invasion, absence of stromal elastosis, as well as increased tumor cell proliferation and interval detection mode. Our findings support a link between immune cells and vascular invasion in more aggressive breast cancer. Notably, presence of TIL subsets showed prognostic value within the luminal A category.
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http://dx.doi.org/10.1002/cjp2.226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363927PMC
September 2021

Fibulin-2 expression associates with vascular invasion and patient survival in breast cancer.

PLoS One 2021 9;16(4):e0249767. Epub 2021 Apr 9.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.

Stromal elastosis is related to good prognosis in breast cancer and fibulin-2 helps to stabilize elastic fibers in basement membranes. Here, we examined the level of perivascular fibulin-2 expression in relation to elastosis content, vascular invasion, molecular subtypes, tumour detection mode, and patient prognosis in breast cancer. We performed a population based retrospective study of invasive breast cancers from the Norwegian Breast Screening Program (Vestfold County, 2004-2009) including 200 screen-detected and 82 interval cancers. Perivascular fibulin-2 staining was semi-quantitatively graded based on immunohistochemistry (1-3) and dichotomized as high expression (grade 2-3) and low expression (grade 1). Elastosis content was graded on a 4-tiered scale and dichotomized as high (score 3) and low (score 0-2) expression, whereas lymphatic (LVI) and blood vessel invasion (BVI) were recorded as absent or present by immunohistochemistry. High perivascular fibulin-2 expression was strongly related to stromal elastosis (p<0.001), and inversely associated with BVI and LVI (p<0.001 for both). High fibulin-2 was associated with luminal breast cancer subgroups (p<0.001) and inversely with interval cancers compared with screen-detected tumours (p<0.001). By univariate analysis, low perivascular fibulin-2 was associated with reduced recurrence-free survival (p = 0.002) and disease specific survival (p = 0.019). Low perivascular fibulin-2 expression was strongly related to vascular invasion, low stromal elastosis, non-luminal breast cancer subtypes, interval presentation, and adverse prognosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249767PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034712PMC
October 2021

Baseline microvessel density predicts response to neoadjuvant bevacizumab treatment of locally advanced breast cancer.

Sci Rep 2021 Feb 9;11(1):3388. Epub 2021 Feb 9.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, Haukeland University Hospital, University of Bergen, Bergen, Norway.

A subset of breast cancer patients benefits from preoperative bevacizumab and chemotherapy, but validated predictive biomarkers are lacking. Here, we aimed to evaluate tissue-based angiogenesis markers for potential predictive value regarding response to neoadjuvant bevacizumab treatment in breast cancer. In this randomized 1:1 phase II clinical trial, 132 patients with large or locally advanced HER2-negative tumors received chemotherapy ± bevacizumab. Dual Factor VIII/Ki-67 immunohistochemical staining was performed on core needle biopsies at baseline and week 12. Microvessel density (MVD), proliferative microvessel density (pMVD; Factor VIII/Ki-67 co-expression), glomeruloid microvascular proliferation (GMP), and a gene expression angiogenesis signature score, were studied in relation to pathologic complete response (pCR), clinico-pathologic features and intrinsic molecular subtype. We found that high baseline MVD (by median) significantly predicted pCR in the bevacizumab-arm (odds ratio 4.9, P = 0.012). High pMVD, presence of GMP, and the angiogenesis signature score did not predict pCR, but were associated with basal-like (P ≤ 0.009) and triple negative phenotypes (P ≤ 0.041). pMVD and GMP did also associate with high-grade tumors (P ≤ 0.048). To conclude, high baseline MVD significantly predicted response to bevacizumab treatment. In contrast, pMVD, GMP, and the angiogenesis signature score, did not predict response, but associated with aggressive tumor features, including basal-like and triple-negative phenotypes.
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http://dx.doi.org/10.1038/s41598-021-81914-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873274PMC
February 2021

Stathmin expression associates with vascular and immune responses in aggressive breast cancer subgroups.

Sci Rep 2020 02 19;10(1):2914. Epub 2020 Feb 19.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, N-5021, Norway.

Studies indicate that stathmin expression associates with PI3K activation in breast cancer, suggesting stathmin as a marker for targetable patient subgroups. Here we assessed stathmin in relation to tumour proliferation, vascular and immune responses, BRCA1 germline status, basal-like differentiation, clinico-pathologic features, and survival. Immunohistochemical staining was performed on breast cancers from two series (cohort 1, n = 187; cohort 2, n = 198), and mass spectrometry data from 24 cases and 12 breast cancer cell lines was examined for proteomic profiles. Open databases were also explored (TCGA, METABRIC, Oslo2 Landscape cohort, Cancer Cell Line Encyclopedia). High stathmin expression associated with tumour proliferation, p53 status, basal-like differentiation, BRCA1 genotype, and high-grade histology. These patterns were confirmed using mRNA data. Stathmin mRNA further associated with tumour angiogenesis, immune responses and reduced survival. By logistic regression, stathmin protein independently predicted a BRCA1 genotype (OR 10.0, p = 0.015) among ER negative tumours. Cell line analysis (Connectivity Map) implied PI3K inhibition in tumours with high stathmin. Altogether, our findings indicate that stathmin might be involved in the regulation of tumour angiogenesis and immune responses in breast cancer, in addition to tumour proliferation. Cell data point to potential effects of PI3K inhibition in tumours with high stathmin expression.
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http://dx.doi.org/10.1038/s41598-020-59728-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031232PMC
February 2020

MRPS23 amplification and gene expression in breast cancer; association with proliferation and the non-basal subtypes.

Breast Cancer Res Treat 2020 Feb 16;180(1):73-86. Epub 2020 Jan 16.

Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Erling Skjalgssons gate, 7030, Trondheim, Norway.

Purpose: MRPS23 is recognized as a driver of proliferation in luminal breast cancer. The aims of the present study were to describe MRPS23 copy number change in breast cancer, and to assess associations between MRPS23 copy number change and molecular subtype, proliferation and prognosis, and between MRPS23 gene expression and molecular subtype and prognosis.

Methods: Using fluorescence in situ hybridization (FISH), we examined MRPS23 and centromere 17 copy number in 590 formalin-fixed, paraffin-embedded primary tumours and 144 corresponding lymph node metastases from a cohort of Norwegian breast cancer patients. Furthermore, we analysed MRPS23 gene expression data in 1971 primary breast cancer tumours from the METABRIC dataset. We used Pearson's χ test to assess associations between MRPS23 copy number and molecular subtype and proliferation, and between MRPS23 expression and molecular subtype. We studied prognosis by estimating hazard ratios and cumulative incidence of death from breast cancer according to MRPS23 copy number and MRPS23 expression status.

Results: We found MRPS23 amplification (mean MRPS23 copy number ≥ 6 and/or MRPS23/chromosome 17 ratio ≥ 2) in 8% of primary tumours. Copy number increase associated with non-basal subtypes and higher tumour cell proliferation (Ki67). Higher MRPS23 expression associated with the Luminal B subtype. We found no significant association between MRPS23 amplification or MRSP23 gene expression, and prognosis.

Conclusion: Amplification of MRPS23 is associated with higher proliferation and non-basal subtypes in breast cancer. High MRPS23 expression is associated with the Luminal B subtype.
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http://dx.doi.org/10.1007/s10549-020-05532-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031208PMC
February 2020

Integrin α11β1 is expressed in breast cancer stroma and associates with aggressive tumor phenotypes.

J Pathol Clin Res 2020 01 3;6(1):69-82. Epub 2019 Dec 3.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

Cancer-associated fibroblasts are essential modifiers of the tumor microenvironment. The collagen-binding integrin α11β1 has been proposed to be upregulated in a pro-tumorigenic subtype of cancer-associated fibroblasts. Here, we analyzed the expression and clinical relevance of integrin α11β1 in a large breast cancer series using a novel antibody against the human integrin α11 chain. Several novel monoclonal antibodies against the integrin α11 subunit were tested for use on formalin-fixed paraffin-embedded tissues, and Ab 210F4B6A4 was eventually selected to investigate the immunohistochemical expression in 392 breast cancers using whole sections. mRNA data from METABRIC and co-expression patterns of integrin α11 in relation to αSMA and cytokeratin-14 were also investigated. Integrin α11 was expressed to varying degrees in spindle-shaped cells in the stroma of 99% of invasive breast carcinomas. Integrin α11 co-localized with αSMA in stromal cells, and with αSMA and cytokeratin-14 in breast myoepithelium. High stromal integrin α11 expression (66% of cases) was associated with aggressive breast cancer features such as high histologic grade, increased tumor cell proliferation, ER negativity, HER2 positivity, and triple-negative phenotype, but was not associated with breast cancer specific survival at protein or mRNA levels. In conclusion, high stromal integrin α11 expression was associated with aggressive breast cancer phenotypes.
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http://dx.doi.org/10.1002/cjp2.148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966706PMC
January 2020

Amplification Associates with Aggressive Phenotype but Not Markers of AKT-MTOR Signaling in Endometrial Carcinoma.

Clin Cancer Res 2019 01 15;25(1):334-345. Epub 2018 Nov 15.

Center for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.

Purpose: Amplification of , encoding the PI3K catalytic subunit alpha, is common in uterine corpus endometrial carcinoma (UCEC) and linked to an aggressive phenotype. However, it is unclear whether amplification acts via PI3K activation. We investigated the association between amplification, markers of PI3K activity, and prognosis in a large cohort of UCEC specimens.

Experimental Design: UCECs from 591 clinically annotated patients including 83 tumors with matching metastasis ( = 188) were analyzed by FISH to determine copy-number status. These data were integrated with mRNA and protein expression and clinicopathologic data. Results were verified in The Cancer Genome Atlas dataset.

Results: amplifications were associated with disease-specific mortality and with other markers of aggressive disease. amplifications were also associated with other amplifications characteristic of the serous-like somatic copy-number alteration (SCNA)-high subgroup of UCEC. Tumors with amplification also demonstrated an increase in phospho-p70S6K but had decreased levels of activated phospho-AKT1-3 as assessed by Reverse Phase Protein Arrays and an mRNA signature of MTOR inhibition.

Conclusions: amplification is a strong prognostic marker and a potential marker for the aggressive SCNA-high subgroup of UCEC. Although amplification associates with some surrogate measures of increased PI3K activity, markers for AKT1-3 and MTOR signaling are decreased, suggesting that this signaling is not a predominant pathway to promote cancer growth of aggressive serous-like UCEC. Moreover, these associations may reflect features of the SCNA-high subgroup of UCEC rather than effects of amplification itself.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384094PMC
January 2019

Deblender: a semi-/unsupervised multi-operational computational method for complete deconvolution of expression data from heterogeneous samples.

BMC Bioinformatics 2018 Nov 7;19(1):408. Epub 2018 Nov 7.

Centre for Cancer Biomarkers CCBIO, Department of Informatics, University of Bergen, Bergen, Norway.

Background: Towards discovering robust cancer biomarkers, it is imperative to unravel the cellular heterogeneity of patient samples and comprehend the interactions between cancer cells and the various cell types in the tumor microenvironment. The first generation of 'partial' computational deconvolution methods required prior information either on the cell/tissue type proportions or the cell/tissue type-specific expression signatures and the number of involved cell/tissue types. The second generation of 'complete' approaches allowed estimating both of the cell/tissue type proportions and cell/tissue type-specific expression profiles directly from the mixed gene expression data, based on known (or automatically identified) cell/tissue type-specific marker genes.

Results: We present Deblender, a flexible complete deconvolution tool operating in semi-/unsupervised mode based on the user's access to known marker gene lists and information about cell/tissue composition. In case of no prior knowledge, global gene expression variability is used in clustering the mixed data to substitute marker sets with cluster sets. In addition, we integrate a model selection criterion to predict the number of constituent cell/tissue types. Moreover, we provide a tailored algorithmic scheme to estimate mixture proportions for realistic experimental cases where the number of involved cell/tissue types exceeds the number of mixed samples. We assess the performance of Deblender and a set of state-of-the-art existing tools on a comprehensive set of benchmark and patient cancer mixture expression datasets (including TCGA).

Conclusion: Our results corroborate that Deblender can be a valuable tool to improve understanding of gene expression datasets with implications for prediction and clinical utilization. Deblender is implemented in MATLAB and is available from ( https://github.com/kondim1983/Deblender/ ).
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http://dx.doi.org/10.1186/s12859-018-2442-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223087PMC
November 2018

Identification of highly connected and differentially expressed gene subnetworks in metastasizing endometrial cancer.

PLoS One 2018 1;13(11):e0206665. Epub 2018 Nov 1.

Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.

We have identified nine highly connected and differentially expressed gene subnetworks between aggressive primary tumors and metastatic lesions in endometrial carcinomas. We implemented a novel pipeline combining gene set and network approaches, which here allows integration of protein-protein interactions and gene expression data. The resulting subnetworks are significantly associated with disease progression across tumor stages from complex atypical hyperplasia, primary tumors to metastatic lesions. The nine subnetworks include genes related to metastasizing features such as epithelial-mesenchymal transition (EMT), hypoxia and cell proliferation. TCF4 and TWIST2 were found as central genes in the subnetwork related to EMT. Two of the identified subnetworks display statistically significant association to patient survival, which were further supported by an independent validation in the data from The Cancer Genome Atlas data collection. The first subnetwork contains genes related to cell proliferation and cell cycle, while the second contains genes involved in hypoxia such as HIF1A and EGLN3. Our findings provide a promising context to elucidate the biological mechanisms of metastasis, suggest potential prognostic markers and further identify therapeutic targets. The pipeline R source code is freely available, including permutation tests to assess statistical significance of the identified subnetworks.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206665PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211718PMC
April 2019

Transient elevation of anti-transglutaminase and anti-endomysium antibodies in Giardia infection.

Scand J Gastroenterol 2018 Jun - Jul;53(7):809-812. Epub 2018 Jun 16.

e National Centre of Functional Gastrointestinal Disorders, Section of Gastroenterology, Department of Medicine , Haukeland University Hospital , Bergen , Norway.

Markers of celiac disease (CeD) may be elevated in various conditions of intestinal inflammation or autoimmune disease. Recent reports argue that intestinal infection may induce development of CeD in susceptible individuals. Serum anti-tissue transglutaminase (tTG) and anti-endomysium antibodies (EMA) have been proposed in previous reports to be helpful in differentiating between giardiasis and CeD. In this report, we describe eight cases with elevated CeD serological markers and pathological duodenal histology during, or shortly after, Giardia infection. We present follow-up clinical and serological findings to determine which of these that were diagnosed with CeD. Serum levels of tTGand EMA did not discriminate well between patients where CeD was excluded, and those who were later diagnosed with CeD. The value of these serological CeD markers is discussed in relation to CeD diagnosis in cases with chronic or recent giardiasis.
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http://dx.doi.org/10.1080/00365521.2018.1481522DOI Listing
November 2018

Tumor-associated macrophages are strongly related to vascular invasion, non-luminal subtypes, and interval breast cancer.

Hum Pathol 2017 11 18;69:72-80. Epub 2017 Sep 18.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, 5021, Bergen, Norway; Department of Pathology, Haukeland University Hospital, 5021, Bergen, Norway. Electronic address:

Tumor-associated macrophages (TAM) resemble M2 macrophages, promote tumor invasion and show strong expression of CD163 in breast cancer. We here investigated the association between CD163-positive macrophages and vascular invasion, molecular subgroups, mode of detection, and patient outcome. We performed a population-based, retrospective study of invasive breast cancer from the Norwegian Breast Cancer Screening Programme in Vestfold County (2004-2009), including 200 screen-detected and 82 interval cancers. Immunohistochemically CD163-positive macrophages were counted in the most active areas (hotspots) and dichotomized as high (upper quartile) and low counts. Lymphatic vessel involvement (LVI) and blood vessel invasion (BVI) were recorded separately based on immunohistochemical staining (D2-40 and CD31 antibodies). High levels of CD163-positive macrophages were associated with BVI and lymphatic involvement as well as interval cancer detection when compared to screening-detected tumors. In addition, the presence of high CD163+ TAM levels was more often observed in HER2-positive, basal-like and Triple-negative breast cancers and was associated with several features of aggressive tumors. In survival analyses, cases with combined high CD163 counts and BVI showed a significantly reduced recurrence-free survival (RFS) and disease-specific survival (DSS) (P < .001 for both) compared with all other cases. The presence of CD163-positive, tumor-associated macrophages is strongly related to aggressive features of breast cancer such as vessel invasion, detection between screening intervals, non-luminal molecular subgroups and reduced survival.
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http://dx.doi.org/10.1016/j.humpath.2017.09.001DOI Listing
November 2017

C77G in PTPRC (CD45) is no risk allele for ovarian cancer, but associated with less aggressive disease.

PLoS One 2017 31;12(7):e0182030. Epub 2017 Jul 31.

Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.

The pan lymphocyte marker CD45 exists in various isoforms arising from alternative splicing of the exons 4, 5 and 6. While naïve T cells express CD45RA translated from an mRNA containing exon 4, exons 4-6 are spliced out to encode the shorter CD45R0 in antigen-experienced effector/memory T cells. The SNP C77G (rs17612648) is located in exon 4 and blocks the exon's differential splicing from the pre-mRNA, enforcing expression of CD45RA. Several studies have linked C77G to autoimmune diseases but lack of validation in other cohorts has left its role elusive. An incidental finding in an ovarian cancer patient cohort from West Norway (Bergen region, n = 312), suggested that the frequency of C77G was higher among ovarian cancer patients than in healthy Norwegians (n = 1,357) (3.0% vs. 1.8% allele frequency). However, this finding could not be validated in a larger patient cohort from South-East Norway (Oslo region, n = 1,198) with 1.2% allele frequency. Hence, C77G is not associated with ovarian cancer in the Norwegian population. However, its frequency was increased in patients with FIGO stage II, endometrioid histology or an age at diagnosis of 60 years or older indicating a possible association with a less aggressive cancer type.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182030PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536273PMC
September 2017

Expression of Nestin associates with BRCA1 mutations, a basal-like phenotype and aggressive breast cancer.

Sci Rep 2017 04 24;7(1):1089. Epub 2017 Apr 24.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.

We here examined whether Nestin, by protein and mRNA levels, could be a predictor of BRCA1 related breast cancer, a basal-like phenotype, and aggressive tumours. Immunohistochemical staining of Nestin was done in independent breast cancer hospital cohorts (Series I-V, total 1257 cases). Also, TCGA proteomic data (n = 103), mRNA microarray data from TCGA (n = 520), METABRIC (n = 1992), and 6 open access breast cancer datasets (n = 1908) were analysed. Patients with Nestin protein expression in tumour cells more often had BRCA1 germline mutations (OR 8.7, p < 0.0005, Series III), especially among younger patients (<40 years at diagnosis) (OR 16.5, p = 0.003). Nestin protein positivity, observed in 9-28% of our hospital cases (Series I-IV), was independently associated with reduced breast cancer specific survival (HR = 2.0, p = 0.035) and was consistently related to basal-like differentiation (by Cytokeratin 5, OR 8.7-13.8, p < 0.0005; P-cadherin OR 7.0-8.9, p < 0.0005; EGFR staining, OR 3.7-8.2, p ≤ 0.05). Nestin mRNA correlated significantly with Nestin protein expression (ρ = 0.6, p < 0.0005), and high levels were seen in the basal-like intrinsic subtype. Gene expression signalling pathways linked to high Nestin were explored, and revealed associations with stem-like tumour features. In summary, Nestin was strongly associated with germline BRCA1 related breast cancer, a basal-like phenotype, reduced survival, and stemness characteristics.
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http://dx.doi.org/10.1038/s41598-017-00862-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430803PMC
April 2017

Extra-nodal extension is a significant prognostic factor in lymph node positive breast cancer.

PLoS One 2017 15;12(2):e0171853. Epub 2017 Feb 15.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.

Presence of lymph node (LN) metastasis is a strong prognostic factor in breast cancer, whereas the importance of extra-nodal extension and other nodal tumor features have not yet been fully recognized. Here, we examined microscopic features of lymph node metastases and their prognostic value in a population-based cohort of node positive breast cancer (n = 218), as part of the prospective Norwegian Breast Cancer Screening Program NBCSP (1996-2009). Sections were reviewed for the largest metastatic tumor diameter (TD-MET), nodal afferent and efferent vascular invasion (AVI and EVI), extra-nodal extension (ENE), number of ENE foci, as well as circumferential (CD-ENE) and perpendicular (PD-ENE) diameter of extra-nodal growth. Number of positive lymph nodes, EVI, and PD-ENE were significantly increased with larger primary tumor (PT) diameter. Univariate survival analysis showed that several features of nodal metastases were associated with disease-free (DFS) or breast cancer specific survival (BCSS). Multivariate analysis demonstrated an independent prognostic value of PD-ENE (with 3 mm as cut-off value) in predicting DFS and BCSS, along with number of positive nodes and histologic grade of the primary tumor (for DFS: P = 0.01, P = 0.02, P = 0.01, respectively; for BCSS: P = 0.02, P = 0.008, P = 0.02, respectively). To conclude, the extent of ENE by its perpendicular diameter was independently prognostic and should be considered in line with nodal tumor burden in treatment decisions of node positive breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171853PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310784PMC
August 2017

Aneuploidy related transcriptional changes in endometrial cancer link low expression of chromosome 15q genes to poor survival.

Oncotarget 2017 Feb;8(6):9696-9707

Center for Cancer Biomarkers CCBIO, Department of Clinical Science (K2), University of Bergen, Bergen, Norway.

Aneuploidy is a widely studied prognostic marker in endometrial cancer (EC), however, not implemented in clinical decision-making. It lacks validation in large prospective patient cohorts adjusted for currently standard applied prognostic markers, including estrogen/progesterone receptor status (ER/PR). Also, little is known about aneuploidy-related transcriptional alterations, relevant for understanding its role in EC biology, and as therapeutic target.We included 825 EC patients with available ploidy status and comprehensive clinicopathologic characterization to analyze ploidy as a prognostic marker. For 144 patients, gene expression data were available to explore aneuploidy-related transcriptional alterations.Aneuploidy was associated with high age, FIGO stage and grade, non-endometrioid histology, ER/PR negativity, and poor survival (p-values<0.001). In patients with ER/PR negative tumors, aneuploidy independently predicted poor survival (p=0.03), lymph node metastasis (p=0.007) and recurrence (p=0.002). A prognostic 'aneuploidy signature', linked to low expression of chromosome 15q genes, was identified and validated in TCGA data.In conclusion, aneuploidy adds prognostic information in ER/PR negative EC, identifying high-risk patients that could benefit from more aggressive therapies. The 'aneuploidy signature' equally identifies these aggressive tumors and suggests a link between aneuploidy and low expression of 15q genes. Integrated analyses point at various dysregulated pathways in aneuploid EC, underlining a complex biology.
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http://dx.doi.org/10.18632/oncotarget.14201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354764PMC
February 2017

Tumour cell invasion into blood vessels is significantly related to breast cancer subtypes and decreased survival.

J Clin Pathol 2017 Apr 9;70(4):313-319. Epub 2016 Sep 9.

Department of Clinical Medicine, Section for Pathology and Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway.

Aims: Vascular invasion in breast cancer is associated with increased risk of recurrence, metastases and death from disease. However, there are few studies discriminating between blood vessel invasion (BVI) and lymphatic vessel involvement (LVI).

Methods: A population-based series of 282 breast cancers was examined (200 screen-detected and 82 interval patients) with respect to BVI and LVI in addition to basic features and molecular subtypes, using CD31 and D2-40 antibodies. This series is part of the prospective Norwegian Breast Cancer Screening Program.

Results: The frequency of LVI and BVI was 25% and 15%, respectively. BVI was associated with HER2-positive and basal-like tumours, and several features of aggressive breast cancer, whereas LVI showed weaker associations. BVI was the strongest factor to predict interval cancer presentation. BVI showed significant associations with recurrence-free survival and disease-specific survival in univariate and multivariate analyses, whereas LVI was not significant.

Conclusions: Our findings indicate that BVI by tumour cells is strongly associated with aggressive tumour features including a basal-like phenotype, and BVI was an independent prognostic factor in contrast to what was found for LVI.
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http://dx.doi.org/10.1136/jclinpath-2016-203861DOI Listing
April 2017

Evaluation of Tumor Cell Proliferation by Ki-67 Expression and Mitotic Count in Lymph Node Metastases from Breast Cancer.

PLoS One 2016 8;11(3):e0150979. Epub 2016 Mar 8.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.

Few studies have addressed the risk of recurrence by assessing proliferation markers in lymph node metastasis from breast cancer. Here, we aimed to examine Ki-67 expression and mitotic count in lymph nodes in comparison with primary tumors. A cohort of node positive breast cancer (n = 168) was studied as a part of the prospective Norwegian Breast Cancer Screening Program (1996-2009). The percentage of Ki-67 positivity was counted per 500 tumor cells in hot-spot areas (x630). Mitotic count was conducted in the most cellular and mitotic active areas in 10 high power fields (x400). Our results showed that Ki-67 and mitotic count were significantly correlated between primary tumor and lymph nodes (Spearman`s correlation 0. 56 and 0.46, respectively) and were associated with most of the histologic features of the primary tumor. Univariate survival analysis (log-rank test) showed that high Ki-67 and mitotic count in the primary tumor and lymph node metastasis significantly predicted risk of recurrence. In multivariate analysis, mitotic count in the lymph node metastasis was an independent predictor of tumor recurrence. In conclusion, proliferation markers in lymph node metastases significantly predicted disease free survival in node positive breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150979PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783103PMC
August 2016

Intra-Gene DNA Methylation Variability Is a Clinically Independent Prognostic Marker in Women's Cancers.

PLoS One 2015 2;10(12):e0143178. Epub 2015 Dec 2.

Department of Women's Cancer, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom.

We introduce a novel per-gene measure of intra-gene DNA methylation variability (IGV) based on the Illumina Infinium HumanMethylation450 platform, which is prognostic independently of well-known predictors of clinical outcome. Using IGV, we derive a robust gene-panel prognostic signature for ovarian cancer (OC, n = 221), which validates in two independent data sets from Mayo Clinic (n = 198) and TCGA (n = 358), with significance of p = 0.004 in both sets. The OC prognostic signature gene-panel is comprised of four gene groups, which represent distinct biological processes. We show the IGV measurements of these gene groups are most likely a reflection of a mixture of intra-tumour heterogeneity and transcription factor (TF) binding/activity. IGV can be used to predict clinical outcome in patients individually, providing a surrogate read-out of hard-to-measure disease processes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143178PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667934PMC
June 2016

HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer.

Genome Med 2015 Oct 24;7:108. Epub 2015 Oct 24.

Department of Women's Cancer, UCL Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK.

Background: Understanding carboplatin resistance in ovarian cancer is critical for the improvement of patients' lives. Multipotent mesenchymal stem cells or an aggravated epithelial to mesenchymal transition phenotype of a cancer are integrally involved in pathways conferring chemo-resistance. Long non-coding RNA HOTAIR (HOX transcript antisense intergenic RNA) is involved in mesenchymal stem cell fate and cancer biology.

Methods: We analyzed HOTAIR expression and associated surrogate DNA methylation (DNAme) in 134 primary ovarian cancer cases (63 received carboplatin, 55 received cisplatin and 16 no chemotherapy). We validated our findings by HOTAIR expression and DNAme analysis in a multicentre setting of five additional sets, encompassing 946 ovarian cancers. Chemo-sensitivity has been assessed in cell culture experiments.

Results: HOTAIR expression was significantly associated with poor survival in carboplatin-treated patients with adjusted hazard ratios for death of 3.64 (95 % confidence interval [CI] 1.78-7.42; P < 0.001) in the discovery and 1.63 (95 % CI 1.04-2.56; P = 0.032) in the validation set. This effect was not seen in patients who did not receive carboplatin (0.97 [95 % CI 0.52-1.80; P = 0.932]). HOTAIR expression or its surrogate DNAme signature predicted poor outcome in all additional sets of carboplatin-treated ovarian cancer patients while HOTAIR expressors responded preferentially to cisplatin (multivariate interaction P = 0.008).

Conclusions: Non-coding RNA HOTAIR or its more stable DNAme surrogate may indicate the presence of a subset of cells which confer resistance to carboplatin and can serve as (1) a marker to personalise treatment and (2) a novel target to overcome carboplatin resistance.
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http://dx.doi.org/10.1186/s13073-015-0233-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619324PMC
October 2015

Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses.

Oncotarget 2015 Nov;6(37):39676-91

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.

Aims: Tumor necrosis is associated with aggressive features of endometrial cancer and poor prognosis. Here, we investigated gene expression patterns and potential treatment targets related to presence of tumor necrosis in primary endometrial cancer lesions.

Methods And Results: By DNA microarray analysis, expression of genes related to tumor necrosis reflected multiple tumor-microenvironment interactions like tissue hypoxia, angiogenesis and inflammation pathways. A tumor necrosis signature of 38 genes and a related patient cluster (Cluster I, 67% of the cases) were associated with features of aggressive tumors such as type II cancers, estrogen receptor negative tumors and vascular invasion. Further, the tumor necrosis signature was increased in tumor cells grown in hypoxic conditions in vitro. Multiple genes with increased expression are known to be activated by HIF1A and NF-kB.

Conclusions: Our findings indicate that the presence of tumor necrosis within primary tumors is associated with hypoxia, angiogenesis and inflammation responses. HIF1A, NF-kB and PI3K/mTOR might be potential treatment targets in aggressive endometrial cancers with presence of tumor necrosis.
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http://dx.doi.org/10.18632/oncotarget.5344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741854PMC
November 2015

Increased angiogenesis is associated with a 32-gene expression signature and 6p21 amplification in aggressive endometrial cancer.

Oncotarget 2015 Apr;6(12):10634-45

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, Section for Pathology, University of Bergen, Bergen, Norway.

Background: Angiogenesis is a hallmark of cancer. The aim of this study was to explore whether microvessel proliferation is associated with gene expression profiles or copy number alterations in endometrial cancer.

Methods: A prospective series of endometrial carcinomas was studied for angiogenesis markers, gene expression profiles, and gene copy number data. For validation, an independent series of endometrial carcinomas as well as an external cohort of endometrial cancer patients were examined by gene expression microarrays.

Results: Increased microvessel proliferation (MVP) was associated with aggressive tumor features and reduced survival, and a 32-gene expression signature was found to separate tumors with high versus low MVP. An increased 32-gene signature score was confirmed to associate with high-grade tumor features and reduced survival by independent cohorts. Copy number studies revealed that amplification of the 6p21 region was significantly associated with MVP, a high 32-gene score, as well as reduced survival.

Conclusion: Increased MVP was significantly associated with aggressive endometrial cancer and reduced survival. Integrated analyses demonstrated significant associations between increased vascular proliferation, amplification of the 6p21 region, VEGF-A mRNA expression, and the 32-gene angiogenesis signature. Our findings indicate amplification of 6p21 as a possible driver of tumor vascular proliferation in endometrial cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496381PMC
http://dx.doi.org/10.18632/oncotarget.3521DOI Listing
April 2015

Breast cancer stromal elastosis is associated with mammography screening detection, low Ki67 expression and favourable prognosis in a population-based study.

Diagn Pathol 2014 Dec 19;9:230. Epub 2014 Dec 19.

Department of Pathology, Oslo University Hospital, 0424, Oslo, Norway.

Background: Mammography screen-detected breast cancers have a better prognosis than predicted from established prognostic markers. A search for additional features that are characteristic for these tumours and their prognosis is needed to reduce overtreatment, a recognized challenge in breast cancer patient management today. Here, we have investigated the occurrence and importance of tumour elastosis.

Methods: We performed a population based retrospective study of breast cancers detected in the Norwegian Breast Cancer Screening Programme in Vestfold County during 2004-2009. In total, 197 invasive screen-detected cancers and 75 interval cancers in patients aged 50-69 years were compared with regard to standard clinico-pathological parameters and tumour shape, as well as ER, PR, HER2 and Ki67 expression. In particular, the presence of elastotic material in tumours was graded on a 4-tiered scale (score 0-3).

Results: Screen-detected cancers had a significantly higher content of stromal elastosis than interval cancers (p < 0.001). High content of elastosis (score 3) correlated strongly with stellate tumour shape, low histological grade, and ER+/HER2- status. Further, high elastosis score was significantly associated with lower Ki67 expression. In survival analyses, cases with high elastosis demonstrated increased recurrence free (p = 0.03) and disease-specific survival (p = 0.11) compared to cases with low elastosis.

Conclusion: There is a strong correlation between the presence of tumour elastosis, stellate tumour shape and mammography detection of breast cancers. To our knowledge, this is the first time elastosis has been studied in relation to breast cancer detection method. Presence of elastosis is associated with low tumour cell proliferation (Ki67) and a good prognosis.

Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_230.
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http://dx.doi.org/10.1186/s13000-014-0230-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300053PMC
December 2014

Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients.

Oncotarget 2015 Jan;6(2):1327-39

Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway.Department of Gynecology and Obstetrics, Haukeland University Hospital, Norway.

Obesity is linked to increased incidence of endometrioid endometrial cancer (EEC) and complex atypical hyperplasia (CAH). We here explore pattern and sequence of molecular alterations characterizing endometrial carcinogenesis in general and related to body mass index (BMI), to improve diagnostic stratification and treatment strategies. We performed molecular characterization of 729 prospectively collected EEC and CAH. Candidate biomarkers were identified in frozen samples by whole-exome and Sanger sequencing, oligonucleotide gene expression and Reverse Phase Protein Arrays (investigation cohort) and further explored in formalin fixed tissues by immunohistochemistry and Fluorescent in Situ Hybridization (validation cohort). We here demonstrate that PIK3CA mutations, PTEN loss, PI3K and KRAS activation are early events in endometrial carcinogenesis. Molecular changes related to KRAS activation and inflammation are more common in obese CAH patients, suggesting different prevention and systemic treatment strategies in obese and non-obese patients. We also found that oncoprotein Stathmin might improve preoperative diagnostic distinction between premalignant and malignant endometrial lesions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359236PMC
http://dx.doi.org/10.18632/oncotarget.2675DOI Listing
January 2015

Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer.

Mol Cancer 2014 Sep 27;13:223. Epub 2014 Sep 27.

Background: About 20% of patients diagnosed with endometrial cancer (EC) are considered high-risk with unfavorable prognosis. In the framework of the European Network for Individualized Treatment in EC (ENITEC), we investigated the presence and phenotypic features of Circulating Tumor Cells (CTC) in high-risk EC patients.

Methods: CTC isolation was carried out in peripheral blood samples from 34 patients, ranging from Grade 3 Stage IB to Stage IV carcinomas and recurrences, and 27 healthy controls using two methodologies. Samples were subjected to EpCAM-based immunoisolation using the CELLection™ Epithelial Enrich kit (Invitrogen, Dynal) followed by RTqPCR analysis. The phenotypic determinants of endometrial CTC in terms of pathogenesis, hormone receptor pathways, stem cell markers and epithelial to mesenchymal transition (EMT) drivers were asked. Kruskal-Wallis analysis followed by Dunn's post-test was used for comparisons between groups. Statistical significance was set at p < 0.05.

Results: EpCAM-based immunoisolation positively detected CTC in high-risk endometrial cancer patients. CTC characterization indicated a remarkable plasticity phenotype defined by the expression of the EMT markers ETV5, NOTCH1, SNAI1, TGFB1, ZEB1 and ZEB2. In addition, the expression of ALDH and CD44 pointed to an association with stemness, while the expression of CTNNB1, STS, GDF15, RELA, RUNX1, BRAF and PIK3CA suggested potential therapeutic targets. We further recapitulated the EMT phenotype found in endometrial CTC through the up-regulation of ETV5 in an EC cell line, and validated in an animal model of systemic dissemination the propensity of these CTC in the accomplishment of metastasis.

Conclusions: Our results associate the presence of CTC with high-risk EC. Gene-expression profiling characterized a CTC-plasticity phenotype with stemness and EMT features. We finally recapitulated this CTC-phenotype by over-expressing ETV5 in the EC cell line Hec1A and demonstrated an advantage in the promotion of metastasis in an in vivo mouse model of CTC dissemination and homing.
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http://dx.doi.org/10.1186/1476-4598-13-223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190574PMC
September 2014

An 18-gene signature for vascular invasion is associated with aggressive features and reduced survival in breast cancer.

PLoS One 2014 6;9(6):e98787. Epub 2014 Jun 6.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Norway; Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway.

Aims: Vascular invasion by tumor cells is known to be important for cancer progression. By microarray and qPCR analyses, we earlier identified an 18-gene signature associated with vascular involvement in endometrial cancer. Here, we explored the significance of this vascular invasion signature in multiple series of breast cancer patients.

Methods And Results: The study includes 11 open access gene expression data sets which collectively provide information on 2423 breast cancer patients. The 18-gene signature showed consistent associations with aggressive features of breast cancer, like high tumor grade, hormone receptor negativity, HER2 positivity, a basal-like phenotype, reduced patient survival, and response to neoadjuvant chemotherapy. Also, the vascular invasion signature was associated with several other gene expression profiles related to vascular biology and tumor progression, including the Oncotype DX breast cancer recurrence signature.

Conclusions: The 18-gene vascular invasion signature showed strong and consistent associations with aggressive features of breast cancer and reduced survival.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098787PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048217PMC
January 2015

Hypomethylation of the CTCFL/BORIS promoter and aberrant expression during endometrial cancer progression suggests a role as an Epi-driver gene.

Oncotarget 2014 Feb;5(4):1052-61

Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.

Cancers arise through accumulating genetic and epigenetic alterations, considered relevant for phenotype and approaches to targeting new therapies. We investigated a unique collection of endometrial cancer precursor samples and clinically annotated primary and metastatic lesions for two evolutionary and functionally related transcription factors, CCCTC-binding factor (zinc finger protein) (CTCF) and its paralogue CTCF-like factor, also denoted Brother of the Regulator of Imprinted Sites (CTCFL/BORIS). CTCF, a chromatin modeling- and transcription factor, is normally expressed in a ubiquitous fashion, while CTCFL/BORIS is restricted to the testis. In cancer, CTCF is thought to be a tumor suppressor, while CTCFL/BORIS has been suggested as an oncogene. CTCF mutations were identified in 13%, with CTCF hotspot frameshift mutations at p.T204, all observed solely in the endometrioid subtype, but with no association with outcome. Interestingly, CTCFL/BORIS was amongst the top ranked genes differentially expressed between endometrioid and non-endometrioid tumors, and increasing mRNA level of CTCFL/BORIS was highly significantly associated with poor survival. As aberrant CTCFL/BORIS expression might relate to loss of methylation, we explored methylation status in clinical samples from complex atypical hyperplasia, through primary tumors to metastatic lesions, demonstrating a pattern of DNA methylation loss during disease development and progression in line with the increase in CTCFL/BORIS mRNA expression observed. Thus, CTCF and CTCFL/BORIS are found to diverge in the different subtypes of endometrial cancer, with CTCFL/BORIS activation through demethylation from precursors to metastatic lesions. We thus propose, CTCFL/BORIS as an Epi-driver gene in endometrial cancer, suggesting a potential for future vaccine development.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011582PMC
http://dx.doi.org/10.18632/oncotarget.1697DOI Listing
February 2014

Stathmin protein level, a potential predictive marker for taxane treatment response in endometrial cancer.

PLoS One 2014 25;9(2):e90141. Epub 2014 Feb 25.

Centre for Cancer Biomarkers, Department of Clinical Science, The University of Bergen, Bergen, Norway ; Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.

Stathmin is a prognostic marker in many cancers, including endometrial cancer. Preclinical studies, predominantly in breast cancer, have suggested that stathmin may additionally be a predictive marker for response to paclitaxel. We first evaluated the response to paclitaxel in endometrial cancer cell lines before and after stathmin knock-down. Subsequently we investigated the clinical response to paclitaxel containing chemotherapy in metastatic endometrial cancer in relation to stathmin protein level in tumors. Stathmin level was also determined in metastatic lesions, analyzing changes in biomarker status on disease progression. Knock-down of stathmin improved sensitivity to paclitaxel in endometrial carcinoma cell lines with both naturally higher and lower sensitivity to paclitaxel. In clinical samples, high stathmin level was demonstrated to be associated with poor response to paclitaxel containing chemotherapy and to reduced disease specific survival only in patients treated with such combination. Stathmin level increased significantly from primary to metastatic lesions. This study suggests, supported by both preclinical and clinical data, that stathmin could be a predictive biomarker for response to paclitaxel treatment in endometrial cancer. Re-assessment of stathmin level in metastatic lesions prior to treatment start may be relevant. Also, validation in a randomized clinical trial will be important.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090141PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934991PMC
October 2014

Clinical value of DNA content assessment in endometrial cancer.

Cytometry B Clin Cytom 2014 May 14;86(3):154-63. Epub 2014 Feb 14.

Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science (K2), University of Bergen, Bergen, Norway.

Endometrial carcinoma (EC) is the most common gynecologic cancer in industrialized countries. Traditional prognostic markers include FIGO stage, histologic subtype, and histologic grade. DNA ploidy was introduced as a prognostic marker 30 years ago, and the majority of published literature demonstrates significant associations between tumor aneuploidy and poorer prognosis in EC. However, ploidy analysis is not routinely implemented in the clinic. We reviewed the literature on clinical value of ploidy measured by DNA content as a prognostic marker, and its potential role as a predictive marker in EC.  PubMed was searched for papers evaluating the prognostic or predictive role of ploidy in EC. Search criteria were "DNA ploidy prognosis/predictive value endometrial cancer/carcinoma". Only articles written in English, published year 2000 or later were included.  The majority of the studies demonstrated highly significant correlation between DNA index (DI) and survival, in univariate analysis including stages I-IV, and in subgroup analysis of stage I and stage I-II EC. Several studies also showed significant association between DI and survival in multivariate analysis. Few studies have evaluated DI as a prognostic marker in a prospective setting. No studies evaluating DI as a predictive marker in EC were identified. In other cancer types, ploidy has been linked to prediction of response to hormonal therapy and chemotherapy.  Ploidy assessment in EC by DI is a strong prognostic marker. Still, its clinical applicability needs validation in a routine diagnostic, prospective setting with sufficient number of patients, characterized by state of the art histopathological evaluation and surgical staging.
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http://dx.doi.org/10.1002/cyto.b.21164DOI Listing
May 2014

Clinical value of dna content assessment in endometrial cancer.

Cytometry B Clin Cytom 2014 Jan 31. Epub 2014 Jan 31.

Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science (K2), University of Bergen, Bergen, Norway.

Endometrial carcinoma (EC) is the most common gynecologic cancer in industrialized countries. Traditional prognostic markers include FIGO stage, histologic subtype and histologic grade. DNA ploidy was introduced as a prognostic marker 30 years ago, and the majority of published literature demonstrates significant associations between tumor aneuploidy and poorer prognosis in EC. However, ploidy analysis is not routinely implemented in the clinic. We reviewed the literature on clinical value of ploidy measured by DNA content as a prognostic marker, and its potential role as a predictive marker in EC. PubMed was searched for papers evaluating the prognostic or predictive role of ploidy in EC. Search criteria were "DNA ploidy prognosis/predictive value endometrial cancer/carcinoma". Only articles written in English, published year 2000 or later were included. The majority of the studies demonstrated highly significant correlation between DNA index (DI) and survival, in univariate analysis including stages I-IV, and in subgroup analysis of stage I and stage I-II EC. Several studies also showed significant association between DI and survival in multivariate analysis. Few studies have evaluated DI as a prognostic marker in a prospective setting. No studies evaluating DI as a predictive marker in EC were identified. In other cancer types, ploidy has been linked to prediction of response to hormonal therapy and chemotherapy. Ploidy assessment in EC by DI is a strong prognostic marker. Still, its clinical applicability needs validation in a routine diagnostic, prospective setting with sufficient number of patients, characterized by state of the art histopathological evaluation and surgical staging. © 2014 Clinical Cytometry Society.
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http://dx.doi.org/10.1002/cytob.21164DOI Listing
January 2014

Landscape of genomic alterations in cervical carcinomas.

Nature 2014 Feb 25;506(7488):371-5. Epub 2013 Dec 25.

1] Department of Obstetrics and Gynecology, Haukeland University Hospital, N5021 Bergen, Norway [2] Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, N5020 Bergen, Norway.

Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.
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http://dx.doi.org/10.1038/nature12881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161954PMC
February 2014
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