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Djureinovic, Dijana
Publications (10 of 24) Show all publications
Biswas, D., Birkbak, N. J., Rosenthal, R., Hiley, C. T., Lim, E. L., Papp, K., . . . Swanton, C. (2019). A clonal expression biomarker associates with lung cancer mortality. Nature Medicine, 25(10), 1540-1548
Open this publication in new window or tab >>A clonal expression biomarker associates with lung cancer mortality
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2019 (English)In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 25, no 10, p. 1540-1548Article in journal (Refereed) Published
Abstract [en]

An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage(1). Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types(2-6). Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.

National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-396656 (URN)10.1038/s41591-019-0595-z (DOI)000489166700023 ()31591602 (PubMedID)
Funder
EU, European Research Council, FP7-THESEUS-617844EU, European Research Council, 835297
Available from: 2019-11-14 Created: 2019-11-14 Last updated: 2020-01-08Bibliographically approved
Djureinovic, D., Pontén, V., Landelius, P., Al Sayegh, S., Kappert, K., Kamali-Moghaddam, M., . . . Ståhle, E. (2019). Multiplex plasma protein profiling identifies novel markers to discriminate patients with adenocarcinoma of the lung. BMC Cancer, 19, Article ID 741.
Open this publication in new window or tab >>Multiplex plasma protein profiling identifies novel markers to discriminate patients with adenocarcinoma of the lung
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2019 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, article id 741Article in journal (Refereed) Published
Abstract [en]

Background:The overall prognosis of non-small cell lung cancer (NSCLC) is poor, and currently only patients with localized disease are potentially curable. Therefore, preferably non-invasively determined biomarkers that detect NSCLC patients at early stages of the disease are of high clinical relevance. The aim of this study was to identify and validate novel protein markers in plasma using the highly sensitive DNA-assisted multiplex proximity extension assay (PEA) to discriminate NSCLC from other lung diseases. 

Methods:Plasma samples were collected from a total of 343 patients who underwent surgical resection for different lung diseases, including 144 patients with lung adenocarcinoma (LAC),68 patients with non-malignant lung disease, 83 with lung metastasis of colorectal cancers and 48 patients with typical carcinoid. One microliter of plasma was analyzed using PEA, allowing detection and quantification of 92 established cancer related proteins. The concentrations of the plasma proteins were compared between disease groups.

Results:The comparison between LAC and benign samples revealed significantly different plasma levels for four proteins; CXL17, CEACAM5, VEGFR2 and ERBB3 (adjusted p-value < 0.05). A multi-parameter classifier was developed to discriminate between samples from LAC patients and from patients with non-malignant lung conditions. With a bootstrap aggregated decision tree algorithm (TreeBagger) a sensitivity of 93% and specificity of 64% was achieved to detect LAC in this risk population. 

Conclusion:By applying the highly sensitive PEA, reliable protein profiles could be determined in microliter amounts of plasma. We further identified proteins that demonstrated different plasma concentration in defined disease groups and developed a signature that holds potential to be included in a screening assay for early lung cancer detection. 

Keywords
lung cancer, tumor markers, blood, serum, screening, biomarker
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-347805 (URN)10.1186/s12885-019-5943-3 (DOI)000477815100004 ()31357969 (PubMedID)
Funder
Swedish Cancer Society, 2012/738
Available from: 2018-04-07 Created: 2018-04-07 Last updated: 2020-01-03Bibliographically approved
Edlund, K., Madjar, K., Mattsson, J. S., Djureinovic, D., Lindskog, C., Brunnström, H., . . . Hengstler, J. G. (2019). Prognostic Impact of Tumor Cell Programmed Death Ligand 1 Expression and Immune Cell Infiltration in NSCLC. Journal of Thoracic Oncology, 14(4), 628-640, Article ID S1556-0864(19)30009-7.
Open this publication in new window or tab >>Prognostic Impact of Tumor Cell Programmed Death Ligand 1 Expression and Immune Cell Infiltration in NSCLC
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2019 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 14, no 4, p. 628-640, article id S1556-0864(19)30009-7Article in journal (Refereed) Published
Abstract [en]

Introduction: Infiltration of T and B/plasma cells has been linked to NSCLC prognosis, but this has not been thoroughly investigated in relation to the expression of programmed death ligand 1 (PD-L1). Here, we determine the association of lymphocytes and PD-L1 with overall survival (OS) in two retrospective cohorts of operated NSCLC patients who were not treated with checkpoint inhibitors targeting the programmed death 1/PD-L1 axis. Moreover, we evaluate how PD-L1 positivity and clinicopathologic factors affect the prognostic association of lymphocytes.

Methods: Cluster of differentiation (CD) 3 (CD3)-, CD8-, CD4-, forkhead box P3 (FOXP3)-, CD20-, CD79A-, and immunoglobulin kappa constant (IGKC)-positive immune cells, and tumor PD-L1 positivity, were determined by immunohistochemistry on tissue microarrays (n = 705). Affymetrix data was analyzed for a patient subset, and supplemented with publicly available transcriptomics data (N = 1724). Associations with OS were assessed by Kaplan-Meier plots and uni- and multivariate Cox regression.

Results: Higher levels of T and B plasma cells were associated with longer OS (p = 0.004 and p < 0.001, for CD8 and IGKC, respectively). Highly proliferative tumors with few lymphocytes had the worst outcome. No association of PD-L1 positivity with OS was observed in a nonstratified patient population; however, a significant association with shorter OS was observed in never-smokers (p = 0.009 and p = 0.002, 5% and 50% cutoff). Lymphocyte infiltration was not associated with OS in PD-L1–positive tumors (50% cutoff). The prognostic association of lymphocyte infiltration also depended on the patients’ smoking history and histologic subtype.

Conclusions: Proliferation, PD-L1 status, smoking history, and histology should be considered if lymphocyte infiltration is to be used as a prognostic biomarker.

Keywords
Adenocarcinoma, Ki67, Lymphocyte, Prognosis, Squamous cell carcinoma
National Category
Clinical Laboratory Medicine Cell and Molecular Biology
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-380592 (URN)10.1016/j.jtho.2018.12.022 (DOI)000462167700021 ()30639618 (PubMedID)
Funder
Swedish Cancer Society, 15 0831
Available from: 2019-03-29 Created: 2019-03-29 Last updated: 2020-01-03Bibliographically approved
Miyashita, N., Horie, M., Suzuki, H. I., Yoshihara, M., Djureinovic, D., Persson, J., . . . Nagase, T. (2018). An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1-Positive Lung Adenocarcinomas. Journal of Thoracic Oncology, 13(11), 1676-1691
Open this publication in new window or tab >>An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1-Positive Lung Adenocarcinomas
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2018 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, no 11, p. 1676-1691Article in journal (Refereed) Published
Abstract [en]

Introduction: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute family bHLH transcription factor 1 (ASCL1), common to high-grade neuroendocrine tumors, small-cell lung cancer and large cell neuroendocrine carcinoma. Methods: The aim of this study was to characterize clinical and molecular features of ASCL1-positive lung adenocarcinoma by using recent transcriptome profiling in multiple patient cohorts and genome-wide epigenetic profiling including data from The Cancer Genome Atlas. Results: The ASCL1-positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor EGFR mutations. In transcriptome profiling, this subtype overlapped with the recently proposed proximal-proliferative molecular subtype. Gene expression profiling of ASCL1-positive cases suggested generally poor immune cell infiltration and none of the tumors were positive for programmed cell death ligand 1 protein expression. Genome-wide methylation analysis showed global DNA hypomethylation in ASCL1-positive cases. ASCL1 was associated with super-enhancers in ASCL1-positive lung adenocarcinoma cells, and ASCL1 silencing suppressed other super-enhancer-associated genes, suggesting thatASCL1 acts as a master transcriptional regulator. This was further reinforced by the essential roles of ASCL1 in cell proliferation, survival, and cell cycle control. Conclusions: These results suggest that ASCL1 defines a subgroup of lung adenocarcinoma with distinct molecular features by driving super-enhancer-mediated transcriptional programs.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2018
Keywords
Lung cancer, Adenocarcinoma, Neuroendocrine, ASCL1, NSCLC
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-371088 (URN)10.1016/j.jtho.2018.07.096 (DOI)000450088600020 ()30121393 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer Society
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-03-29Bibliographically approved
Djureinovic, D., Dodig-Crnkovic, T., Hellström, C., Holgersson, G., Bergqvist, M., Mattsson, J. S., . . . Micke, P. (2018). Detection of autoantibodies against cancer-testis antigens in non-small cell lung cancer. Lung Cancer, 125, 157-163
Open this publication in new window or tab >>Detection of autoantibodies against cancer-testis antigens in non-small cell lung cancer
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2018 (English)In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 125, p. 157-163Article in journal (Refereed) Published
Abstract [en]

Cancer testis antigens (CTAs) are defined as proteins that are specifically expressed in testis or placenta and their expression is frequently activated in cancer. Due to their ability to induce an immune response, CTAs may serve as suitable targets for immunotherapy. The aim of this study was to evaluate if there is reactivity against CTAs in the plasma of non-small cell lung cancer (NSCLC) patients through the detection of circulating antibodies. 

To comprehensively analyse auto-antibodies against CTAs the multiplexing capacities of suspension bead array technology was used. Bead arrays were created with 120 protein fragments, representing 112 CTAs. Reactivity profiles were measured in plasma samples from 133 NSCLC patients and 57 cases with benign lung diseases. Altogether reactivity against 69 antigens, representing 81 CTAs, was demonstrated in at least one of the analysed samples. Twenty-nine of the antigens (45 CTAs) demonstrated exclusive reactivity in NSCLC samples. Reactivity against CT47A genes, PAGE3, VCX, MAGEB1, LIN28B and C12orf54 were only found in NSCLC patients at a frequency of 1%-4%. The presence of autoantibodies towards these six antigens was confirmed in an independent group of 34 NSCLC patients.

In conclusion, we identified autoantibodies against CTAs in the plasma of lung cancer patients. The reactivity pattern of autoantibodies was higher in cancer patients compared to the benign group, stable over time, but low in frequency of occurrence. The findings suggest that some CTAs are immunogenic and that these properties can be utilized as immune targets.

Keywords
Lung cancer, adenocarcinoma, squamous cell cancer, cancer immunity, tumor markers, MAGE, PAGE
National Category
Medical and Health Sciences Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-347809 (URN)10.1016/j.lungcan.2018.09.012 (DOI)000450378500023 ()
Funder
Swedish Cancer Society, 2012/738Knut and Alice Wallenberg FoundationErik, Karin och Gösta Selanders Foundation
Available from: 2018-04-07 Created: 2018-04-07 Last updated: 2019-03-29Bibliographically approved
La Fleur, L., Boura, V. F., Alexeyenko, A., Berglund, A., Ponten, V., Mattsson, J. S., . . . Botling, J. (2018). Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer. International Journal of Cancer, 143(7), 1741-1752
Open this publication in new window or tab >>Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer
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2018 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 7, p. 1741-1752Article in journal (Refereed) Published
Abstract [en]

Tumor-associated macrophages (TAMs) are attractive targets for immunotherapy. Recently, studies in animal models showed that treatment with an anti-TAM antibody directed against the scavenger receptor MARCO resulted in suppression of tumor growth and metastatic dissemination. Here we investigated the expression of MARCO in relation to other macrophage markers and immune pathways in a non-small cell lung cancer (NSCLC) cohort (n=352). MARCO, CD68, CD163, MSR1 and programmed death ligand-1 (PD-L1) were analyzed by immunohistochemistry and immunofluorescence, and associations to other immune cells and regulatory pathways were studied in a subset of cases (n=199) with available RNA-seq data. We observed a large variation in macrophage density between cases and a strong correlation between CD68 and CD163, suggesting that the majority of TAMs present in NSCLC exhibit a protumor phenotype. Correlation to clinical data only showed a weak trend toward worse survival for patients with high macrophage infiltration. Interestingly, MARCO was expressed on a distinct subpopulation of TAMs, which tended to aggregate in close proximity to tumor cell nests. On the transcriptomic level, we found a positive association between MARCO gene expression and general immune response pathways including strong links to immunosuppressive TAMs, T-cell infiltration and immune checkpoint molecules. Indeed, a higher macrophage infiltration was seen in tumors expressing PD-L1, and macrophages residing within tumor cell nests co-expressed MARCO and PD-L1. Thus, MARCO is a potential new immune target for anti-TAM treatment in a subset of NSCLC patients, possibly in combination with available immune checkpoint inhibitors.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
lung cancer, MARCO, tumor-associated macrophages, immune therapy, PD-L1
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-364230 (URN)10.1002/ijc.31545 (DOI)000443392100020 ()29667169 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-10-24 Created: 2018-10-24 Last updated: 2019-08-20Bibliographically approved
Mezheyeuski, A., Bergsland, C. H., Backman, M., Djureinovic, D., Sjöblom, T., Bruun, J. & Micke, P. (2018). Multispectral imaging for quantitative and compartment-specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients.. Journal of Pathology, 244(4), 421-431
Open this publication in new window or tab >>Multispectral imaging for quantitative and compartment-specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients.
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2018 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 244, no 4, p. 421-431Article in journal (Refereed) Published
Abstract [en]

Semiquantitative assessment of immune markers by immunohistochemistry (IHC) has significant limitations for describing the diversity of the immune response in cancer. Therefore, we evaluated a fluorescence-based multiplexed immunohistochemical method in combination with a multispectral imaging system to quantify immune infiltrates in situ in the environment of non-small-cell lung cancer (NSCLC). A tissue microarray including 57 NSCLC cases was stained with antibodies against CD8, CD20, CD4, FOXP3, CD45RO, and pan-cytokeratin, and immune cells were quantified in epithelial and stromal compartments. The results were compared with those of conventional IHC, and related to corresponding RNA-sequencing (RNAseq) expression values. We found a strong correlation between the visual and digital quantification of lymphocytes for CD45RO (correlation coefficient: r = 0.52), FOXP3 (r = 0.87), CD4 (r = 0.79), CD20 (r = 0.81) and CD8 (r = 0.90) cells. The correlation with RNAseq data for digital quantification (0.35-0.65) was comparable to or better than that for visual quantification (0.38-0.58). Combination of the signals of the five immune markers enabled further subpopulations of lymphocytes to be identified and localized. The specific pattern of immune cell infiltration based either on the spatial distribution (distance between regulatory CD8(+) T and cancer cells) or the relationships of lymphocyte subclasses with each other (e.g. cytotoxic/regulatory cell ratio) were associated with patient prognosis. In conclusion, the fluorescence multiplexed immunohistochemical method, based on only one tissue section, provided reliable quantification and localization of immune cells in cancer tissue. The application of this technique to clinical biopsies can provide a basic characterization of immune infiltrates to guide clinical decisions in the era of immunotherapy.

Keywords
PD-L1, checkpoint therapy, deep-learning microscopy, digital pathology, prognosis, tumour microenvironment
National Category
Clinical Medicine Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-343644 (URN)10.1002/path.5026 (DOI)000428213800006 ()29282718 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2019-03-29Bibliographically approved
Djureinovic, D. (2018). Transcriptomic and Proteomic Analysis of Tumor Markers in Tissue and Blood from Patients with Lung Cancer. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Transcriptomic and Proteomic Analysis of Tumor Markers in Tissue and Blood from Patients with Lung Cancer
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Despite recent treatment advancements, the survival outcome remains poor for the majority of patients with non-small cell lung cancer (NSCLC). The aim of this thesis was to evaluate protein expression to predict prognosis and identify biomarkers that can be used as targets for immunotherapy or for early detection of NSCLC.

In Paper I an optimized immunohistochemistry (IHC)-based prognostic model was developed for NSCLC. The prognostic performance of the model was compared to the clinicopathological parameters that are used in the clinical setting to predict outcome. The protein model failed to outperform clinicopathological parameters in predicting survival outcome questioning the potential of IHC-based assessment of prognostic markers in NSCLC.

In Paper II the human testis-specific proteome was profiled using RNA-sequencing (RNA-seq) data from testis and 26 other organs. More than 1000 genes demonstrated a testis-enriched expression pattern which makes testis the tissue with the most tissue-specific genes. The majority of the testis-enriched genes were previously poorly described and were further profiled by IHC. This analysis provides a starting point to increase the molecular understanding of testicular biology.

In Paper III the profiling of cancer-testis antigens (CTAs) was performed in NSCLC by using RNA-seq data from 32 normal organs and NSCLC. Ninety genes showed CTA expression profiles. The transcriptomic data were validated by IHC for several CTAs. The comprehensive analysis of CTAs can guide biomarker studies or help to identify targets for immunotherapeutic strategies.

In Paper IV the reactivity of CTAs was evaluated by measuring the abundance of autoantibodies in plasma from patients with NSCLC and benign lung diseases. Twenty-nine CTAs demonstrated exclusive reactivity in NSCLC and six of them were reactive in an independent NSCLC cohort. These findings suggest that some CTAs are immunogenic and could be utilized in immunotherapy.

In Paper V an immunoassay was used on lung adenocarcinoma plasma samples and samples from benign lung diseases. The plasma levels of 92 cancer related proteins were used to build a model that discriminated lung adenocarcinoma from benign controls with a sensitivity of 93% and a specificity of 64%. The results indicate that this assay is promising for the early detection of NSCLC.

In summary, this thesis presents an integrative analysis of lung cancer tissue and blood samples to characterize NSCLC on the transcriptomic and proteomic level and to identify cancer specific proteins.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 52
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1463
Keywords
non-small cell lung cancer, prognostic biomarkers, cancer-testis antigens, prediction model, tumor markers, autoantibodies, testis, screening
National Category
Medical and Health Sciences
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-348349 (URN)978-91-513-0328-4 (ISBN)
Public defence
2018-06-08, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2018-05-09 Created: 2018-04-11 Last updated: 2018-10-08
Uhlen, M., Zhang, C., Lee, S., Sjöstedt, E., Fagerberg, L., Bidkhori, G., . . . Ponten, F. (2017). A pathology atlas of the human cancer transcriptome. Science, 357(6352), Article ID eaan2507.
Open this publication in new window or tab >>A pathology atlas of the human cancer transcriptome
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2017 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 357, no 6352, article id eaan2507Article in journal (Refereed) Published
Abstract [en]

Cancer is one of the leading causes of death, and there is great interest in understanding the underlying molecular mechanisms involved in the pathogenesis and progression of individual tumors. We used systems-level approaches to analyze the genome-wide transcriptome of the protein-coding genes of 17 major cancer types with respect to clinical outcome. A general pattern emerged: Shorter patient survival was associated with up-regulation of genes involved in cell growth and with down-regulation of genes involved in cellular differentiation. Using genome-scale metabolic models, we show that cancer patients have widespread metabolic heterogeneity, highlighting the need for precise and personalized medicine for cancer treatment. All data are presented in an interactive open-access database (www.proteinatlas.org/pathology) to allow genome-wide exploration of the impact of individual proteins on clinical outcomes.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2017
National Category
Medical and Health Sciences Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-334302 (URN)10.1126/science.aan2507 (DOI)000407793600028 ()
Funder
Swedish Cancer SocietyScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg FoundationSwedish Research Council
Available from: 2017-11-22 Created: 2017-11-22 Last updated: 2019-03-29Bibliographically approved
Gremel, G., Djureinovic, D., Niinivirta, M., Laird, A., Ljungqvist, O., Johannesson, H., . . . Pontén, F. (2017). A systematic search strategy identifies cubilin as independent prognostic marker for renal cell carcinoma. BMC Cancer, 17, Article ID 9.
Open this publication in new window or tab >>A systematic search strategy identifies cubilin as independent prognostic marker for renal cell carcinoma
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2017 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, article id 9Article in journal (Refereed) Published
Abstract [en]

Background: There is an unmet clinical need for better prognostic and diagnostic tools for renal cell carcinoma (RCC). Methods: Human Protein Atlas data resources, including the transcriptomes and proteomes of normal and malignant human tissues, were searched for RCC-specific proteins and cubilin (CUBN) identified as a candidate. Patient tissue representing various cancer types was constructed into a tissue microarray (n = 940) and immunohistochemistry used to investigate the specificity of CUBN expression in RCC as compared to other cancers. Two independent RCC cohorts (n = 181; n = 114) were analyzed to further establish the sensitivity of CUBN as RCC-specific marker and to explore if the fraction of RCCs lacking CUBN expression could predict differences in patient survival. Results: CUBN was identified as highly RCC-specific protein with 58% of all primary RCCs staining positive for CUBN using immunohistochemistry. In venous tumor thrombi and metastatic lesions, the frequency of CUBN expression was increasingly lost. Clear cell RCC (ccRCC) patients with CUBN positive tumors had a significantly better prognosis compared to patients with CUBN negative tumors, independent of T-stage, Fuhrman grade and nodal status (HR 0.382, CI 0.203-0.719, P = 0.003). Conclusions: CUBN expression is highly specific to RCC and loss of the protein is significantly and independently associated with poor prognosis. CUBN expression in ccRCC provides a promising positive prognostic indicator for patients with ccRCC. The high specificity of CUBN expression in RCC also suggests a role as a new diagnostic marker in clinical cancer differential diagnostics to confirm or rule out RCC.

Keywords
Cubilin, Renal cell carcinoma, Independent prognostic biomarker, Immunohistochemistry
National Category
Cancer and Oncology Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-315058 (URN)10.1186/s12885-016-3030-6 (DOI)000391341500003 ()28052770 (PubMedID)
Funder
Swedish Cancer SocietyKnut and Alice Wallenberg Foundation
Available from: 2017-03-03 Created: 2017-03-03 Last updated: 2017-11-29Bibliographically approved
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