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Profiling cancer testis antigens in non-small-cell lung cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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2016 (English)In: JCI INSIGHT, ISSN 2379-3708, Vol. 1, no 10, article id e86837Article in journal (Refereed) Published
Abstract [en]

Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non-small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.

Place, publisher, year, edition, pages
2016. Vol. 1, no 10, article id e86837
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-310039DOI: 10.1172/jci.insight.86837ISI: 000387113300012PubMedID: 27699219OAI: oai:DiVA.org:uu-310039DiVA, id: diva2:1054821
Available from: 2016-12-09 Created: 2016-12-09 Last updated: 2018-04-11Bibliographically approved
In thesis
1. Transcriptomic and Proteomic Analysis of Tumor Markers in Tissue and Blood from Patients with Lung Cancer
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
Keyword
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: 2018-05-09

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Djureinovic, DijanaMattsson, Johanna Sofia MargaretaLa Fleur, LinneaLindskog, CeciliaEkman, SimonStåhle, ElisabethKoyi, HirshBrandén, EvaBotling, JohanPontén, FredrikMicke, Patrick

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Djureinovic, DijanaMattsson, Johanna Sofia MargaretaLa Fleur, LinneaLindskog, CeciliaEkman, SimonStåhle, ElisabethKoyi, HirshBrandén, EvaBotling, JohanPontén, FredrikMicke, Patrick
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Department of Immunology, Genetics and PathologyExperimental and Clinical OncologyUCR-Uppsala Clinical Research CenterCentre for Research and Development, GävleborgMolecular tools
Cancer and Oncology

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