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Gene Copy Number Aberrations Are Associated with Survival in Histologic Subgroups of Non-small Cell Lung Cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Cancer pharmacology and computational medicine)
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2011 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 6, no 11, 1833-1840 p.Article in journal (Refereed) Published
Abstract [en]

Introduction:

Non-small cell lung cancer (NSCLC) is characterized by a multitude of genetic aberrations with unknown clinical impact. In this study, we aimed to identify gene copy number changes that correlate with clinical outcome in NSCLC. To maximize the chance to identify clinically relevant events, we applied a strategy involving two prognostically extreme patient groups.

Methods:

Short-term (<20 month; n = 53) and long-term survivors (>58 month; n = 47) were selected from a clinically well-characterized NSCLC patient cohort with available fresh frozen tumor specimens. The samples were analyzed using high-resolution single-nucleotide polymorphism array technology to assess gene copy number variations and array-based gene expression profiling. The molecular data were combined with information on clinical parameters.

Results:

Genetic aberrations were strongly associated with tumor histology. In adenocarcinoma (n = 50), gene copy number gains on chromosome 8q21-q24.3 (177 genes) were more frequent in long-term than in short-term survivors. In squamous cell carcinoma (n = 28), gains on chromosome 14q23.1-24.3 (133 genes) were associated with shorter survival, whereas losses in a neighboring region, 14q31.1-32.33 (110 genes), correlated with favorable outcome. In accordance with copy number gains and losses, messenger RNA expression levels of corresponding genes were increased or decreased, respectively.

Conclusion:

Comprehensive tumor profiling permits the integration of genomic, histologic, and clinical data. We identified gene copy number gains and losses, with corresponding changes in messenger RNA levels that were associated with prognosis in adenocarcinoma and squamous cell carcinoma of the lung.

Place, publisher, year, edition, pages
2011. Vol. 6, no 11, 1833-1840 p.
Keyword [en]
Lung cancer, Prognosis, SNP array, CGH, Gene expression profile
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-162455DOI: 10.1097/JTO.0b013e3182295917ISI: 000296700400008OAI: oai:DiVA.org:uu-162455DiVA: diva2:460779
Available from: 2011-12-01 Created: 2011-11-30 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Molecular Characterisation and Prognostic Biomarker Discovery in Human Non-Small Cell Lung Cancer
Open this publication in new window or tab >>Molecular Characterisation and Prognostic Biomarker Discovery in Human Non-Small Cell Lung Cancer
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Non-small cell lung cancer (NSCLC) constitutes a clinically, histologically, and genetically heterogeneous disease entity that represents a major cause of cancer-related death. Early-stage patients, who undergo surgery with curative intent, experience high recurrence rates and the effect of adjuvant treatment is modest. Prognostic biomarkers would be of particular relevance to guide intensified treatment depending on expected outcome and moreover often infer a biological role in tumourigenesis.

This thesis presents a translational study approach to establish a well-characterised NSCLC frozen-tissue cohort and to obtain a profile of each specimen with regard to genome-wide copy number alterations, global gene expression levels and somatic mutations in selected cancer-related genes. Furthermore, the generation of a formalin-fixed, paraffin-embedded tissue microarray enabled validation of findings on the protein level using immunohistochemistry. The comprehensive molecular characterisation, combined with data on clinical parameters, enabled the analysis of biomarkers linked to disease outcome. In Paper I, single nucleotide polymorphism arrays were applied to assess copy number alterations in NSCLC and associations with overall survival in adenocarcinoma and squamous cell carcinoma were described. In Paper II, we evaluated expression levels of selected stromal proteins in NSCLC using immunohistochemistry and the adhesion molecule CD99 was identified as an outcome-related biomarker in two independent cohorts. Paper III presents a strategy for prognostic biomarker discovery based on gene expression profiling, meta-analysis, and validation of protein expression on tissue microarrays, and suggests the putative tumour suppressor CADM1 as a candidate biomarker. In Paper IV, we propose a prognostic role for tumour-infiltrating IGKC-expressing plasma cells in the local tumour microenvironment, indicating an involvement of the humoral immune response in anti-tumor activity. In Paper V, we combined next-generation deep sequencing with statistical analysis of the TP53 database to define novel parameters for database curation.

In summary, this thesis exemplifies the benefits of a translational study approach, based on a comprehensive tumour characterisation, and describes molecular markers associated with clinical outcome in NSCLC.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 817
Keyword
non-small cell lung cancer, biomarker, prognosis, microarray, copy number aberration
National Category
Other Basic Medicine Cancer and Oncology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-181912 (URN)978-91-554-8482-8 (ISBN)
Public defence
2012-11-16, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15 (English)
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Supervisors
Available from: 2012-10-26 Created: 2012-10-01 Last updated: 2013-06-19Bibliographically approved

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Micke, PatrickEdlund, KarolinaHolmberg, LarsMansouri, LarryBergqvist, MichaelLamberg, KristinaMyrdal, GunnarAndersson, AnnsofieIsaksson, AndersBotling, Johan

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Micke, PatrickEdlund, KarolinaHolmberg, LarsMansouri, LarryBergqvist, MichaelLamberg, KristinaMyrdal, GunnarAndersson, AnnsofieIsaksson, AndersBotling, Johan
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Molecular and Morphological PathologyEndocrine SurgeryDepartment of Medical SciencesHematology and ImmunologyOncologyDepartment of Immunology, Genetics and PathologyRespiratory Medicine and AllergologyThoracic Surgery
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