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On Predictive Factors of Treatment Response in Head and Neck Squamous Cell Carcinoma
Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery . Linköping University, Faculty of Health Sciences.
2008 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and yearly include 500 000 new cases worldwide. The outcomes for these patients have not been significantly improved over the last decades and the five year survival is still around 50 %. Establishing predictive markers of treatment response will have great impact on the clinical management of this disease.

The aim of this thesis was to elucidate markers of intrinsic response to radiotherapy and cisplatin. Combining expression patterns of 14 proteins and identifying mutations in the p53 gene, we were able to incorporate both protein and genetic changes to create a predictive model termed Number of Negative Points (NNP). We used the NNP model to statistically calculate the combination of factors that had the best correlation to intrinsic radiosensitivity (IR). We established that a panel of three markers, epidermal growth factor receptor (EGFR), survivin and splice site/missence mutations of p53, had the best correlation to IR (R=0.990, p<0.0001).

We also conducted gene expression analysis to investigate what genes and gene ontologies that are different between cell lines with varying IR. Furthermore, we wanted to identify key regulator genes with central positions of molecular networks, which were generated from the transcripts included in the deregulated gene ontologies. A transcriptional profile of 28 key regulator genes was generated. Immunoblot analysis supported deregulation at the protein level of three markers implicated from the transcriptional profile. We propose that these proteins, notch1, thrombospondin 1, and pai‐1 are predictive markers of IR.

Finally, on a subset of cell lines with sensitivity or resistance to cisplatin, we performed gene expression analysis. Markers of intrinsic cisplatin sensitivity (ICS) such as gene ontologies and key regulators of molecular networks were proposed and five genes, APOE, CTNNB1, MMP7, MMP13, and THBS1 were selected for further analysis. Quantitative polymerase chain reaction (qPCR) analysis of these genes in 25 cell lines established that MMP7 (p=0.0013) and MMP13 (p=0.058) are possible predictive markers of ICS.

The markers of IR and ICS presented here could, if confirmed in a clinical setting, guide clinicians in the choice of treatment and thus give a more individualized and effective therapy for patients with HNSCC.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2008. , 37 p.
Series
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 90
National Category
Otorhinolaryngology
Identifiers
URN: urn:nbn:se:liu:diva-17781ISBN: 978-91-7393-736-8 (print)OAI: oai:DiVA.org:liu-17781DiVA: diva2:211939
Presentation
(English)
Supervisors
Available from: 2009-06-29 Created: 2009-04-20 Last updated: 2009-09-15Bibliographically approved
List of papers
1. Number of negative points: a novel method for predicting radiosensitivity in head and neck tumor cell lines.
Open this publication in new window or tab >>Number of negative points: a novel method for predicting radiosensitivity in head and neck tumor cell lines.
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2008 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 20, no 2, 453-461 p.Article in journal (Refereed) Published
Abstract [en]

The present study was aimed at establishing a method that combines multiple factors of protein and genetic changes that enables prediction of radiosensitivity in the head and neck squamous cell carcinoma (HNSCC) cell lines. In nine HNSCC cell lines, the quantity of protein expression and the type of genetic alterations were translated into a point system, called the Number of Negative Points. The expression of 14 proteins involved in growth control and/or apoptosis was quantified using a densitometric assessment of Western blots. The blots were adjusted to actin and standardised to normal oral keratinocytes classifying them into four groups depending on the amount of protein expressed (0-3 points). Mutations of the p53 gene were classified into three groups and each mutation was given one point. Since the cell lines each had a known intrinsic radiosensitivity, a multivariate statistical calculation could then be performed to select for the combination of factors having the strongest correlation to radiosensitivity. The strongest correlation of the investigated factors was the combination of epidermal growth factor receptor, survivin and splice site/missense p53 mutations (R=0.990 and P<0.0001). No single factor had a significant correlation to the intrinsic radiosensitivity. Since a significant correlation to the intrinsic radiosensitivity was achieved only when two or more factors were combined, we conclude that a method such as the Number of Negative Points is necessary for prediction of treatment response. We present a novel method to combine factors which enables the prediction of radiosensitivity of HNSCC cell lines.

Keyword
Predictive markers, p53, epidermal growth factor receptor, survivin, squamous cell carcinoma
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19558 (URN)10.3892/or_00000028 (DOI)18636211 (PubMedID)
Available from: 2009-06-26 Created: 2009-06-26 Last updated: 2017-12-13Bibliographically approved
2. Identification of Key Regulator Genes Linked to Radioresistance in Head and Neck Squamous Cell Carcinoma by Bioinformatic Processing of Transcript Data
Open this publication in new window or tab >>Identification of Key Regulator Genes Linked to Radioresistance in Head and Neck Squamous Cell Carcinoma by Bioinformatic Processing of Transcript Data
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Purpose: We analyzed basal expression patterns of cell lines with different intrinsic radiosensitivity to discover predictive markers of radiotherapy response.

Experimental Design: Five head and neck squamous cell carcinoma (HNSCC) cell lines were selected for microarray analysis. Two cell lines showed high resistance to radiation, two cell lines showed an intermediate resistance and one cell line was sensitive and therefore used as reference to other cell lines. Three gene lists were generated from this analysis; one list with commonly deregulated genes in all cell lines compared to the reference and two lists with deregulated genes for the intermediate and highly resistant cell lines compared to the reference, respectively. Gene Ontology enrichment profiling and Ingenuity Pathway Analysis was applied on all gene lists. Key transcript findings were verified at the protein level by Western blot.

Results: Expression analysis of the high and intermediate resistant cell lines compared to the reference resulted in approximately 1300 significantly altered transcripts, respectively; 552 transcripts were found commonly differently expressed. The deregulated transcripts enriched several GO-categories under biological process, cellular component and molecular function as well as multiple molecular networks in Ingenuity Pathway Analysis. A transcriptional profile of 28 key-regulator genes from the molecular networks was generated from the four resistant lines compared to the reference. Finally, immunoblot analysis supported deregulation at the protein level of markers implicated from the transcriptional-profile.

Conclusions: Novel markers for prediction of radiation sensitivity could be proposed from bioinformatic processing of gene-expression profiles in HNSCC carcinoma cells.

Keyword
Microarray, Radiotherapy, Predictive biomarkers, Gene Ontology, Pathway analysis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19570 (URN)
Available from: 2009-06-29 Created: 2009-06-29 Last updated: 2010-01-14Bibliographically approved
3. Matrix metalloproteinase-7 and -13 predict response to cisplatin in head and neck cancer
Open this publication in new window or tab >>Matrix metalloproteinase-7 and -13 predict response to cisplatin in head and neck cancer
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Purpose: To identify gene ontology categories and key regulators with impact on the intrinsic cisplatin sensitivity (ICS) in head and neck squamous cell carcinoma (HNSCC).

Experimental design: The ICS was determined in 35 HNSCC cell lines. Three of these cell lines, one sensitive and two resistant, were selected for microarray analysis. Gene Ontology (GO) categories were assessed using the gene ontology tree machine (GOTM) tool, and transcripts included in these categories were further analyzed using Ingenuity Pathway Analysis (IPA) for detection of key regulator genes. A group of key regulators were verified at protein level by Western blot analysis and on mRNA level using quantitative real-time PCR (qPCR).

Results: 781 transcripts were detected as significantly differently expressed for the resistant cell lines compared to the sensitive cell line. A total of ten different categories were enriched in GOTM by these transcripts and a transcriptional profile was made from the 20 key regulators identified in the IPA analysis. Five key regulator genes, apolipoprotein E (APOE), catenin beta1 (CTNNB1), matrix metalloproteinase-7 (MMP-7), matrix metalloproteinase-13 (MMP-13), and thrombospondin 1 (THBS1), were verified in 25 HNSCC cell lines on mRNA level using qPCR. The results confirmed MMP-7 (p=0.0013) and implied MMP-13 (p=0.058) as potential biomarkers of ICS.

Conclusions: We conclude that genome-wide transcriptional analysis and appropriate bioinformatics enable the identification of genes with impact on treatment response. Furthermore, we propose MMP-7 and MMP-13 as predictive markers of cisplatin resistance in HNSCC.

Keyword
Predictive markers, chemotherapy, microarray and intrinsic cisplatin resistance
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19571 (URN)
Available from: 2009-06-29 Created: 2009-06-29 Last updated: 2010-01-14Bibliographically approved

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On Predictive Factors of Treatment Response in Head and Neck Squamous Cell Carcinoma(653 kB)800 downloads
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Jerhammar, Fredrik

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