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Predictive markers: for treatment sensitivity 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. Östergötlands Läns Landsting, Reconstruction Centre, Department of ENT - Head and Neck Surgery UHL.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Head and neck cancer is the sixth most common cancer world wide. In Sweden approximately 850 new cases are diagnosed each year, and two thirds are men. The past decades of improved treatment strategies have unfortunately not significantly improved the five-year survival rates for this group of patients. Therefore, it is important to rapidly find combinations of new and strong predictive markers for treatment response. Different predictive markers have been investigated for decades, without succeeding in finding means to securely predict response to treatment. Models to combine markers are called for.

The aim of this thesis was to test multiple predictive markers on both gene and protein level to evaluate their predictive value for radiotherapy and cisplatin response. Furthermore, to combine, and correlate them to treatment response in order to extract the panel of markers that strongest correlated to the investigated treatment. Cell lines derived from 42 patients with head and neck squamous cell carcinoma (HNSCC) were used for protein quantification with Western blot and ELISA of the proteins survivin, Epidermal Growth Factor Receptor, Bcl-2, Bcl-XL, Bax, Bad, Bak, PUMA, Heat shock protein 70, MDM2, p53, SMAD4, Cyclooxygenase-2, and Cyclin D1. The expression of the selected proteins was related to the mean expression of normal oral keratinocytes (NOK) from healthy individuals. Furthermore, mutations in the p53 gene, along with single nucleotide polymorphisms in the genes of p53, MDM2, FGFR4, XRCC1, XRCC3, XPD, and XPC were analysed. To allow a large number of predictive markers on both protein and gene level to be combined and correlated to treatment response, the number of negative points (NNP) model was introduced. Both correlations of sensitivity to radiotherapy and to cisplatin treatment was analysed among the cell lines. In the first paper, including nine cell lines, the panel of EGFR, survivin, and splice site/missense p53 mutations correlated strongest to radioresponse. In paper II, 42 cell lines were used and the combination of survivin, Bcl-2, Bcl-XL, Bax, COX-2, and the p53 Arg72Pro polymorphism was found to most strongly correlate with radioresponse. In paper IV, the panel correlating strongest with cisplatin sensitivity consisted of EGFR, Hsp70, Bax, and Bcl-2 in combination with SNPs in the DNA-repair genes XRCC3 and XPD.

The predisposition of the FGFR4 Gly388Arg polymorphism for the development of HNSCC was investigated in paper III. DNA was isolated from 110 tumour biopsies, and restriction fragment length polymorphism analysis showed that 58% of the individuals in the control group carried the FGFR4 Arg388 allele, whereas the frequency in the tumour group was 45%. The Gly388 allele gave a significantly higher risk of developing HNSCC, suggesting Gly388 to be the risk allele for cancer development. Furthermore, a novel mutation was found in the FGFR4 gene. The influence of this new mutation is however unknown.

In conclusion, predictive markers for treatment sensitivity need to be combined to receive an accurate prediction of treatment response.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2010. , 84 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1205
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-61586ISBN: 978-91-7393-319-3 (print)OAI: oai:DiVA.org:liu-61586DiVA: diva2:370476
Public defence
2010-11-12, Elsa Brändströmsalen, Campus US, Linköpings universitet, Linköping, 09:00
Opponent
Supervisors
Available from: 2010-11-16 Created: 2010-11-16 Last updated: 2012-05-09Bibliographically 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, 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: 2012-03-29Bibliographically approved
2. Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines
Open this publication in new window or tab >>Combining factors on protein and gene level to predict radioresponse in head and neck cancer cell lines
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2011 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 40, no 10, 739-746 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Radiotherapy is the main therapy for head and neck squamous cell carcinoma (HNSCC); however, treatment resistance and local recurrence are significant problems, highlighting the need for predictive markers. In this study, we evaluated selected proteins, mutations, and single nucleotide polymorphisms (SNPs) involved in apoptosis, cell proliferation, and DNA repair alone or combined as predictive markers for radioresponse in 42 HNSCC cell lines.

METHODS: The expression of epidermal growth factor receptor, survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and heat shock protein 70 was analyzed by ELISA. Furthermore, mutations and SNPs in the p53 gene as well as SNPs in the MDM2, XRCC1, and XRCC3 genes were analyzed for their relation to radioresponse. To enable the evaluation of the predictive value of several factors combined, each cell line was allocated points based on the number of negative points (NNP) system, and the NNP sum was correlated with radioresponse.

RESULTS: Survivin was the only factor that alone was significantly correlated with the intrinsic radiosensitivity (r=0.36, p=0.02). The combination of survivin, Bax, Bcl-2, Bcl-XL, cyclooxygenase-2, and the p53 Arg72Pro polymorphism was found to most strongly correlate with radioresponse (r=0.553, p<0.001).

CONCLUSION: These data indicate that the intrinsic radiosensitivity of 42 HNSCC cell lines can be predicted by a panel of factors on both the protein and gene levels. Moreover, among the investigated factors, survivin was the most promising biomarker of radioresponse.

Place, publisher, year, edition, pages
John Wiley and sons, 2011
Keyword
head and neck tumors, radiotherapy, survivin, Bcl-2 family, p53 Arg72Pro
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-61585 (URN)10.1111/j.1600-0714.2011.01036.x (DOI)000296607200002 ()
Note
Funding agencies|Swedish Laryng Foundation||County Council of Ostergotland (OLL)||Swedish Cancer Foundation||Foundation of Olle Engkvist||Linkoping University Hospital||Available from: 2010-11-16 Created: 2010-11-16 Last updated: 2017-12-12Bibliographically approved
3. Polymorphism of FGFR4 in cancer development and sensitivity to cisplatin and radiation in head and neck cancer
Open this publication in new window or tab >>Polymorphism of FGFR4 in cancer development and sensitivity to cisplatin and radiation in head and neck cancer
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2009 (English)In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 45, no 1, 23-29 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to investigate the predisposition of the FGFR4 Gly/Arg polymorphism for development of head and neck squamous cell carcinoma (HNSCC) and, furthermore, to examine if the FGFR4 Arg(388) allele can be associated with resistance to chemo-and radiotherapy.

When analysing 110 tumour biopsies a significant 1.7-fold increased risk to develop HNSCC in individuals carrying the Gly(388) allele (p = 0.026) was found. Moreover a 2-fold increased risk for mates harbouring the Gly(388) allele (p = 0.031) to develop HNSCC was detected. In 39 HNSCC cell lines the role of the Arg(388) allele for radiation and cisplatin sensitivity was investigated. Our results show no rote of the Arg(388) allele for the radiosensitivity (p = 0.996) but indicate a tendency to increased cisplatin sensitivity (p = 0.141). When screening the transmembrane and kinase domains in the FGFR4 gene a novel mutation, probably generating a truncated protein lacking exons 14-18, was found in six of eight selected cell lines.

Taken together, we have here identified a marker that predicts the risk to develop HNSCC and possibly the sensitivity to cisplatin as well as a novel. mutation in the FGFR4 gene.

Place, publisher, year, edition, pages
Elsevier, 2009
Keyword
Oral tumours, Radiotherapy, Chemotherapy
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-16724 (URN)10.1016/j.oraloncology.2008.03.007 (DOI)000262607900005 ()18487077 (PubMedID)
Available from: 2009-02-14 Created: 2009-02-13 Last updated: 2015-11-18Bibliographically approved
4. Proteins and single nucleotide polymorphisms involved in apoptosis, growth control, and DNA repair predict cisplatin sensitivity in head and neck cancer cell lines
Open this publication in new window or tab >>Proteins and single nucleotide polymorphisms involved in apoptosis, growth control, and DNA repair predict cisplatin sensitivity in head and neck cancer cell lines
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2009 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 24, no 4, 549-556 p.Article in journal (Refereed) Published
Abstract [en]

The present study was undertaken to evaluate the possibility of using a panel of proteins and single nucleotide polymorphisms (SNPs) involved in apoptosis, growth control, and DNA repair as predictive markers for cisplatin sensitivity. For this purpose the intrinsic cisplatin sensitivity (ICS) was determined in 39 cell lines derived from squamous cell carcinomas of the head and neck using a colony-forming assay. In these cell lines and in normal oral keratinocytes (NOK), the expression of epidermal growth factor receptor (EGFR), Hsp70, Bax, Bcl-2, Bcl-XL, survivin, and COX-2 was determined. Moreover, the p53, MDM2, FGFR4, XPC, XPD, XRCC1, and XRCC3 genes were analyzed for the presence of specific single nucleotide polymorphisms (SNPs). Pearsons correlation test showed that EGFR was the only protein that was significantly correlated to the ICS (r=0.388, p=0.015). The combination of EGFR, Hsp70, Bax, and Bcl-2 gave the strongest correlation (r=0.566, p andlt;= 0.001), whereas Bax alone had the second highest influence on the ICS. Furthermore, all four SNPs within genes involved in DNA repair, i.e. XPC, XPD, XRCC1, and XRCC3, tended to influence the ICS. In order to find the combination of factors, on both protein and gene levels, with the highest correlation to ICS, a multivariate statistical calculation was performed. Our results indicate that SNPs in DNA repair genes (XRCC3(241) and XPD751) influence the ICS and together with the expression of EGFR, Hsp70, Bax, and Bcl-2, they could predict the cisplatin sensitivity of head and neck cancer cell lines (r=0.614, p andlt;= 0.001).

Keyword
epidermal growth factor receptor, Bax, Bcl-2, heat shock protein 70, DNA repair genes
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-21513 (URN)10.3892/ijmm_00000264 (DOI)
Available from: 2009-10-02 Created: 2009-10-02 Last updated: 2015-01-29

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Farnebo, Lovisa

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