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Polymorphism of FGFR4 in cancer development and sensitivity to cisplatin and radiation in head and neck cancer
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
Department of Otorhinolaryngology, Head & Neck Surgery, and Medical Biochemistry, University of Turku, Finland.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Öronkliniken US.
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2009 (Engelska)Ingår i: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 45, nr 1, s. 23-29Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Elsevier, 2009. Vol. 45, nr 1, s. 23-29
Nyckelord [en]
Oral tumours, Radiotherapy, Chemotherapy
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:liu:diva-16724DOI: 10.1016/j.oraloncology.2008.03.007ISI: 000262607900005PubMedID: 18487077OAI: oai:DiVA.org:liu-16724DiVA, id: diva2:160506
Tillgänglig från: 2009-02-14 Skapad: 2009-02-13 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
Ingår i avhandling
1. Predictive markers: for treatment sensitivity in head and neck squamous cell carcinoma
Öppna denna publikation i ny flik eller fönster >>Predictive markers: for treatment sensitivity in head and neck squamous cell carcinoma
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2010. s. 84
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1205
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-61586 (URN)978-91-7393-319-3 (ISBN)
Disputation
2010-11-12, Elsa Brändströmsalen, Campus US, Linköpings universitet, Linköping, 09:00
Opponent
Handledare
Tillgänglig från: 2010-11-16 Skapad: 2010-11-16 Senast uppdaterad: 2012-05-09Bibliografiskt granskad

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