Investigation of the associations of smoking-related DNA damages with biomarkers in a human lung cancer population.

2.50
Hdl Handle:
http://hdl.handle.net/10146/283152
Title:
Investigation of the associations of smoking-related DNA damages with biomarkers in a human lung cancer population.
Authors:
Anna, Livia
Abstract:
The aim of my PhD research was to further explore the associations among smoking status, two different DNA adduct types, the O4-etT and bulky DNA adduct, the TP53 tumour suppressor gene mutations and lung cancer in a molecular epidemiological study in a Hungarian lung cancer study population. The levels of O4-etT and bulky DNA adducts were significantly higher in the combined group of subjects who smoked until surgery or gave up smoking at most one year before surgery than in the combined group of those subjects who gave up smoking more than one year before the surgery or never smoked. O4-etT appeared to be a highly persistent DNA damage. There was no statistically significant correlation between the individual levels of O4-etT and of bulky DNA adducts. The TP53 mutation frequency and the variety of mutation types were higher in the present study population as compared to the IARC database. 45% of the samples carried TP53 mutation. The mutation frequency was significantly higher in squamous cell carcinoma than in adenocarcinoma, and in the cases with more than 20 years of smoking history. The most common mutations were G→A (19%), G→T (19%) and G→C (16%) base changes. The mutation pattern was influenced by the smoking status. G→T transversion was detected exclusively in smokers, and most carriers of the G→T transversions had also high level of bulky DNA adducts. My results confirm that O4-etT level is increased by smoking in the lung. O4-etT is persistent in human lung, and the activation and elimination pathways of O4-etT and bulky DNA adducts are not closely linked. I consider O4-etT a suitable biomarker of smoking exposure for comparison of exposure groups in molecular epidemiological studies. For the first time at international level, I demonstrated strong association between G→T mutation of TP53 and high level of bulky DNA adducts in a human study, which is a significant scientific progress from the in vitro studies in the exploration of the causal relationship between a carcinogen-DNA adduct and a gene mutation.
Citation:
Anna, L.: Investigation of the associations of smoking-related DNA damages with biomarkers in a human lung cancer population. PhD theses. University of Pécs Medical School, Pécs, 2012.
Issue Date:
2012
URI:
http://hdl.handle.net/10146/283152
Type:
Thesis
Language:
en
Sponsors:
This work was supported in parts by Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS), a Network of Excellence operating within the European Union 6th Framework Program, Priority 5: ‘Food Quality and Safety’ (Contract No 513943); the Országos Tudományos Kutatási Alap [OTKA T034616]; the Hungarian-Finnish Science and Technology Foundation [SF-02/01, SF-14/03]. I was awarded an ECNIS Exchange Fellowship to DKFZ, where I conducted the O4-ethyltymidine measurements.
Appears in Collections:
Theses

Full metadata record

DC FieldValue Language
dc.contributor.authorAnna, Livia-
dc.date.accessioned2013-04-19T08:32:28Z-
dc.date.available2013-04-19T08:32:28Z-
dc.date.issued2012-
dc.identifier.citationAnna, L.: Investigation of the associations of smoking-related DNA damages with biomarkers in a human lung cancer population. PhD theses. University of Pécs Medical School, Pécs, 2012.en_GB
dc.identifier.urihttp://hdl.handle.net/10146/283152-
dc.description.abstractThe aim of my PhD research was to further explore the associations among smoking status, two different DNA adduct types, the O4-etT and bulky DNA adduct, the TP53 tumour suppressor gene mutations and lung cancer in a molecular epidemiological study in a Hungarian lung cancer study population. The levels of O4-etT and bulky DNA adducts were significantly higher in the combined group of subjects who smoked until surgery or gave up smoking at most one year before surgery than in the combined group of those subjects who gave up smoking more than one year before the surgery or never smoked. O4-etT appeared to be a highly persistent DNA damage. There was no statistically significant correlation between the individual levels of O4-etT and of bulky DNA adducts. The TP53 mutation frequency and the variety of mutation types were higher in the present study population as compared to the IARC database. 45% of the samples carried TP53 mutation. The mutation frequency was significantly higher in squamous cell carcinoma than in adenocarcinoma, and in the cases with more than 20 years of smoking history. The most common mutations were G→A (19%), G→T (19%) and G→C (16%) base changes. The mutation pattern was influenced by the smoking status. G→T transversion was detected exclusively in smokers, and most carriers of the G→T transversions had also high level of bulky DNA adducts. My results confirm that O4-etT level is increased by smoking in the lung. O4-etT is persistent in human lung, and the activation and elimination pathways of O4-etT and bulky DNA adducts are not closely linked. I consider O4-etT a suitable biomarker of smoking exposure for comparison of exposure groups in molecular epidemiological studies. For the first time at international level, I demonstrated strong association between G→T mutation of TP53 and high level of bulky DNA adducts in a human study, which is a significant scientific progress from the in vitro studies in the exploration of the causal relationship between a carcinogen-DNA adduct and a gene mutation.en_GB
dc.description.sponsorshipThis work was supported in parts by Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS), a Network of Excellence operating within the European Union 6th Framework Program, Priority 5: ‘Food Quality and Safety’ (Contract No 513943); the Országos Tudományos Kutatási Alap [OTKA T034616]; the Hungarian-Finnish Science and Technology Foundation [SF-02/01, SF-14/03]. I was awarded an ECNIS Exchange Fellowship to DKFZ, where I conducted the O4-ethyltymidine measurements.en_GB
dc.language.isoenen
dc.subjectTobacco smoke carcinogensen_GB
dc.subjectLung canceren_GB
dc.subjectDNA damageen_GB
dc.subjectBiomarkersen_GB
dc.subjectDNA adductsen_GB
dc.subjectOncogenesen_GB
dc.subjectCarcinogenesisen_GB
dc.subjectMutationsen_GB
dc.subjectHumanen_GB
dc.subjectMolecular mechanismsen_GB
dc.subjectEpidemiological studiesen_GB
dc.titleInvestigation of the associations of smoking-related DNA damages with biomarkers in a human lung cancer population.en
dc.typeThesisen
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