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Radiation induced biomarkers of individual sensitivity to radiation therapy
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fifty percent of solid cancers are treated with radiation therapy (RT). The dose used in RT is adjusted to the most sensitive individuals so that not more than 5% of the patients will have severe adverse healthy tissue effects. As a consequence, the majority of the patients will receive a suboptimal dose, as they would have tolerated a higher total dose and received a better tumor control. Thus, if RT could be individualized based on radiation sensitivity (RS), more patients would be cured and the most severe adverse reactions could be avoided. At present the mechanisms behind RS are not known.

The long term aim of this thesis was to develop diagnostic tools to assess the individual RS of breast cancer patients and to better understand the mechanisms behind the RS and radiation effects after low dose exposures. The approach was based on the hypothesis that biomarkers of individual RS, in terms of acute adverse skin reactions after breast cancer RT, can be found in whole blood that has been stressed by low doses of ionizing radiation (IR). 

To reach this goal two different approaches to identify biomarkers of RS have been investigated. A protocol for the analysis of differential protein expression in response to low dose in vitro irradiated whole blood was developed (paper I). This protocol was then used to investigate the proteomic profile of radiation sensitive and normo-sensitive patients, using isotope-coded protein labeled proteomics (ICPL). The results from the ICPL study (paper III) show that the two patient groups have different protein expression profiles both at the basal level and after IR. In paper II the potential biomarker 8-oxo-dG was investigated in serum after IR. The relative levels of IR induced 8-oxo-dG from radiation sensitive patients differ significantly from normo-sensitive patients. This indicates that the sensitive patients differ in their cellular response to IR and that 8-oxo-dG is a potential biomarker for RS.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2014. , 42 p.
Keyword [en]
low dose ionizing radiation, radiation sensitivity, proteomics, whole blood, 8-oxo-dG, oxidative stress, acute adverse healthy tissue effects
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-97123ISBN: 978-91-7447-824-2 (print)OAI: oai:DiVA.org:su-97123DiVA: diva2:676039
Public defence
2014-01-31, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.

Available from: 2014-01-09 Created: 2013-12-04 Last updated: 2015-03-10Bibliographically approved
List of papers
1. Low doses of γ-radiation induce consistent protein expression changes in human leukocytes
Open this publication in new window or tab >>Low doses of γ-radiation induce consistent protein expression changes in human leukocytes
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2011 (English)In: International Journal of Low Radiation, ISSN 1477-6545, E-ISSN 1741-9190, Vol. 8, no 5/6, 374-387 p.Article in journal (Refereed) Published
Abstract [en]

Twenty percent of cancer patients experience adverse effects after radiotherapy. The therapeutic doses are adjusted to the most sensitive individuals, resulting in a suboptimal dose for many patients. At present there is no screening system available to predict individual radiosensitivity. The main aim of this study is to investigate differences in protein expression pathways induced by low doses of radiation in whole blood obtained from radiosensitive and non–radiosensitive patients. To address this aim, a protocol for exposure condition, dose and analysis of whole blood was developed. The conditions for handling blood samples were optimised. The optimal doses and post irradiation conditions were determined. We found that 1 mGy and 150 mGy significantly changed protein expression in leukocytes collected from the two donors. The result shows that the protocol developed is suitable for characterisation of proteomic profiles associated with low dose exposure of leukocytes.

Place, publisher, year, edition, pages
Inderscience Publishers: , 2011
Keyword
low dose radiation; Oxidative stress; proteomics; whole blood; gamma radiation
National Category
Cell Biology Other Biological Topics
Research subject
Molecular Biology
Identifiers
urn:nbn:se:su:diva-97111 (URN)10.1504/IJLR.2011.047188 (DOI)
Funder
Swedish Radiation Safety AuthoritySwedish Cancer Society
Available from: 2013-12-03 Created: 2013-12-03 Last updated: 2017-12-06Bibliographically approved
2. Radiation-induced stress response in peripheral blood of breast cancer patients differs between patients with severe acute skin reactions and patients with no side effects to radiotherapy
Open this publication in new window or tab >>Radiation-induced stress response in peripheral blood of breast cancer patients differs between patients with severe acute skin reactions and patients with no side effects to radiotherapy
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2013 (English)In: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 756, no 1-2, 152-157 p.Article in journal (Refereed) Published
Abstract [en]

The aim of the study was to compare the radiation-induced oxidative stress response in blood samples from breast cancer patients that developed severe acute skin reactions during the radiotherapy, with the response in blood samples from patients with no side effects. Peripheral blood was collected from 12 breast cancer patients showing no early skin reactions after radiotherapy (RTOG grade 0) and from 14 breast cancer patients who developed acute severe skin reactions (RTOG grade 3-4). Whole blood was irradiated with 0, 5 and 2000 mGy gamma-radiation and serum was isolated. The biomarker for oxidative stress, 8-oxo-dG, was analyzed in the serum by a modified ELISA. While a significant radiation-induced increase of serum 8-oxo-dG levels was observed in serum of the RTOG 0 patients, no increase was seen in serum of the RTOG 3-4 patients. The radiation induced increase in serum 8-oxo-dG levels after 5 mGy did not differ significantly from the increase observed for 2000 mGy in the RTOG 3-4 cohort, thus no dose response relation was observed. A receiver operating characteristic (ROC) value of 0.97 was obtained from the radiation-induced increase in 8-oxo-dG indicating that the assay could be used to identify patients with severe acute adverse reactions to radiotherapy. The results show that samples of whole blood from patients, classified as highly radiosensitive (RTOG 3-4) based on their skin reactions to radiotherapy, differ significantly in their oxidative stress response to ionizing radiation compared to samples of whole blood from patients with no skin reactions (RTOG 0). Extracellular 8-oxo-dG is primarily a biomarker of nucleotide damage and the results indicate that the patients with severe acute skin reactions differ in their cellular response to ionizing radiation at the level of induction of oxidative stress or at the level of repair or both.

Keyword
8-Oxo-dG, Oxidative stress, Predictive assay, Radiosensitivity, Breast cancer, Radiotherapy
National Category
Medical Biotechnology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Genetics
Identifiers
urn:nbn:se:su:diva-96120 (URN)10.1016/j.mrgentox.2013.04.014 (DOI)000325600300021 ()
Note

AuthorCount:9;

Funding agencies:

Swedish Cancer and Allergy Foundation;  Swedish Cancer Foundation;  Swedish Radiation Safety Authority 

Available from: 2013-11-13 Created: 2013-11-11 Last updated: 2017-12-06Bibliographically approved
3. Unique proteomic signature for radiation sensitive patients: a comparative study between normo-sensitive and radiation sensitive breast cancer patients
Open this publication in new window or tab >>Unique proteomic signature for radiation sensitive patients: a comparative study between normo-sensitive and radiation sensitive breast cancer patients
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Nearly every fourth person will be diagnosed with a cancer during their lifetime1 and approximately 50 percent of all cancers are treated with radiation therapy2. The therapy is adjusted to the most sensitive patients where 5 percent severe adverse acute healthy tissue effects are accepted. Twenty percent of all patients experience milder adverse effects from radiation therapy and there are indications that the patients with no signs of adverse effects have a higher probability of local reoccurrence of cancer within 5 years, indicating that they would have benefited from a higher dose of ionizing radiation (IR)3,4. If the individual radiation sensitivity could be determined before the start of radiation therapy, the dose could be personalized and the adverse effects reduced in sensitive patients. In addition, the probability to eradicate all cancer cells in normo-sensitive patients would increase. There is no generally accepted method available to diagnose radiation sensitivity before the start of the therapy and several studies on the mechanisms indicate that multifactorial mechanisms are involved.

The long-term aim of this study is to identify biomarkers of radiation sensitivity to enable an individualized treatment. We have previously shown that radiation sensitive and normo-sensitive patients differ in their radiation induced 8-oxo-dG levels (a marker of oxidative stress). We hypothesized that this difference is due to different cellular capability to handle oxidative stress, were radiation sensitive patients doesn’t induce an oxidative stress response or are incapable of repairing oxidative stress related damages.

To investigate the mechanisms behind radiation sensitivity 8 radiation sensitive (RTOG4) and 9 normo-sensitive (RTOG0) patients from a cohort of 2914 breast cancer patients with known normal tissue reactions after radiation therapy were selected. Whole blood was sampled and irradiated in vitro with 0, 1, or 150 mGy followed by 3 hour post-irradiation incubation at 37°C. The samples in the two groups were pooled to reduce individual variability not associated with radiation sensitivity responses. The protein expression profile of leukocytes was investigated with isotope-coded protein label (ICPL). First the differences in proteomic profiles of leukocytes isolated from normo-sensitive patients (RTOG 0) and extremely sensitive patients (RTOG 4) were investigated. Secondly, we analyzed leukocytes isolated from in vitro irradiated whole blood compared to non-irradiated whole blood within both groups. These two studies were done independent of each other using two different protein labeling methods.

Here we show unique proteomic signatures separating the two groups both at the basal level (non-irradiated samples) and after doses of 1 and 150 mGy. Pathway analyses of both proteomic approaches suggest that oxidative stress response, coagulation properties and acute phase response are hallmarks of radiation sensitivity. Additionally the oxidative stress response can be linked mechanistically to our previous 8-oxo-dG study. Finally this investigation provides unique protein expression profiles which might be useful in future to predict radiation sensitivity. 

Keyword
low dose radiation, proteomics, acute adverse healthy tissue effects, radiation sensitivity
National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-97122 (URN)
Available from: 2013-12-04 Created: 2013-12-04 Last updated: 2013-12-16

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