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Unique proteomic signature for radiation sensitive patients: a comparative study between normo-sensitive and radiation sensitive breast cancer patients
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Institute of Radiation Biology, German Research Center for Environmental Health, Helmholtz Zentrum München.
Division of Radiotherapy, Radiumhemmet, Karolinska University Hospital.
Division of Radiotherapy, Radiumhemmet, Karolinska University Hospital.
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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 [en]
low dose radiation, proteomics, acute adverse healthy tissue effects, radiation sensitivity
National Category
Natural Sciences
URN: urn:nbn:se:su:diva-97122OAI: diva2:675670
Available from: 2013-12-04 Created: 2013-12-04 Last updated: 2013-12-16
In thesis
1. Radiation induced biomarkers of individual sensitivity to radiation therapy
Open this publication in new window or tab >>Radiation induced biomarkers of individual sensitivity to radiation therapy
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.
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
urn:nbn:se:su:diva-97123 (URN)978-91-7447-824-2 (ISBN)
Public defence
2014-01-31, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)

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

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Skiöld, SaraHarms-Ringdahl, MatsHaghdoost, Siamak
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