Unique proteomic signature for radiation sensitive patients: a comparative study between normo-sensitive and radiation sensitive breast cancer patients
(English)Manuscript (preprint) (Other academic)
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.
low dose radiation, proteomics, acute adverse healthy tissue effects, radiation sensitivity
IdentifiersURN: urn:nbn:se:su:diva-97122OAI: oai:DiVA.org:su-97122DiVA: diva2:675670