Discovering Clinical Biomarkers of Ionizing Radiation Exposure with Serum Proteomic Analysis

Abstract

In this study, we sought to explore the merit of proteomic profiling strategies in patients with cancer before and during radiotherapy in an effort to discover clinical biomarkers of radiation exposure. Patients with a diagnosis of cancer provided informed consent for enrollment on a study permitting the collection of serum immediately before and during a course of radiation therapy. High-resolution surfaceenhanced laser desorption and ionization-time of flight (SELDI-TOF) mass spectrometry (MS) was used to generate high-throughput proteomic profiles of unfractionated serum samples using an immobilized metal ion-affinity chromatography nickel-affinity chip surface. Resultant proteomic profiles were analyzed for unique biomarker signatures using supervised classification techniques. MS-based protein identification was then done on pooled sera in an effort to begin to identify specific protein fragments that are altered with radiation exposure. Sixty-eight patients with a wide range of diagnoses and radiation treatment plans provided serum samples both before and during ionizing radiation exposure. Computer-based analyses of the SELDI protein spectra could distinguish unexposed from radiation-exposed patient samples with 91% to 100% sensitivity and 97% to 100% specificity using various classifier models. The method also showed an ability to distinguish high from low dose-volume levels of exposure with a sensitivity of 83% to 100% and specificity of 91% to 100%. Using direct identity techniques of albuminbound peptides, known to underpin the SELDI-TOF fingerprints, 23 protein fragments/peptides were uniquely detected in the radiation exposure group, including an interleukin-6 precursor protein. The composition of proteins in serum seems to change with ionizing radiation exposure. Proteomic analysis for the discovery of clinical biomarkers of radiation exposure warrants further study. (Cancer Res 2006; 66(3): 1844-50)

Humoral response to a viral glycan correlates with survival on PROSTVAC-VF

“…As mentioned previously, spontaneous changes in antibody levels to these glycans were not found in healthy subjects or in nonvaccinated prostate cancer patients treated with radiation in another study (Fig. 2B) (28). This pattern of antibody changes occurring after inoculation with PROSTVAC-VF or its control viral vectors, but not in healthy subjects or nonvaccinated patients, is consistent with a response to glycans on the viral vectors, as discussed in more detail below.…”

“…A number of patients also showed changes for BG-A di (discovery set = 46%; maximum fold change = 33.7×) and BG-A tri (discovery set = 39%; maximum fold change = 9.2×). However, spontaneous changes in antibody levels to these glycans were not found in healthy subjects or nonvaccinated prostate cancer patients treated with radiation in another study (28) (Fig. 2B).…”

Time‐course analysis of mouse serum proteome changes following exposure of the skin to ionizing radiation

“…A solution for a more extensive analysis of the serum proteome after irradiation may consist in the utilization of different methodologies, for instance fractionation by HPLC and/or immunoaffinity column in combination with LC-MS/MS, 2-DE (using different gradient pH in the first dimension), and SELDI-TOF. To a lesser extent, it would be interesting to explore the proteins bound to albumin, as reported by Menard et al [6] who investigated the albumin bound fraction of serum in patient before and during radiotherapy, because this may increase the number of biomarker candidates.…”

“…Previous studies have emphasized the importance of this investigation in the field of occupational exposure [1], nuclear accident [2], and for early markers of clinical response to radiation therapy [3][4][5][6]. A report from the International Atomic Energy Agency has recently pointed out the increasing interest in the characterization of molecular profiles that predict normal tissue radiotherapy response [7].…”

Proteomic technology for biomarker profiling in cancer: an update

“…Yet, the identity of the biomarkers remains unknown. The technique has also been used to study pancreatic cancer, prostate cancer, and recently head and neck cancer (Menard et al, 2006;Kozak et al, 2005;Clarke et al, 2005;Nishizuka et al, 2003;Paweletz et al, 2001). This technique has some reported disadvantages, including protein concentrations responsible for the 'peaks' in SELDI that are in the µg/ml range, much higher than known biomarkers such as PSA (prostate specific antigen).…”