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Vesicular AGR2 splice variants for noninvasive diagnostic of prostate carcinoma (VEDIPRO)

Projektbeschreibung:
Prostate cancer (PC) is the most widespread malignancy in men and the second most common cause of cancer-related death in men. For Europe, the incidence of PC in 2012 was 417/100,000 with a mortality rate of 92.2/100,000 (Ferlay et al., 2012). In Germany, 70.000 new PC cases were diagnosed in 2014 (RKI) and about 12.000 men die of PC every year (RKI and GEKID). Current diagnostic gold standard is histological confirmation by invasive needle biopsy with partly severe side effects. The conventional indication for histological confirmation is given by elevated levels of the prostate specific antigen (PSA) in blood. The sensitivity and specificity of PSA show high variability in different trials dependent on the cohort chosen and the design of the study. Accordingly, a recent database search revealed a sensitivity range from 78% to 100% and a specificity range from 6% to 66%. The lack of biomarkers with high sensitivity results in delayed or non-diagnosed relevant PC cases. Low specificity leads to high rates of false positives and a substantial number of unnecessary invasive confirmatory biopsies accompanied by severe psychological burdens. There is an obvious need for new, reliable biomarkers, which should fulfill two main criteria: high sensitivity, allowing to recognize relevant PC cases in early stages, and high specificity, sufficient to protect patients with insignificant PC or benign disorders of the prostate from overtreatment. Additionally, biomarkers with prognostic value suitable for better risk stratification and delineation of different risk groups among the identified PC cases should be established as an essential prerequisite for further personalization of medicine, allowing to improve therapeutic strategies and to reduce cases of overtreatment. In this project, we will validate a recently described potential biomarker for early detection of PC cases by the analysis of RNA from urine EV. In our preliminary study, we described new splice variants (SV) of the Anterior-Gradient 2 (AGR2) gene and demonstrated that the mRNAs levels of AGR2-SVs in the vesicles isolated from the urine of patients with PC can serve as diagnostic markers with sensitivity and specificity significantly higher as PSA serum level. However only a limited number of patients (n39) was analyzed in this study (Neeb et al., Oncotarget 2014). A larger clinical study (n230) will be carried out in the current project for the validation of the AGR2-SVs as potential biomarkers. Additionally to AGR2, TMRSS2:EGR fusion RNA, PCA3 and PSA will be examined as established PC biomarker. To increase sensitivity of AGR2 detection, digital PCR will be established and carried out instead of the conventional PCR. Additionally, improvements of the EV isolation routine will be conducted in collaboration with Exosomics Siena SpA. For that additional 10 ml urine will be collected from all patients. EVs from first 30 patients of the cohort will be isolated using ultracentrifugation and isolation kit provided by the Exosomics Siena SpA. RNA isolated from the vesicles will be further processed using ddPCR. Based on the results of ddPCR, one of the methods will be chosen to process remaining patient cohort (n=200). As a results, a conclusion about applicability of AGR2 SVs as biomarkers for early PC detection will be done.

Ansprechpartner: PD Irina Nazarenko
Tel: 270-82100
Email: irina.nazarenko@uniklinik-freiburg.de
Projektlaufzeit:
Projektbeginn: 01.08.2018
Projektende: 31.07.2020
Projektleitung:
Nazarenko I

Albert-Ludwigs-Universität Freiburg
Institut für Infektionsprävention und Krankenhaushygiene

Breisacher Str. 115 B
79106 Freiburg

Telefon: 0761-270-82060
Fax: 0761-270-82030
http://www.uniklinik-freiburg.de/iuk/live/index.html
Finanzierung:

  • Exosomics Siena S.p.A., Firma

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