Gene Profile Highlights Late Rectal Bleeding Protection in Prostate Cancer 3D Conformal Radiation

Article Outline

• Purpose/Objective(s)
• Materials/Methods
• Results
• Conclusions
• Copyright

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Purpose/Objective(s) 

Despite 3-D CRT, 5–10% patients (pts) treated for prostate cancer can still suffer from significant morbidity (tox). Based on recent findings where abnormal transcriptional responses to DNA damage were associated to acute tox, to identify markers predicting late rectal bleeding (lrb), we analysed 35 genes involved in DNA-repair or pathways known as targets for RT. Pts were selected within the AIROPROS 0101 trial, designed to study the correlation between lrb and dosimetric parameters. Accurate dose-volume information (DVH) can help minimize the potential bias due to inaccurate dose delivery.

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Materials/Methods 

30 pts undergoing high dose (>74 Gy) CRT (min f-up: 24 mos) were selected: a) 10 pts in the low risk group (V70 < 15% and V50 < 45%) showing G2-3 lrb (“radio-sensitive” pts); b) 10 pts in the high risk group (V70 > 25% and V50 > 60%) with G2-3 lrb; c) 10 pts in the high risk group showing no tox (“radio-resistant” pts). As control group 10 healthy donors were used. Quantitative RT-PCR was performed using Taqman Assays-on-Demand on RNA from lymphoblastoid cells (LCL) obtained from EBV-immortalized peripheral blood mononuclear cells. LCLs from each pt were partly irradiated using a 137Cs source (5 Gy), partly left untreated. Inter- and intra-group expression levels with and without RT and class prediction were compared using the BRB ArrayTools, at p < 0.05.

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Results 

Intra-group comparison before and after RT showed that RT modulated 75% of the analyzed genes in at least one of the 4 groups and most were up-regulated. 10 genes were modulated in the “resistant”, 4 were decreased by RT. The other groups presented 18–21 modulated genes, most of them (14–20) RT induced. Inter-group comparison highlighted many differences before treatment, mostly among the “resistant” and the “sensitive” groups. 10 genes, mainly involved in cell cycle, DNA repair and proteasome degradation were significantly higher in the “resistant” suggesting a protection from adverse reactions. Differences were strongly reduced after treatment, when only 3 genes were modulated. Most genes were expressed at the same levels in untreated “resistant” pts and in all the other groups after RT, including healthy donors, suggesting a constitutive activation of these genes in the “resistant” pts. One of the identified genes distinguishes resistant pts from the others.

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Conclusions 

To the best of our knowledge this is the first report identifying genes predicting pts radioresistant to lrb. Pts showing no lrb despite high-risk DVH reveal several genes with higher basal levels than other pts/donors. One of these genes might be proposed as a putative biomarker able to predict late tox protection. Markers recognizing pts at low risk for late tox could permit the use of more “flexible” DVH constraints and/or to safely deliver higher RT doses.

This study is partially financed by Fondazione I. Monzino.