Association of polymorphisms in TGFB1, XRCC1, XRCC3 genes and CD8 T-lymphocyte apoptosis with adverse effect of radiotherapy for prostate cancer

The genetic background of each person might affect the severity of radiotherapy (RT)-induced normal tissue toxicity. The aim of study was to evaluate the influence of TGFB1 C-509T and Leu10Pro, XRCC1 Arg280His and XRCC3 Thr241Met polymorphisms as well as the level of radiation-induced CD8 T-lymphocyte apoptosis (RILA) on adverse effects of RT for prostate cancer (PCa). The study included 88 patients with localized or locally advanced PCa who were treated with RT. The polymorphisms were determined by PCR–RFLP analysis on DNA from peripheral blood mononuclear cells. RILA values were measured by flow cytometry. We found that CT genotype of TGFB1 C-509T could be protective biomarker for acute genitourinary (GU) and gastrointestinal (GI) radiotoxicity, while Thr variant of XRCC3 Thr241Met could predict the risk for acute GU radiotoxicity. Correlation between RILA values and toxicity was not detected. Univariate logistic regression analysis showed that Gleason score and risk group were risk factors for late GU, while for late GI radiotoxicity it was diabetes mellitus type 2. However, in multivariate model those were not proven to be significant and independent risk factors. Identification of assays combination predicting individual radiosensitivity is a crucial step towards personalized RT approach

Spleen plays a major role in DLL4-driven acute T-cell lymphoblastic leukemia.

The Notch pathway is highly active in almost all patients with T-cell acute lymphoblastic leukemia (T-ALL), but the implication of Notch ligands in T-ALL remains underexplored. Methods: We used a genetic mouse model of Notch ligand delta like 4 (DLL4)-driven T-ALL and performed thymectomies and splenectomies in those animals. We also used several patient-derived T-ALL (PDTALL) models, including one with DLL4 expression on the membrane and we treated PDTALL cells in vitro and in vivo with demcizumab, a blocking antibody against human DLL4 currently being tested in clinical trials in patients with solid cancer. Results: We show that surgical removal of the spleen abrogated T-ALL development in our preclinical DLL4-driven T-ALL mouse model. Mechanistically, we found that the spleen, and not the thymus, promoted the accumulation of circulating CD4+CD8+ T cells before T-ALL onset, suggesting that DLL4-driven T-ALL derives from these cells. Then, we identified a small subset of T-ALL patients showing higher levels of DLL4 expression. Moreover, in mice xenografted with a DLL4-positive PDTALL model, treatment with demcizumab had the same therapeutic effect as global Notch pathway inhibition using the potent γ-secretase inhibitor dibenzazepine. This result demonstrates that, in this PDTALL model, Notch pathway activity depends on DLL4 signaling, thus validating our preclinical mouse model. Conclusion: DLL4 expression in human leukemic cells can be a source of Notch activity in T-ALL, and the spleen plays a major role in a genetic mouse model of DLL4-driven T-ALL.We thank Drs. Susan Schwab, Dan Littman, Sherif Ibrahim, Angel Pellicer, Susanne Tranguch and Adolfo Ferrando for helpful discussions and/or critically comments on the manuscript. Elisabetta Andermarcher professionally edited the manuscript. We are indebted to Dr. M. Yan (Genentech) for the anti-DLL4 antibody for cytometry. We are also in debt with Christopher Murriel from Oncomed who provided the therapeutic murine anti-DLL4 antibody and demcizumab (anti-human DLL4 antibody). We thank the NYU School of Medicine Flow Cytometry Core facility, particularly Dr. Peter Lopez, Keith Kobylarz and Michael Gregory, and also the NYU School of Medicine Confocal imaging facility, particularly Yan Deng. We also thank Henry Alexandre Michaud for his great help with the FACS analysis of PDTALL cells. We thank Nelly Pirot and the rest of members of the IRCM IHC platform for their fantastic work. M.M. is supported by a contract from Fondation ARC. The NYU Cancer Institute Center Support Grant partially funded this core through grant NIH/NCI 5 P30CA16087-31. Work in JJL's laboratory is supported by the NIH/NIAID, National Multiple Sclerosis Society, and the Helmsley Charitable Trust. Work in AM's laboratory is supported by the Fondation ARC (PJA 20131200405), the European Commission (CIG631431), the Institute de Cancer de Montpellier Fondation, and the Institut National du Cancer (INCa_9257 and INCa-DGOS-Inserm 12553).S

REQUITE: A prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer

Purpose: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. Methods: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. Results: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician-(47,025 forms) and patient-(54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade >= 2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). Conclusion: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. Patient summary: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short-and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity

Métabolisme des ARNm au cours de la germination des spores de S. cerevisiae

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

One Size Fits All: Does the Dogma Stand in Radiation Oncology?

International audienceNearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency , decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08-4.69, p-value 4.16 × 10 −8) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90-3.86, p-value = 3.21 × 10 −8). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetranc

Personalizing Breast Cancer Irradiation Using Biology: From Bench to the Accelerator

International audienceWhile adjuvant treatments of early breast cancers (BCs) had significantly improved patients' overall survival, some of them will still develop locoregional relapses and/or severe late radio-induced toxicities. Here, we propose to review how to personalize locoregional treatment by identifying patients at high and low risk of locoregional relapse, patients at risk of late radio-induced side effects. We will, therefore, discuss how to enhance BC radiosensitivity. Finally, we will address how personalized radiotherapy could be implemented in prospective clinical trials

In Regard to Pereira et al

International audienc

The Alpha Helix of Ubiquitin Interacts with Yeast Cyclin-Dependent Kinase Subunit CKS1 †

International audienc

T lymphocytes to predict radiation-induced late effects in normal tissues

International audienceRadiotherapy is one of the main treatments for solid tumors. The total dose that can be delivered to the tumor is limited by the radiation amount received by the surrounding normal tissues, which are at risk of developing acute and late radiation-induced effects. Areas covered: Severe late radiation-induced toxicity occurs in 5% to 10% of patients following radiotherapy. However, the current radiotherapy and radiation protection protocols do not take into account the variations in radiosensitivity among individuals. This review will focus on late radiotherapy-induced side effects and on the different cellular assays (γ-H2AX/53BP1 focus formation, G2 metaphase, G0 micronucleus formation and radio-induced apoptosis in CD8+ T-lymphocytes: level I evidence) that have been developed to predict their occurrence in patients. Expert commentary: The routine prediction of late radiation-induced toxicity in normal tissues in the clinic will allow personalized radiotherapy with better outcome and less side effects. Patients at low risk of late toxicity could receive a higher total dose to the tumor. Conversely, patients at high risk of late toxicity should receive lower radiation doses per fraction, using state-of-the-art treatment techniques, or alternative therapies to avoid radiation-induced side effects