Michel Bourguignon

Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity

PURPOSE Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. METHODS AND MATERIALS Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. RESULTS OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. CONCLUSIONS Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III).

Individual response to ionizing radiation

The human response to ionizing radiation (IR) varies among individuals. The first evidence of the individual response to IR was reported in the beginning of the 20th century. Considering nearly one century of observations, we here propose three aspects of individual IR response: radiosensitivity for early or late adverse tissue events after radiotherapy on normal tissues (non-cancer effects attributable to cell death); radiosusceptibility for IR-induced cancers; and radiodegeneration for non-cancer effects that are often attributable to mechanisms other than cell death (e.g., cataracts and circulatory disease). All the molecular and cellular mechanisms behind IR-induced individual effects are not fully elucidated. However, some specific assays may help their quantification according to the dose and to the genetic status. Accumulated data on individual factors have suggested that the individual IR response cannot be ignored and raises some clinical and societal issues. The individual IR response therefore needs to be taken into account to better evaluate the risks related to IR exposure.

100 Years of Individual Radiosensitivity: How We Have Forgotten the Evidence

The time has come to individualize radiation prescriptions on the basis of individual response rather than on population averages of organ tolerance.

Functional Assays for Individual Radiosensitivity: A Critical Review☆

A complete understanding of the mechanisms of the response to radiation would help in a better evaluation of the radiation-induced risks. To this aim, individual radiosensitivity, that is, the proneness to radiation-induced tissue reactions attributable to cell death, has been documented since the beginning of the 20th century. For several decades, developing informative predictive assays has been one of the most important challenges of radiobiologists. This article is a critical review devoted to the major functional assays to predict radiosensitivity and their strengths and weaknesses, notably those based on the quantification of clonogenic cell survival, micronuclei, p21 expression, apoptosis, chromosome and DNA repair, and signaling. Genomic approaches of radiosensitivity are reviewed in another article of this issue.

The use of the term ‘radiosensitivity’ through history of radiation: from clarity to confusion

Abstract Purposes: The term ‘radiosensitivity’ appeared for the first time at the beginning of the 20th century, few years after the discovery of X-rays. Initially used by French and German radiologists, it illustrated the risk of radiation-induced (RI) skin reactions. From the 1950s, ‘radiosensitivity’ was progressively found to describe other features of RI response such as RI cancers or cataracts. To date, such confusion may raise legal issues and complexify the message addressed to general public. Here, through an historical review, we aimed to better understand how this confusion appeared. Methods: To support our historical review, a quantitative and qualitative wording analysis of the ‘radiosensitivity’ occurrences and its derived terms was performed with Google books, Pubmed, Web of Science™ databases, and in all the ICRP publications. Conclusions: While ‘radiosensitivity’ was historically related to RI adverse tissue events attributable to cell death, the first efforts to quantify the RI risk specific to each organ/tissue revealed some different semantic fields that are not necessarily compatible together (e.g. adverse tissue events for skin, cataracts for eyes, RI cancer for breast or thyroid). To avoid such confusion, we propose to keep the historical definition of ‘radiosensitivity’ to any clinical and cellular consequences of radiation attributable to cell death and to introduce the term ‘radiosusceptibility’ to describe the RI cancers or any feature that is attributable to cell transformation.