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Genetics and genomics of radiotherapy toxicity: towards prediction

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      Abstract

      Radiotherapy is involved in many curative treatments of cancer; millions of survivors live with the consequences of treatment, and toxicity in a minority limits the radiation doses that can be safely prescribed to the majority. Radiogenomics is the whole genome application of radiogenetics, which studies the influence of genetic variation on radiation response. Work in the area focuses on uncovering the underlying genetic causes of individual variation in sensitivity to radiation, which is important for effective, safe treatment. In this review, we highlight recent advances in radiotherapy and discuss results from four genome-wide studies of radiotoxicity.

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      Finding the missing heritability of complex diseases.

      Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
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        Tolerance of normal tissue to therapeutic irradiation.

        The importance of knowledge on tolerance of normal tissue organs to irradiation by radiation oncologists cannot be overemphasized. Unfortunately, current knowledge is less than adequate. With the increasing use of 3-D treatment planning and dose delivery, this issue, particularly volumetric information, will become even more critical. As a part of the NCI contract N01 CM-47316, a task force, chaired by the primary author, was formed and an extensive literature search was carried out to address this issue. In this issue. In this manuscript we present the updated information on tolerance of normal tissues of concern in the protocols of this contract, based on available data, with a special emphasis on partial volume effects. Due to a lack of precise and comprehensive data base, opinions and experience of the clinicians from four universities involved in the contract have also been contributory. Obviously, this is not and cannot be a comprehensive work, which is beyond the scope of this contract.
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          Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications.

          Genome integrity is constantly monitored by sophisticated cellular networks, collectively termed the DNA damage response (DDR). A common feature of DDR proteins is their mobilization in response to genotoxic stress. Here, we outline how the development of various complementary methodologies has provided valuable insights into the spatiotemporal dynamics of DDR protein assembly/disassembly at sites of DNA strand breaks in eukaryotic cells. Considerable advances have also been made in understanding the underlying molecular mechanisms for these events, with post-translational modifications of DDR factors being shown to play prominent roles in controlling the formation of foci in response to DNA-damaging agents. We review these regulatory mechanisms and discuss their biological significance to the DDR.
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            Author and article information

            Affiliations
            [1 ]School of Cancer and Enabling Sciences, The University of Manchester, Manchester Academic Health Science Centre, The Christie, Wilmslow Road, Manchester M20 4BX, UK
            [2 ]University of Cambridge Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
            Contributors
            Journal
            Genome Med
            Genome Medicine
            BioMed Central
            1756-994X
            2011
            23 August 2011
            23 August 2012
            : 3
            : 8
            : 52
            3238178
            gm268
            21861849
            10.1186/gm268
            Copyright ©2011 BioMed Central Ltd.
            Categories
            Review

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