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      An integrative view on sex differences in brain tumors

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          Abstract

          Sex differences in human health and disease can range from undetectable to profound. Differences in brain tumor rates and outcome are evident in males and females throughout the world and regardless of age. These observations indicate that fundamental aspects of sex determination can impact the biology of brain tumors. It is likely that optimal personalized approaches to the treatment of male and female brain tumor patients will require recognizing and understanding the ways in which the biology of their tumors can differ. It is our view that sex-specific approaches to brain tumor screening and care will be enhanced by rigorously documenting differences in brain tumor rates and outcomes in males and females, and understanding the developmental and evolutionary origins of sex differences. Here we offer such an integrative perspective on brain tumors. It is our intent to encourage the consideration of sex differences in clinical and basic scientific investigations.

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          Most cited references172

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          Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis.

          Previously undescribed prognostic subclasses of high-grade astrocytoma are identified and discovered to resemble stages in neurogenesis. One tumor class displaying neuronal lineage markers shows longer survival, while two tumor classes enriched for neural stem cell markers display equally short survival. Poor prognosis subclasses exhibit markers either of proliferation or of angiogenesis and mesenchyme. Upon recurrence, tumors frequently shift toward the mesenchymal subclass. Chromosomal locations of genes distinguishing tumor subclass parallel DNA copy number differences between subclasses. Functional relevance of tumor subtype molecular signatures is suggested by the ability of cell line signatures to predict neurosphere growth. A robust two-gene prognostic model utilizing PTEN and DLL3 expression suggests that Akt and Notch signaling are hallmarks of poor prognosis versus better prognosis gliomas, respectively.
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            Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.

            Mutations in the p53 tumour-suppressor gene are the most frequently observed genetic lesions in human cancers. To investigate the role of the p53 gene in mammalian development and tumorigenesis, a null mutation was introduced into the gene by homologous recombination in murine embryonic stem cells. Mice homozygous for the null allele appear normal but are prone to the spontaneous development of a variety of neoplasms by 6 months of age. These observations indicate that a normal p53 gene is dispensable for embryonic development, that its absence predisposes the animal to neoplastic disease, and that an oncogenic mutant form of p53 is not obligatory for the genesis of many types of tumours.
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              Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions.

              Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue's homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to "bad luck," that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes. Copyright © 2015, American Association for the Advancement of Science.
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                Author and article information

                Contributors
                314-286-2790 , rubin_j@kids.wustl.edu
                Journal
                Cell Mol Life Sci
                Cell. Mol. Life Sci
                Cellular and Molecular Life Sciences
                Springer Basel (Basel )
                1420-682X
                1420-9071
                19 May 2015
                19 May 2015
                2015
                : 72
                : 17
                : 3323-3342
                Affiliations
                [ ]Department of Pediatrics, Washington University School of Medicine, St Louis, USA
                [ ]Department of Philosophy, Washington University in St Louis, St Louis, USA
                [ ]Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 South Euclid Ave, St Louis, MO 63110 USA
                [ ]Campus Box 8208, 660 South Euclid Ave, St Louis, MO 63110 USA
                Article
                1930
                10.1007/s00018-015-1930-2
                4531141
                25985759
                8f51d0a2-87f5-439c-9eb6-b10e86ac6648
                © The Author(s) 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 26 February 2015
                : 27 April 2015
                : 11 May 2015
                Categories
                Review
                Custom metadata
                © Springer Basel 2015

                Molecular biology
                metabolism,cancer,immunity,sex determination,evolution,sexual dimorphism
                Molecular biology
                metabolism, cancer, immunity, sex determination, evolution, sexual dimorphism

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