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Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies

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Abstract

Cancer cachexia is a complex and multifactorial disease. Evolving definitions highlight the fact that a diverse range of biological processes contribute to cancer cachexia. Part of the variation in who will and who will not develop cancer cachexia may be genetically determined. As new definitions, classifications and biological targets continue to evolve, there is a need for reappraisal of the literature for future candidate association studies. This review summarizes genes identified or implicated as well as putative candidate genes contributing to cachexia, identified through diverse technology platforms and model systems to further guide association studies. A systematic search covering 1986–2012 was performed for potential candidate genes / genetic polymorphisms relating to cancer cachexia. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Pathway analysis software was used to reveal possible network associations between genes. Functionality of SNPs/genes was explored based on published literature, algorithms for detecting putative deleterious SNPs and interrogating the database for expression of quantitative trait loci (eQTLs). A total of 154 genes associated with cancer cachexia were identified and explored for functional polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e., inflammation, loss of fat mass and/or lean mass and reduced survival). Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and to develop their potential as susceptibility biomarkers of cachexia.

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Authors and Affiliations

  1. Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK

    N. JOHNS, M. MACMILLAN, J. A. ROSS & K. C. H. FEARON

  2. Department of Surgery, Royal Derby Hospital, Uttoxeter Rd, Derby, DE22 3NE, UK

    B. H. TAN

  3. Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), 7030, Trondheim, Norway

    T. S. SOLHEIM

  4. Department of Oncology, Division of Palliative Care Medicine, University of Alberta, Edmonton, Alberta, T6G IZ2, Canada

    V. E. BARACOS

  5. Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, T6G IZ2, Canada

    S. DAMARAJU

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Johns N., Tan B. H., MacMillan M., Solheim T. S., Ross J. A., Baracos V. E., Damaraju S. and Fearon K. C. H. 2014 Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies. J. Genet. 93, xx–xx

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JOHNS, N., TAN, B.H., MACMILLAN, M. et al. Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies. J Genet 93, 893–916 (2014). https://doi.org/10.1007/s12041-014-0405-9

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