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      The genetic heterogeneity of colorectal cancer predisposition - guidelines for gene discovery

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          Abstract

          Background

          Colorectal cancer (CRC) is a cumulative term applied to a clinically and genetically heterogeneous group of neoplasms that occur in the bowel. Based on twin studies, up to 45 % of the CRC cases may involve a heritable component. Yet, only in 5–10 % of these cases high-penetrant germline mutations are found (e.g. mutations in APC and DNA mismatch repair genes) that result in a familial aggregation and/or an early onset of the disease. Genome-wide association studies have revealed that another ~5 % of the CRC cases may be explained by a cumulative effect of low-penetrant risk factors. Recent attempts to identify novel genetic factors using whole exome and whole genome sequencing has proven to be difficult since the remaining, yet to be discovered, high penetrant CRC predisposing genes appear to be rare. In addition, most of the moderately penetrant candidate genes identified so far have not been confirmed in independent cohorts. Based on literature examples, we here discuss how careful patient and cohort selection, candidate gene and variant selection, and corroborative evidence may be employed to facilitate the discovery of novel CRC predisposing genes.

          Conclusions

          The picture emerges that the genetic predisposition to CRC is heterogeneous, involving complex interplays between common and rare (inter)genic variants with different penetrances. It is anticipated, however, that the use of large clinically well-defined patient and control datasets, together with improved functional and technical possibilities, will yield enough power to unravel this complex interplay and to generate accurate individualized estimates for the risk to develop CRC.

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          Most cited references125

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          A genetic model for colorectal tumorigenesis.

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            Cancer genes and the pathways they control.

            The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.
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              Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors.

              In this article, the incidence, mortality, and survival rates for colorectal cancer are reviewed, with attention paid to regional variations and changes over time. A concise overview of known risk factors associated with colorectal cancer is provided, including familial and hereditary factors, as well as environmental lifestyle-related risk factors such as physical inactivity, obesity, smoking, and alcohol consumption.
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                Author and article information

                Contributors
                31-24-3614017 , roland.kuiper@radboudumc.nl
                Journal
                Cell Oncol (Dordr)
                Cell Oncol (Dordr)
                Cellular Oncology (Dordrecht)
                Springer Netherlands (Dordrecht )
                2211-3428
                2211-3436
                9 June 2016
                9 June 2016
                2016
                : 39
                : 6
                : 491-510
                Affiliations
                Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
                Article
                284
                10.1007/s13402-016-0284-6
                5121185
                27279102
                5c9ba8e3-0269-4884-bd86-af58886ea0f7
                © The Author(s) 2016

                Open Access This 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
                : 27 May 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001826, ZonMw;
                Award ID: 917-10-358
                Funded by: KWF Kankerbestrijding (NL)
                Award ID: KUN2009-4335
                Funded by: FundRef http://dx.doi.org/10.13039/501100004622, KWF Kankerbestrijding;
                Award ID: KUN2014-6666
                Categories
                Review
                Custom metadata
                © International Society for Cellular Oncology 2016

                Oncology & Radiotherapy
                colorectal cancer,genetic predisposition,next generation sequencing,candidate gene identification

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