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Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes

Although family history is a major risk factor for colorectal cancer (CRC) a genetic diagnosis cannot be obtained in over 50 % of familial cases when screened for known CRC cancer susceptibility genes. The genetics of undefined-familial CRC is complex and recent studies have implied additional clini...

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Autores principales: Dobbins, Sara E., Broderick, Peter, Chubb, Daniel, Kinnersley, Ben, Sherborne, Amy L., Houlston, Richard S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Netherlands 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010824/
https://www.ncbi.nlm.nih.gov/pubmed/27356891
http://dx.doi.org/10.1007/s10689-016-9914-4
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author Dobbins, Sara E.
Broderick, Peter
Chubb, Daniel
Kinnersley, Ben
Sherborne, Amy L.
Houlston, Richard S.
author_facet Dobbins, Sara E.
Broderick, Peter
Chubb, Daniel
Kinnersley, Ben
Sherborne, Amy L.
Houlston, Richard S.
author_sort Dobbins, Sara E.
collection PubMed
description Although family history is a major risk factor for colorectal cancer (CRC) a genetic diagnosis cannot be obtained in over 50 % of familial cases when screened for known CRC cancer susceptibility genes. The genetics of undefined-familial CRC is complex and recent studies have implied additional clinically actionable mutations for CRC in susceptibility genes for other cancers. To clarify the contribution of non-CRC susceptibility genes to undefined-familial CRC we conducted a mutational screen of 114 cancer susceptibility genes in 847 patients with early-onset undefined-familial CRC and 1609 controls by analysing high-coverage exome sequencing data. We implemented American College of Medical Genetics and Genomics standards and guidelines for assigning pathogenicity to variants. Globally across all 114 cancer susceptibility genes no statistically significant enrichment of likely pathogenic variants was shown (6.7 % cases 57/847, 5.3 % controls 85/1609; P = 0.15). Moreover there was no significant enrichment of mutations in genes such as TP53 or BRCA2 which have been proposed for clinical testing in CRC. In conclusion, while we identified genes that may be considered interesting candidates as determinants of CRC risk warranting further research, there is currently scant evidence to support a role for genes other than those responsible for established CRC syndromes in the clinical management of familial CRC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10689-016-9914-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-50108242016-09-16 Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes Dobbins, Sara E. Broderick, Peter Chubb, Daniel Kinnersley, Ben Sherborne, Amy L. Houlston, Richard S. Fam Cancer Original Article Although family history is a major risk factor for colorectal cancer (CRC) a genetic diagnosis cannot be obtained in over 50 % of familial cases when screened for known CRC cancer susceptibility genes. The genetics of undefined-familial CRC is complex and recent studies have implied additional clinically actionable mutations for CRC in susceptibility genes for other cancers. To clarify the contribution of non-CRC susceptibility genes to undefined-familial CRC we conducted a mutational screen of 114 cancer susceptibility genes in 847 patients with early-onset undefined-familial CRC and 1609 controls by analysing high-coverage exome sequencing data. We implemented American College of Medical Genetics and Genomics standards and guidelines for assigning pathogenicity to variants. Globally across all 114 cancer susceptibility genes no statistically significant enrichment of likely pathogenic variants was shown (6.7 % cases 57/847, 5.3 % controls 85/1609; P = 0.15). Moreover there was no significant enrichment of mutations in genes such as TP53 or BRCA2 which have been proposed for clinical testing in CRC. In conclusion, while we identified genes that may be considered interesting candidates as determinants of CRC risk warranting further research, there is currently scant evidence to support a role for genes other than those responsible for established CRC syndromes in the clinical management of familial CRC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10689-016-9914-4) contains supplementary material, which is available to authorized users. Springer Netherlands 2016-06-29 2016 /pmc/articles/PMC5010824/ /pubmed/27356891 http://dx.doi.org/10.1007/s10689-016-9914-4 Text en © The Author(s) 2016 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.
spellingShingle Original Article
Dobbins, Sara E.
Broderick, Peter
Chubb, Daniel
Kinnersley, Ben
Sherborne, Amy L.
Houlston, Richard S.
Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes
title Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes
title_full Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes
title_fullStr Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes
title_full_unstemmed Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes
title_short Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes
title_sort undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010824/
https://www.ncbi.nlm.nih.gov/pubmed/27356891
http://dx.doi.org/10.1007/s10689-016-9914-4
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