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Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort

The underlying genetic cause of colorectal cancer (CRC) can be identified for 5-10% of all cases, while at least 20% of CRC cases are thought to be due to inherited genetic factors. Screening for highly penetrant mutations in genes associated with Mendelian cancer syndromes using next-generation seq...

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Autores principales: Raskin, Leon, Guo, Yan, Du, Liping, Clendenning, Mark, Rosty, Christophe, Lindor, Noralane M., Gruber, Stephen B., Buchanan, Daniel D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706810/
https://www.ncbi.nlm.nih.gov/pubmed/29212164
http://dx.doi.org/10.18632/oncotarget.18596
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author Raskin, Leon
Guo, Yan
Du, Liping
Clendenning, Mark
Rosty, Christophe
Lindor, Noralane M.
Gruber, Stephen B.
Buchanan, Daniel D.
author_facet Raskin, Leon
Guo, Yan
Du, Liping
Clendenning, Mark
Rosty, Christophe
Lindor, Noralane M.
Gruber, Stephen B.
Buchanan, Daniel D.
author_sort Raskin, Leon
collection PubMed
description The underlying genetic cause of colorectal cancer (CRC) can be identified for 5-10% of all cases, while at least 20% of CRC cases are thought to be due to inherited genetic factors. Screening for highly penetrant mutations in genes associated with Mendelian cancer syndromes using next-generation sequencing (NGS) can be prohibitively expensive for studies requiring large samples sizes. The aim of the study was to identify rare single nucleotide variants and small indels in 40 established or candidate CRC susceptibility genes in 1,046 familial CRC cases (including both MSS and MSI-H tumor subtypes) and 1,006 unrelated controls from the Colon Cancer Family Registry Cohort using a robust and cost-effective DNA pooling NGS strategy. We identified 264 variants in 38 genes that were observed only in cases, comprising either very rare (minor allele frequency <0.001) or not previously reported (n=90, 34%) in reference databases, including six stop-gain, three frameshift, and 255 non-synonymous variants predicted to be damaging. We found novel germline mutations in established CRC genes MLH1, APC, and POLE, and likely pathogenic variants in cancer susceptibility genes BAP1, CDH1, CHEK2, ENG, and MSH3. For the candidate CRC genes, we identified likely pathogenic variants in the helicase domain of POLQ and in the LRIG1, SH2B3, and NOS1 genes and present their clinicopathological characteristics. Using a DNA pooling NGS strategy, we identified novel germline mutations in established CRC susceptibility genes in familial CRC cases. Further studies are required to support the role of POLQ, LRIG1, SH2B3 and NOS1 as CRC susceptibility genes.
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spelling pubmed-57068102017-12-05 Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort Raskin, Leon Guo, Yan Du, Liping Clendenning, Mark Rosty, Christophe Lindor, Noralane M. Gruber, Stephen B. Buchanan, Daniel D. Oncotarget Research Paper The underlying genetic cause of colorectal cancer (CRC) can be identified for 5-10% of all cases, while at least 20% of CRC cases are thought to be due to inherited genetic factors. Screening for highly penetrant mutations in genes associated with Mendelian cancer syndromes using next-generation sequencing (NGS) can be prohibitively expensive for studies requiring large samples sizes. The aim of the study was to identify rare single nucleotide variants and small indels in 40 established or candidate CRC susceptibility genes in 1,046 familial CRC cases (including both MSS and MSI-H tumor subtypes) and 1,006 unrelated controls from the Colon Cancer Family Registry Cohort using a robust and cost-effective DNA pooling NGS strategy. We identified 264 variants in 38 genes that were observed only in cases, comprising either very rare (minor allele frequency <0.001) or not previously reported (n=90, 34%) in reference databases, including six stop-gain, three frameshift, and 255 non-synonymous variants predicted to be damaging. We found novel germline mutations in established CRC genes MLH1, APC, and POLE, and likely pathogenic variants in cancer susceptibility genes BAP1, CDH1, CHEK2, ENG, and MSH3. For the candidate CRC genes, we identified likely pathogenic variants in the helicase domain of POLQ and in the LRIG1, SH2B3, and NOS1 genes and present their clinicopathological characteristics. Using a DNA pooling NGS strategy, we identified novel germline mutations in established CRC susceptibility genes in familial CRC cases. Further studies are required to support the role of POLQ, LRIG1, SH2B3 and NOS1 as CRC susceptibility genes. Impact Journals LLC 2017-06-21 /pmc/articles/PMC5706810/ /pubmed/29212164 http://dx.doi.org/10.18632/oncotarget.18596 Text en Copyright: © 2017 Raskin et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Raskin, Leon
Guo, Yan
Du, Liping
Clendenning, Mark
Rosty, Christophe
Lindor, Noralane M.
Gruber, Stephen B.
Buchanan, Daniel D.
Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort
title Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort
title_full Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort
title_fullStr Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort
title_full_unstemmed Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort
title_short Targeted sequencing of established and candidate colorectal cancer genes in the Colon Cancer Family Registry Cohort
title_sort targeted sequencing of established and candidate colorectal cancer genes in the colon cancer family registry cohort
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706810/
https://www.ncbi.nlm.nih.gov/pubmed/29212164
http://dx.doi.org/10.18632/oncotarget.18596
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