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Title: Using linkage studies combined with whole-exome sequencing to identify novel candidate genes for familial colorectal cancer
Author: Toma, Claudio
Díaz Gay, Marcos
Franch Expósito, Sebastià
Arnau Collell, Coral
Overs, Bronwyn
Muñoz, Jenifer
Bonjoch Gassol, Laia
Soares de Lima, Yasmin
Ocaña, Teresa
Cuatrecasas Freixas, Miriam
Castells Garangou, Antoni
Bujanda, Luis
Balaguer Prunés, Francesc
Cubiella, Joaquín
Caldés, Trinidad
Fullerton, Janice M.
Castellví Bel, Sergi
Keywords: Càncer colorectal
Colorectal cancer
Issue Date: 16-Sep-2019
Publisher: Wiley
Abstract: Colorectal cancer (CRC) is a complex disorder for which the majority of the underlying germline predisposition factors remain still unidentified. Here, we combined whole‐exome sequencing (WES) and linkage analysis in families with multiple relatives affected by CRC to identify candidate genes harboring rare variants with potential high‐penetrance effects. Forty‐seven affected subjects from 18 extended CRC families underwent WES. Genome‐wide linkage analysis was performed under linear and exponential models. Suggestive linkage peaks were identified on chromosomes 1q22-q24.2 (maxSNP = rs2134095; LODlinear = 2.38, LODexp = 2.196), 7q31.2-q34 (maxSNP = rs6953296; LODlinear = 2.197, LODexp = 2.149) and 10q21.2-q23.1 (maxSNP = rs1904589; LODlinear = 1.445, LODexp = 2.195). These linkage signals were replicated in 10 independent sets of random markers from each of these regions. To assess the contribution of rare variants predicted to be pathogenic, we performed a family‐based segregation test with 89 rare variants predicted to be deleterious from 78 genes under the linkage intervals. This analysis showed significant segregation of rare variants with CRC in 18 genes (weighted p‐value > 0.0028). Protein network analysis and functional evaluation were used to suggest a plausible candidate gene for germline CRC predisposition. Etiologic rare variants implicated in cancer germline predisposition may be identified by combining traditional linkage with WES data. This approach can be used with already available NGS data from families with several sequenced members to further identify candidate genes involved germline predisposition to disease. This approach resulted in one candidate gene associated with increased risk of CRC but needs evidence from further studies.
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It is part of: International Journal of Cancer, 2019, vol. 146, num. 6, p. 1568-1577
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ISSN: 0020-7136
Appears in Collections:Articles publicats en revistes (Fonaments Clínics)
Publicacions de projectes de recerca finançats per la UE
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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